PYRIMIDINE: THE MOLECULE OF DIVERSE BIOLOGICAL AND MEDICINAL IMPORTANCE

PYRIMIDINE: THE MOLECULE OF DIVERSE BIOLOGICAL AND MEDICINAL IMPORTANCE

Raghav Mishra* and Isha Tomar

College Of Pharmacy, Teerthankar Mahaveer University, Delhi Road, Moradabad, Uttar Pradesh, India

ABSTRACTPyrimidine nucleus is one of the most important heterocycles exhibiting remarkable pharmacological activities. The present review provides a broad view of the biological and medicinal activity possessed by compounds having pyrimidine nucleus.

Pyrimidine: medicinal importzance

INTRODUCTION: The practice of medicinal chemistry is devoted to the discovery and development of new agents for treating disease. The process of establishing a new drug is exceeding complex and involves talent of people from variety of disciplines ¹. An important aspect of medicinal chemistry has been to establish a relationship between chemical structure and pharmacological activity ². Pyrimidine is a six membered cyclic compound containing 4 carbon and 2 nitrogen atoms and is pharmacologically inactive but its synthetic derivatives possess an important role in modern medicine.

PYRIMIDINE

Biological Importance of Pyrimidine: In medicinal chemistry pyrimidine derivatives have been very well known for their therapeutic applications. The presence of a pyrimidine base in thymine, cytosine and uracil, which are the essential building blocks of nucleic acids, DNA and RNA is one of the possible reasons for their activities ³.

THYMINE                        CYTOSINE              URACIL

Vitamins are essential for body. Pyrimidine ring is found in vitamins like riboflavin, thiamine and folic acid ⁴.

RIBOFLAVIN

THIAMINE

FOLIC ACID

Pyrimidine nucleus is also present in barbituric acid and its several derivatives e.g. Veranal) which are used as hypnotics ⁵.

              BARBITURIC ACID                            VERANAL

In addition to this, pyrimidine nucleus is also found in alloxan, which is known for its diabetogenic action in a number of animals ⁶.

ALLOXAN

Medicinal Importance of Pyrimidine: In medicinal chemistry pyrimidine derivatives have been very well known for their therapeutic applications. Many pyrimidine derivatives have been developed as chemotherapeutic agents and are widely used.

• Antimicrobial Activity: Microbes are causative agents for various types of disease like pneumonia, amoebiasis, typhoid, malaria, common cough and cold various infections and some severe diseases like tuberculosis, influenza, syphilis, and AIDS as well. Various approaches were made to check the role of pyrimidine moiety as antimicrobial agent from the discovery of molecule to the present scenario.

Hitchings, in 1948, made an important observation that a large number of 2, 4 di amino pyrimidines and some 2- amino- 4 hydroxy pyrimidines are antagonists of folic acid ⁷. These pyrimidines were than eventually proved as inhibitors of the enzyme dihydrofolate reductase (DHFR) ⁸. Amongst the 2, 4-diaminopyrimidine drugs, pyrimethamine is a selective inhibitor of the DHFR of malarial plasmodia. Trimethoprim, an antibacterial drug is also a selective inhibitor and selectively inhibits bacterial DHFR ⁹.

     PYRIMETHAMINE                  TRIMETHOPRIM

Brodimoprim, is also found to be an effective antibacterial compound¹⁰.

BRODIPRIM

Pyrimidine also shows antifungal properties. Flucytosine is a fluorinated pyrimidine used as nucleosidal anti fungal agent for the treatment of serious systemic infections caused by susceptible strains of candida and Cryptococcus ¹¹.

FLUCYTOSINE

Padamshari et al., ¹² synthesized Naptho [2, 1- b] furo [3, 2-a] pyrimidine which were useful in the preparation of pharmacologically active compound like anti-inflammatory, anti- antihelmintic and antimicrobial agents.

Where R= CH₃, C₆H₅; R'=OCH₃, OC₂H₅, NHC₂H₅, NHC₆H₅

Naik et al., ¹³ synthesized 2-[{2 (Morpholino)-3-pyridinyl- 5- thio} - 2 oxoethyl oxadiazolyl]- amino- 4- (2, 4 dichloro- 5- fluorophenyl)- 6- (aryl) pyrimidines, which exhibit maximum zone of inhibition against E.coli, S. aureus, S.typhii and B.subtilis.

R= 4-CH₃.C₆H₄; 4-Cl.C₆H₄; 2, 4-(Cl)₂.C₆H₃; 4-F.C₆H₄; 3, 4, 5-(OCH₃)₃.C₆H₂

Aly et al., ¹⁴ synthesized a series of 1- glycosyl thiopyrimidines, annulated pyrimidines derivatives, pyrazolo[3, 4-d] pyrimidines, ditetrazolo[1, 5- a, 1, 5’-c] pyrimidines thieno [2, 3-d] pyrimidines derivative. The antimicrobial were determined in vitro using cup plate and paper disc method.

Mogilaiah et al., ¹⁵ reported 1, 8 Napthopyridine derivatives which were tested for their antibacterial activity in vitro against E. coli and B. subtilis using filter paper disc technique.

Where R= C₆H₅, p-CH₃C₆H₅, CH₃OC₆H₄, o-ClC₆H₄ p-ClC₆H₄, p-OHC₆H₄

Mishra et al., ¹⁶ synthesized various derivatives of pyrimidines. The fungicidal activities of the compound were evaluated against P. infestans and C. falcatum by the usual agar plate method.

R= C₆H₅, p-ClC₆H₄, m-NO₂C₆H₄, p-OCH₃C₆H₄; R’= m-NO₂C₆H_4, p- OCH₃C₆H₄

1. Alagarsamy et al., ¹⁷ synthesized some 2 substituted (1, 3, 4) thiadiazole(2, 3-b) tetrahydro- benzothieno [3, 2-e] pyrimidines and then screened them for anticancer, antibacterial and antifungal activities.

R= H, CH₃, NHCH₃, (CH₂)₂CH₃

Rajesh Vyas et al., ¹⁸ synthesized some 2 amino- 4, 6 diaryl substituted pyrimidines and than screened them for antibacterial and herbicidal activity.

R₁= H, Cl, Br, OCH₃; R₂= OCH₃, H; R₃= OCH₃, N (CH₃)₂; R₄= OCH₃, H

In other words it can be stated that pyrimidine moiety serves as a royal warrior against almost all types of microbes.

• Anticancer Activity: The pyrimidine moiety with some substitution shows promising antitumor activity as there are large numbers of pyrimidine based antimetabolites. The structural modification may be on the pyrimidine ring or on the pendant sugar groups. Early metabolite prepared was 5-fluorouracil ¹⁹, a pyrimidine derivative followed by 5- Thiouracil which also exhibits some useful antineoplastic activities ²⁰.

5- FLUOROURACIL                          5- THIOURACIL

Palwinder Singh et al., ²¹ reacted 5 benzoyl/ 5-carbaldehyde-/ 5- (3- phenyl acryloyl o- 6- hydroxy- 1H- pyrimidine- 2, 4 diones with amines provided the corresponding enamines. The investigation for anticancer activity of molecule at 59 human tumor cell lines was done representing leukemia, melanoma and cancer of lung, colon, brain, ovary, breast as well as kidney.

R = H, CH=CH-Ph, Ph

Stephane pedeboscq et al., ²² synthesized 4-(2-Methylanilino) benzo[b] thieno [2, 3-d] pyrimidine (1) and 4-(2-Methoxyanilino) benzo [b] thieno[2, 3-d]pyrimidine (2) which showed a similar cytotoxicity to the standard anti-EGFR geftinib suggesting a blockade of the EGFR pathway by binding to the tyrosine kinase receptor.

R₁= CH₃           R₂₌ H for (1)

R₁= OCH₃        R₂₌ H for (2)

Fathalla et al., ²³ synthesized a series of some new pyrimidine derivatives like 7-(2-methoxyphenyl)-3-methyl-5-thioxo-5, 6-dihydro[1, 2, 4]-triazolo[4, 3-c]pyrimidine-8-carbo-nitrile via reaction of ethyl cyanoacetate with thiourea and the appropriate aldehydes namely 2-methyl-benzaldehyde and 2-methoxy-benzaldehyde followed via reaction with different reagents. All structures were than screened for bacterial activity and anticancer activity.

Organic compounds and their complex with various ligands have found many applications in biomedicine. Al Allaf et al., ²⁴ describe the preparation of R₂SnCl₂ complex of some 4 H-pyrido [1, 2-a] pyrimidin-4-one derivatives as donating ligand having multiple donor sites and examine the cytotoxic activity of some of these complex against fine tumor cell lines.

R₁ = H, 7-CH₃, 8-CH₃; R₂ = 2-CH₂Br, 3-CH₃COO

Silvana Raic-Malic et al., ²⁵ synthesized the novel purine and pyrimidine nucleoside analogues possessing a 2, 3-epoxypropyl, 2, 3-epoxypropyl ether, or 3-amino-2-hydroxypropyl moiety bonded at either N-9 of the C-6 substituted purine ring or N-1 and N-3 of the pyrimidine ring, and were evaluated for their antitumour and antiviral activities.

R= NH₂, NHCH(CH₃)_2,

Guanine nucleus containing antineoplastic compounds like mercaptopurine ²⁶, tegafur ²⁷ etc. were discovered after formulation of antimetabolite theory ²⁸.

           MERCAPTOPURINE                               TEGAFUR

Recently, new compounds have been developed like nimustine ²⁹, uramustine ³⁰, raltitrexed ³¹ etc.

NIMUSTINE

URAMUSTINE

RALTITREXED

• Anti-inflammatory Activity: Pyrimidine has a remarkable pharmacological efficiency and therefore an intensive research has been focused on anti-inflammatory activity of pyrimidine nucleus. Recently two PCT international applications have been filed for 2-thiopyrimidine derivatives possessing potent activity against inflammation and immune disorders ³².

Naphtho [2, 1- b] furo [3, 2- d] pyrimidine was reported by Padama shale et al., ³³. Carrageen induced rat paw edema method was employed for evaluating the anti- inflammatory activity. The compounds were given at a dose of 80 mg/kg body weight in albino rats weighing between 150 and 200 g. The edema was produced by injecting carrageenan solution at the left hind paw.

R= CH₃, C₆H₅; R₁= OCH₃, OC₂H₅, NHC₂H₅, NHC₆H₅

Marylene Favre et al., ³⁴ synthesized some substituted thieno pyrimidines-4-one and screened then for analgesic and anti-inflammatory activity.

R₁, R₂= -(CH₂)₃, -(CH₂)₅, -(CH₂)₄; R₃= CH₃

A Cannito et al., ³⁵ synthesized some 3-substituted thienopyrimidin- 4- one- 2- thiones and then screened them for analgesic and anti-inflammatory activity.

R₁, R₂= -(CH₂)₃, -(CH₂)₄

1. Russo et al., ³⁶ synthesized new thienopyrimido benzothiazole and thieno pyrimidobenzo oxazoles and then screened them for analgesic and anti-inflammatory activity.

X= O, S; R₁= CH₃, H; R₂= CH₃, H, C₆H₅

Cenicola et al., ³⁷ evaluated some imidazolo [1, 2-c] pyrimidines for anti-inflammatory, analgesic and antipyretic activities. Anti-inflammatory activity was studied by carrageenan- induced paw oedema in rats and fund to show activity comparable to indomethacin.

R₁= Cl, OCH₃, CH₃; R₂= COOH, CH₂COOH

Nargund et al., ³⁸ reported the synthesis of few substituted 2-mercapto-3-(N-alkyl) pyrimido [5, 4-c] cinnolin- 4- (3H)- ones and screened them for anti-inflammatory and antimicrobial activities. The anti-inflammatory activity was done by carrageenan induced paw oedema method.

R= H, CH₃; R₁= H, o-CH₃, p-CH₃, p-Cl

Thieno tetrazolopyrimidines and thieno triazolo pyrimidine derivatives prepared by Rashand et al., ³⁹ compounds were tested as potent at anti-inflammatory agent and derivatives showed patent activity in Carrageenan test.

Thienotriazolo pyrimidine derivative; (R=H, CH₃; R₁= H, CH₃)

THIENOTRIAZOLOPYRIMIDINE

Antidiabetic Activity: Lee et al., ⁴⁰ synthesized some novel pyrimidines derivative having thiazolidinedione. These compounds were evaluated for their glucose and lipid lowering activity using pioglitazone and rosiglitazone as reference compound.

Desenko et al., ⁴¹ synthesized azolopyrimidine derivatives and compounds were evaluated for hypoglycemic activity.

Analgesic Activity: New forms of thiamine are lipid-soluble like acetiamine, bentiamine ⁴² etc., having therapeutic use in beriberi, polyneuritis, encephalopathy, pain, malnutrition and alcoholism and especially in the treatment of long-standing insulin-dependent diabetes mellitus.

R              R₁

Acetiamine               -CH₂     

Bentiamine              C₆H₅

Ishwaarsinh S. Rathod et al., ⁴³ synthesized substituted thieno [2, 3-d] pyrimidine- 4(3H)-ones and then screened them for analgesic activity.

R= -CH₃,-NHPh; R₁= R₂= Ph, o-Anisyl

Sondhi et al., ⁴⁴ have reported anti-inflammatory and analgesic activity of synthesized pyrimidine derivatives (1 and 2).

         (1)                                                    (2)

Vijay Raj et al., ⁴⁵ synthesized some new 2-[c]- phenyl- 1H- pyrazolo [3, 4- d] pyrimidin- 4- yl) acetohydrazide derivative have been prepared and screened for their analgesic activity by acetic acid induced writhing test using standard drug diclofenac sodium.

Rathod et al., ⁴⁶ synthesized 2- aryl amino- 3- aryl- 5- methyl- 6- (substituted) thione [2, 3- d] pyrimidin- 4 (3H)- ones. All the synthesized compounds were screened for the analgesic activity by tail flick method on albino rats and by writhing method on albino mice.

Afloqualone ⁴⁷ has been evaluated as a successful anti-inflammatory agent with lower back pain patients.

AFLOQUALONE

A condensed pyrimidin-2-one derivative, proquazone ⁴⁸, has been reported to exhibit good NSAID potential.

PROQUAZONE

• Platelet Aggregation Inhibition Activity: Nandeeshaiah et al., ⁴⁹ reported the synthesis of which showed the blood platelet disaggregating property.

Fumiyoshi Ishikawa, et al., ⁵⁰ synthesized cyclic Guanides (Imido [1, 2-a] thienopyrimidin-2-one derivatives and then screened them for blood platelet aggregation inhibitors.

• Antihypertensive Activity: Many pyrimidine ring containing drugs have exhibited antihypertensive activity. A quinozoline derivative, prazosin, is a selective α1-adrenergic antagonist ⁵¹. Its related analogues bunazosin ⁵², trimazosin ⁵³ and terazosin ⁵⁴ are potent antihypertensive agents.

R=               for Prazocin

R= -COOCH₂COH(CH₃)₂      for Bunazosin

R= -COCH₂CH₂ CH₃            for Trimazosin

R=                for Terazosin

Mery. B. Press et al., ⁵⁵ synthesized furo [3, 4-d] pyrimidines-2, 4- dione derivatives, analogues of thienopyrimidines-2, 4-diones and then screened them for antihypertensive activity.

Russell et al., ⁵⁶ synthesized thienopyrimidine diones derivatives and then screened them for antihypertensive agent.

R= 2-OCH_3, 3-OCH_3, H

Ketanserin ⁵⁷ has a similar effect and is an antagonist of both a1-adrenergic and serotonin-S2 receptors. A triaminopyrimidine derivative, minoxidil, whose mechanism of action and therapeutic action are similar to prazosin, has been introduced in therapy for its side effects, in the treatment of alopecia, male baldness etc., ⁵⁸.

KETANSERIN

MINOXIDIL

• CNS Activity: Agents involved in this category include sedatives, hypnotic, anticonvulsants, anxiolytic agents, pyrimidine anaesthetics etc. Large variety of barbiturates are used as CNS active agents and are classified as short, intermediate and long acting depending upon duration of action ⁵⁹.

R            R₁            R₂

Allobarbital   H           H

Hexobarbital H        -CH₃

Gupta et al., ⁶⁰ synthesized a series of nitrophenyl 4, 4, 6 trimethyl, 1 H, 4H pyrimidine 2 thiols (NPTP) and tested their anticonvulsant activity in mice against maximal electro shock and metrazol (MET) induced convulsions.

Song Qing WANG et al., ⁶¹ reported the synthesis of twelve new 5-methyl-7-substituted pyrazolo [1, 5-a] pyrimidine-3-carbonitrile derivatives by using simple starting materials such as propane dinitrile and triethyl orthoformate and were screened for hypnotic activity.

R= H, R'= Allyl

R= H, R'= CH₂Ph

R= R'= CH₂Ph

Risoperidone is an antipsychotic drug, which is a structural hybrid of butyrophenone and can be used as anxiolytic, antidepressant and antiparkinsonian drug ⁶².

RISOPERIDONE

A pyrimidine analogue, thimylal is a short acting general anaesthetic drug ⁶³.

THIMYLAL

• Miscellaneous Activity: Rahaman et al., ⁶⁴ synthesized novel pyrimidines by the condensation of chalcones of 4΄-piperazine acetophenone with guanidine HCl. The recorded % of histamine inhibition showed significant antihistaminic activity when compared to the reference antihistaminic drug mepiramine.

R= , , , ,

Aymn E. Rashad et al., ⁶⁵ synthesized several derivative (1, 2) containing dihydronaphtho-, naphtho[2, 1-b] thiophene- and thieno [2, 3-d] pyrimidine ring systems starting from 2-amino-4,5 dihydronaphtho [2, 1-b] thiophene-1 carbonitrile and were tested for antiviral activity against H5N1 virus.

(1)

(2)

A small library of 20 tri-substituted pyrimidines was synthesized by Anu et al., ⁶⁶ evaluated for their in vitro anti-malarial and anti-tubercular activities. Out of the total screened compound, 16 compounds have shown in-vitro anti-malarial activity against Plasmodium falciparum in the range of 0.25- 2μg/ml and 8 compounds have shown anti- tubercular activity against Mycobacterium tuberculosis at a concentration of 12.5 μg/ml.

Sugiyama et al., ⁶⁷ synthesized condensed thieno pyrimidines (2, 3- dihydro- 5H- oxazolo thieno pyrimidine) derivatives and then they are screened for gastric antisecretory activity.

Erric A. Meade et al., ⁶⁸ synthesized analogues of 4-benzylamino-2, 7-H-pyrrolo [2, 3-d] pyrimidines and then screened them for their anxiolytic activity.

Chamanlal J. Shishoo et al., ⁶⁹ synthesized 2-substituted thieno [3, 2-d] pyrimidin-4(3H)-one and screened for QSAR relationship of antihyperlipaemic.

R= CH₃, CH₂Cl, CHCl₂

Apart from these activities, pyrimidines also possess diuretic, antianthelmentic and calcium channel blocking activity ⁷⁰.

CONCLUSION: Pyrimidines occupy a distinct and unique place in our life. This heterocyclic moiety has great biological and medicinal significance. A vast literature has been accumulated over the years and chemistry of pyrimidines continues to be a blossoming field. The biological profiles of this new generation of pyrimidine represent much progress with regard to the older compounds.

REFERENCE:

1. Delgado JN and Remers WA; Wilson and Giswold’s- Textbook of Organic Chemistry Medicinal and Pharmaceutical Chemistry; 10th ed. Philadelphia: Lippincott Raven; 1998.
2. Miller D; Remington- The Science and Practice of Pharmacy; 19th ed. Pennsylvania: MACK Publishing Company; 1995; 425.
3. Amir M, Javed SA and Kumar H; Indian J. Pharm. Sciences; 2007; 69(3); 337-343.
4. Cox RA; Rev.; 1968; 22; 499.
5. Jain MK, Sharnevas SC; Organic Chem.; 2008; 3; 997-999.
6. Eussell JA; Rev. Biochem.; 1945; 14; 309.
7. Hitchings GH, Elion GB, Wanderers H and Falco EA; Biol. Chem.; 1948; 174; 765.
8. Futterman S; Biol. Chem.; 1957, 228; 1031.
9. Cheng CC and Roth B; In Progress in Medicinal Chem. (eds Ellis GP and West GB), Butterworths London; 1982; 19; 267.
10. Kompis I and Wick A; Chim. Acta; 1977; 60; 3025.
11. Polak A. and Scholer HJ; Chemotherapy; 1975; 21; 113.
12. Padamshari B, Vaidya VP and Vijayayakumar ML; Indian J. Hetero. Chem.; 2002; 12; 89-94.
13. Naik TA and Chikhalia KH; E-Journal of Chem.; 2007; 4(1); 60-66.
14. Aly and AA, Chinese J. of Chem.; 2005; 23; 211-217.
15. Mogilaiah K and Sudhakar GR; Indian J. Chem.; 2003; 42B; 636-640.
16. Mishra A and Singh DV; Indian J. Hetero. Chem.; 2004; 14; 43-46.
17. Alagarsamy V, Pathak US, Rajasolomon V, Meena S, Ramseshu KV, Rajesh R; Indian J. Hetero. Chem.; 2004; 13; 347.
18. Vyas R, Udaibhan Gahlot S, Verma BL, Indian J. Hetero. Chem; 2003; 13; 115.
19. Callery P and Gannett P; Cancer and Cancer Chemotherapy: In Foye’s Principles of Medicinal Chemistry (eds Williams DA and Lemke TL), Lippincott Williams and Wilkins, Philadelphia; 2002; 934–935.
20. Al Safarjalani ON, Zhou XJ, Ras RH, Shi J, Schinazi RF, Naguib FN and El KouniMH; Cancer Chemotherapy Pharmacology; 2005; 55; 541–551.
21. Singh P, Kaur J and Paul K, Indian J. Chem.; 2008; 47B; 291-296.
22. Pedeboscq S, Gravier D, Casadebaig F, Hou G, Gissot A, Giorgi FD, Ichas F, Cambar J, Pometan J; Eur. J. Med. Chem.; 2010(45); 2473-2479.
23. Fathalla OA, Zeid IF, Haiba ME, Soliman AM, Abd- Elmoez and El- Serwy WS; World J. Chem.; 2009; 4 (2); 127-132.
24. Talal A, Allaf KA andRedna I; Applied Organo-metallic Chem.; 1996; 10; 47.
25. Malic S, Grdisab M, Pavelicb K, Mintasa M; J. Med. Chem.; 1999; 34; 405−413.
26. Burchenal JH et al; Blood; 1953; 8; 965.
27. Giller SA, Zhuk RA and Lidak MIU, Akad. Nauk; SSR; 1967; 176; 332.
28. Remers WA; Antineoplastic Agents: In Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry (eds Delgado JN and Remers WA); Lippincott Williams and Wilkins, Philadelphia; 1998; 366–368.
29. Weller M, Muller B, Koch R, Bamberg M and Krauseneck P; Clin. Oncol. 2003; 21; 3276–3284.
30. Kennedy BJ, Torkelson JL and Torlakovic E; Cancer; 1999; 85; 2265–2272.
31. Horton TM et al; Cancer Res.; 2005; 11; 1884–1889.
32. Belema M, Bunker A, Nguyen V, Beaulieu F, Ouellet C, Marinier A, Roy S, Yung X, Zhang Y, Martel and Zuci C; PCT Int. Appl. WO 2003084, Through Chem. Abstr.; 2003; 139; 337987x.
33. Padmashali B, Vaidya VP and Vijaya Kumar ML, Indian J. Hetero. Chem.; 2002; 12; 89-94.
34. Marylenefavre, Cuong Luu Duu, Francios Huguet, Chantal Gaultier; Med. Chem.; 1998; 23; 453.
35. Cannito A, Perrissin M, Luu-Duc C, Huguet F, Gaultier C, Narcisse G; J. Med. Chem.; 1990; 25; 635.
36. Russo F, Romeo G, Caruso A, Cutuli V, Amore D and Santagati NA; J. Med. Chem.; 1999; 29; 569.
37. Cenicola, Donnoli D, Stella L, Paola CD, Constantino M, Anignente E, Arena F, Luraschi E and Saturnino C, Pharmacology Res.; 1990; 22; 80.
38. Nargund LVG, Badiger VV and Yarnal SM; J. Pharm. Sci.; 1992; 81; 365.
39. Rashand AE, Heikal OA and Abdul Megeig FME, Heteroatom Chemistry; 2005; 16; 226-234.
40. Lee HW and Kim BY; Euro. J. Med. Chem.; 2005; 4; 662.
41. Desenko SM, Lipsum VV and Gorbenko NI, J. Chem.; 1995; 29; 265.
42. Gauthier B; Ann. Pharm. Fr; 1963; 21; 655.
43. Ishwaarsinh Rathod S, Ajay Pillai S and Vikas Shirsath S; Indian J. Heterocyclic Chem.; 2000; 10; 93.
44. Sondhi SM, Verma RP; Indian Drugs; 1999; 36(1); 50.
45. Vijaya Raj KK, Naryana B and Ashalatha BV; J. Pharmacology and Toxicology; 2006; 6; 559.
46. Rathod IS, Pillai AS and Shirsath VS; Indian J. Heterocyclic Chem.; 2000; 10; 93.
47. Tani J; Med. Chem.; 1979; 22; 95.
48. Clissold SP and Beresford R; Drugs; 1984; 33; 478–502.
49. Nandeeshwariah SK and Sarvottam Ambekar, Indian J. Chem.; 1998; 37B; 995.
50. Fumiyoshi Ishikawa, Akira Kosasayama, Hitoshi Yamaguchi, Yoshifumi Watanabe, Juji Saegusa, Seiichi Shibamura, Kyoko Sakuma, Shinichiro Ashida and Yasushi Abiko; Med. Chem.; 1981; 24; 376.
51. Pfizer; US Patent; 3 511 836; 1970.
52. Hara H, Ichikawa M, Oku H, Shimazawa M and Araie M; Drug Rev.; 2005; 23; 43–56.
53. Meredith PA, Scott PJ, Kelman AW, Hughes DM and Reid JL; J. Ther.; 1995; 2; 541–545.
54. Honkanen E, Pipuri A, Kairisalo P, Nore P, Karppaness H and Paakari I; Med. Chem.; 1983; 26; 143.
55. Mery Press B, James Mc Nally J, Joan Keisher A, Steve Offord J, Laurence Katz B, Robert Falotico and Alfonso Tobaia J; J. Med. Chem.; 1989; 24; 627.
56. Ronald Russell K, Jeffery Press B, Richard Rampulla A, James Mcnally J, Robert Falotico, Joan Keiser A, David Bright A and Alfonso Tobia; Med. Chem.; 1988; 31; 1786.
57. Ganzevoort W, Rep A, Bonsel G.J, De Vries JI and Wolf H; Hypertension; 2004; 22; 1235–1242.
58. Wong WM; Pharmacotherapy; 1994; 28; 290–291.
59. Daniels TC and Jorgensen EC; Central nervous system depressants-In Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry(ed. Doerge RF); J. B. Lippincott, Philadelphia; 1982; 33.
60. Gupta AK, Sanjay, Kayath HP, Ajit Singh, Geeta Sharma, Mishra KC; Indian J. Pharmacology; 1994; 26: 227 – 228.
61. Song Qing WANG; Lin FANG; Xiu Jie LIU; Kang ZHAO; Chinese Chemical Letters; 2004; 15(8); 885-888.
62. Howard HR and Seeger TF; Rep. Med. Chem.; 1993; 28; 39.
63. Abott; US Patent; 2153729; 1934.
64. Rahaman SA, Rajendra Pasad Y, Phani Kumar and Bharath Kumar; Saudi Pharmaceutical J.; 2009; 17(3); 259-264.
65. Rashad AE, Ahmed H. Shamroukh, Randa E. Abdel-Megeid, Ahmed M. Kandeil, Ahmed Mostafa, Rabeh Elshesheny, Mohamed A. Ali, Klaus Banert; J. Med. Chem.; 2010.
66. Agrawal A, Srivastava K and Puri SK; Bio. Org, and Med. Chem Lett.; 2005; 15; 5218.
67. Sugiyama M., Sakamoto T., Tabata K. and Fuumi H.; Pharm. Bull.; 1989; 37(10); 2717.
68. Erric Meade A, Marcos Sznaidman, Gerald Pollard T, Lilia Beauchamp M, James Howard L and Geraid Pollard T; J. Med .Chem. 1998; 33; 363.
69. Chamanlal Shishoo J, Kishore Jain S, Ishwarsinh Rathod S, Bipin Thakkar J, Samir Brahmbhatt B, Thakorbhai, Ramkrishna Bangaru and Ramesh Goyal K; 1996; Drug Res.; 46(1); Nr.3.
70. Jain KS, Chitre TS, Miniyar PB, Kathiravan MK, Bendre VS, Veer VS, Shahane SR and Shishoo CJ; Current Science; 2006; 90(6).
    

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