Biological Activities of Pyrazoline Derivatives -A ... - IngentaConnect

154

Recent Patents on Anti-Infective Drug Discovery, 2009, 4, 154-163

Biological Activities of Pyrazoline Derivatives -A Recent Development Suresh Kumar*,1, Sandhya Bawa 1, Sushma Drabu 1, Rajiv Kumar1 and Himanshu Gupta2,* 1

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062, 2Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062, India Received: April 25, 2009; Accepted: May 20, 2009; Revised: May 21, 2009

Abstract: Pyrazolines are well known and important nitrogen containing 5-membered heterocyclic compounds and various methods have been worked out for their synthesis. Numerous pyrazoline derivatives have been found to possess considerable biological activities, which stimulated the research activity in this field. They have several prominent effects, such as antimicrobial, antimycobacterial, antifungal, antiamoebic, anti-inflammatory, analgesic, antidepressant and anticancer activities. They also possess some potent receptor selective biological activity like Nitric oxide synthase (NOS) inhibitor and Cannabinoid CB1 receptor antagonists activity. 4,5-dihydro-1H- pyrazolines seem to be the most frequently studied pyrazoline type compounds. As a result, a large number of such pyrazolines using different synthetic methods for their preparation have been described in the chemistry literature. The present review provides an insight view to pyrazolines synthesis and its biological activities along with the compilation of recent patents on pyrazolines.

Keywords: Pyrazolines, anticancer, synthesis, patents.

1. INTRODUCTION

2. BIOLOGICAL ACTIVITIES OF PYRAZOLINES

Diversely substituted pyrazolines and their derivatives embedded with variety of functional groups are important biological agents and a significant amount of research activity has been directed towards this class. In particular, they are used as antitumor, antibacterial, antifungal, antiviral, antiparasitic, anti-tubercular and insecticidal agents. Some of these compounds have also anti-inflammatory, anti-diabetic, anaesthetic, analgesic and potent selective activity such as Nitric oxide synthase (NOS) inhibitor and Cannabinoid CB1 receptor antagonists activity. A classical synthesis of these compounds involves the base-catalyzed aldol condensation reaction of aromatic ketones and aldehydes to give , unsaturated ketones (chalcones), which undergo a subsequent cyclization reaction with hydrazines affording 2pyrazolines. In this method, hydrazones are formed as intermediates, which can be subsequently cyclized to 2pyrazolines in the presence of a suitable cyclizing reagent like acetic acid. In recent years, a significant portion of research in heterocyclic chemistry has been devoted to 2pyrazolines containing different aryl groups as substituents, as evident from the literature. The preceding section of the review is focusing on the recent development on pyrazolines along with their biological properties. The last section of the review dealt on various patents filed on pyrazolines with World Intellectual Proprietary Organization (WIPO) and United State Patent Trademark Office (USPTO).

2.1. Antimicrobial Activity

*Address correspondence to these authors at the Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062; Tel: 91-11-26059688; Ext: 5600, 5601, 5602; E-mail: [email protected]; Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110062; E-mail: [email protected]

1574-891X/09 $100.00+.00

Zampieri et al. reported synthesis of 1-(3,5-diaryl-4,5dihydro-1H-pyrazol-4-yl)-1H-imidazole derivatives 1 tested towards a strain of Candida albicans and a strain of Mycobacterium tuberculosis H37Rv. Imidazole derivatives showed an interesting antifungal and antimycobacterial activity against the tested strains [1]. A series of chlorofluorine containing pyrazoline 2 were prepared by treatment of chalcone dibromides with aryloxy acid hydrazides in the presence of triethylamine gave chloro-fluorine containing hydroxy pyrazolines rather than the expected 1-aryloxy-3aryl-5-aryl pyrazoles. Some compounds showed very good antibacterial and antifungal activity [2]. Shaharyar et al. presented a series of N1-nicotinoyl-3-(4hydroxy-3-methyl phenyl)-5-(substituted phenyl)-2-pyrazolines 3 and tested in vitro for their antimycobacterial activity. Compounds N1-nicotinyl-3-(4-hydroxy-3-methyl phenyl)-5-(1-chlorophenyl)-2-pyrazoline was found to be the most active agent against MTB and INHR-MTB, with minimum inhibitory concentration of 0.26 μm [3]. Ahmed et al. prepared pyrazolines by the treatment of the chalcones with nitromethane under Michael addition condition and their subsequent cyclization with thiosemicarbazide under basic refluxing conditions gave 3-(benzofuran-2-yl)-5-(4aryl)-4,5-dihydropyrazole-1-carbothioamides 4. These pyrazolines were further reacted with phenacyl bromides to give thiazole substituted pyrazolines 5. Some of the compounds showed a significant antimicrobial activity against Escherichia coli and Aspergillus niger [4]. 2.2. Antiamoebic Activity Abid et al. synthesized a series of new 1-N-substituted cyclised pyrazoline analogues of thiosemicarbazones by cyclisation of Mannich bases with thiosemicarbazide and © 2009 Bentham Science Publishers Ltd.

Pyrazolines and Biological Activities Review

Recent Patents on Anti-Infective Drug Discovery, 2009, Vol. 4, No. 3

R

N R

N OH

R

N

CH3

Cl

OH

N N

N

O

N

R1

155

N Cl

O

R1

O

F

R

2

1

N

N

N

N

O NH2

4

3

Ar

Ar O

N

N

Ar1

S

5

S CH2CH2CH3 N

N N

CH3

CH2CH2CH3

N

S

Cl Pd

Cl

Cl

6

were subsequently evaluated for their antiamoebic activity by microdilution method against HM1:1MSS strain of Entamoeba histolytica. Moreover, compound 6 showed the most promising antiamoebic activity with an IC50 = 0.6 μM vs IC50 = 1.8 μM of metronidazole [5]. A series of palladium (II) complexes of 1-N-substituted thiocarbamoyl-3, 5diphenyl-2-pyrazoline derivatives 7 were reported possessed better antiamoebic activity as compared to other ligands and complexes [6].

N

Rathish et al. synthesized new 1,3,5-trisubstituted pyrazolines bearing benzene sulfonamides 11 and evaluated their antiinflammatory activity, several compounds demonstrated promising activity [10]. Various 1-(4sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines 12 were prepared and screened for cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) inhibition [11]. Amir et al. reported a series of 3-(4-biphenyl)-5-substituted phenyl-2-pyrazolines 13 and 1-benzoyl-3-(4-biphenyl)-5-substituted phenyl-2pyrazolines 14 and screened them for their anti-inflammatory and analgesic activity [12].

N

R S

7

S

N

N

N

N

N

R

S

2.3. Antiinflammatory Activity

R N

N H

Thirty new pyrazoline derivatives were synthesized by cyclization of Mannich bases with thiosemicarbazides being substituted by different cyclic and aromatic amines and screened for in vitro antiamoebic activity against Entamoeba histolytica, compound 10 is the most active compound [9].

Bhat and co-workers reported bis-pyrazolines 8 prepared by cyclization of chalcones with N-4 substituted thiosemicarbazides under basic conditions. The antiamoebic activity results showed that the compound with aromatic substituents at the thiocarbamoyl group was more active than those with the cyclic groups [7]. A variety of new pyrazolines bearing thiazolo [4,5-b] quinoxaline 9 were obtained by the refluxing of 1-N-thiocarbamoyl 3,5-diphenyl-2pyrazoline with 2, 3- dichloro quinoxaline and screened for antiamoebic activity against Entamoeba histolytica [8].

N

N

S

S Br 8

HN

N N

9

Cl

10

156 Recent Patents on Anti-Infective Drug Discovery, 2009, Vol. 4, No. 3

Kumar et al.

CF3

R

N

N N

R

N

R1 X

N N H

SO2NH2

NH

13

12

SO2NH2 11

X R R N

R N

N

N

N O

14

R1

O

N

O R1 15

Novel bis (1-acyl-2-pyrazolines) derivatives 15 were synthesized and screened for anti-inflammatory as well as ulcerogenic activities by Barsoum and co-workers, and found some of the compounds showed remarkable anti-inflammatory properties with low ulcerogenic liability than standard drug used [13]. 2.4. Anticancer Activity Havrylyuk et al. examined the anticancer activity of several novel thiazolone-based compounds containing the 5aryl-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl framework 16. The in vitro anticancer activity were tested by the National Cancer Institute and most of them displayed anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast cancer cell lines and the most efficient anticancer compound was found to be active with selective influence on colon cancer cell lines, especially on HT 29 (log GI50 = - 6.37) [14]. Johnson et al. designed and synthesized some new pyrazoline derivatives 17 which are analogous to combretastatin-A4 18 and tested for anticancer activity [15]. 1,4-Diaryl-4,5-dihydropyrazoles 19 were designed and synthesized and reported to be selective inhibitors [16] of the

R R N

mitotic kinesin Spindle Protein (KSP) with KSP IC50 of 0.2 nM and Cell EC50 values of 3.2nM. A series of fused pyrazole derivatives of cyclolignans 20 have been reported and evaluated for their cytotoxic activities in culture cells of P-388 murine leukemia, A-549 lung carcinoma and HT-29 colon carcinoma. Despite the lack of the lactone moiety in their structures, they showed IC50 values in the micromolar levels [17]. Manna et al. prepared a series of substituted pyrazolines 21 and evaluated them for their anticancer activity and for their ability to inhibit P-glycoproteinmediated multidrug resistance by direct binding to a purified protein domain containing an ATP-binding site and a modulator interacting region. Compounds found to bind to P-glycoprotein with greater affinity [18]. A indene fused series of 3-(4-chlorophenyl)-[1, 2-c]pyrazolines-substituted with benzene sulfonamides, N1,N3 disubstituted sulfonylurea and sulfonylthiourea pharmacophores 22a, 22b and some derived thiazolidinone and thiazoline ring systems have been synthesized and evaluated for their antitumor activity according to the protocol of the NCI. Eight compounds showed promising broad spectrum antitumor activity against most of the tested sub panel tumor cell lines [19].

OH OH

N

OCH3

N

OCH3

N N

OH3C

OH3C

S O 16

H3CO

H3CO

OCH3 17

OCH3 18



157

Ph N NMe2

N R1

O

F O H 3C

R

COOMe

N

N

N O

N O

H3CO

H 3C

H3C

OCH3 OCH3

19

21

20

SO2

SO2 N

N H

N

N

N N X

S

N

R

R1

Cl

Cl 22a

22b

Most of the tested compounds showed inhibitory activity with micromolar values and MAO-A selectivity [22].

2.5. Antidepressant Activity Prasad et al. reported new 1, 3, 5-triphenyl-2-pyrazolines 23 and evaluated them for antidepressant activity with a majority of the synthesized compounds possessing significant antidepressant activity in mice (P < 0.05) in the Porsolt behavioral despair test [20]. Similarly, some 1-phenyl-, 1thio carbamoyl- and 1-N-substituted thiocarbamoyl-3-(2furyl)-5-phenyl/(2-furyl)-2-pyrazoline derivatives 24 were synthesized and investigated for antidepressant activitiy by the Porsolt test (forced swimming) test on albino mice. Compound 1-N-Ethylthiocarbamoyl-3-(2-furyl)-5-phenyl-2pyrazoline and 1-N-allylthiocarbamoyl-3,5-di(2-furyl)-2pyrazoline reduced 33.80-31.42% duration of immobility times at 10 mg kg1 dose level [21]. Chimenti et al. reported a series of N1-propanoyl-3,5diphenyl-4,5-dihydro-(1H)-pyrazole derivatives 25 and assayed as inhibitors of MAO-A and MAO-B isoforms.

A novel series of 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-(1H)-pyrazole derivatives 26 synthesized and found to inhibit selectively A and B isoforms of monoamine oxidase (MAO). Most of compounds showed high activity against both the MAO-A and the MAO-B isoforms with Ki values between 27 and 4 nM and between 50 and 1.5nM, respectively [23]. 2.6. Steroidal Activity Zhang et al. designed and synthesized a novel series of pyrazolines 27 and evaluated by in vivo screening as tissueselective androgen receptor modulators (SARMs). Structureactivity relationships (SAR) was investigated at the R1 to R6 positions as well as the core pyrazoline ring and the anilide linker. Overall, strong electron-withdrawing groups at the R1 and R2 positions and a small group at the R5 and R6 position

R4 O

R3

R N R1

N N

R2 23

R1 R

Ar

R'

N Ar'

Ar = C6H5-, 2-furyl Ar' = C6H5- , -CSNH2, -CSNHR 24

N

N

N

N S

O H3C 25

H2N 26


R1

R4

R2

N H

R CH3 N N 1 H

R3

R2 O

Kumar et al.

R5 H N

N SO2 R1

N

CH3

N

R4

R3 27

H

H

H R2

R3

R6

H

H

28

29

are optimal for AR agonist activity [24]. Mifepristone is a non-selective antagonist of 3-oxosteroid receptors with both abortifacient and anti-endometriotic activities. Non-steroidal mimetics of mifepristone and progesterone are important templates for modulation of the progesterone receptor (PR). Jones et al. identified 4-substituted pyrazolines derivatives 28 by docking of compounds into a PR homology model and when the same was synthesized and tested, exhibited functional antagonism of PR [25].

1H-pyrazole show the highest activities with inhibition percentages of 70% and 62%, respectively [27]. Similarly, Carrión et al. reported preparation and the preliminary evaluation of a series of 1-alkyl-3-benzoyl-4,5-dihydro-1Hpyrazoles 31 and 1-alkyl-3-benzoyl-1H-pyrazoles 32 as potential inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS) [28].

A series of androstano [17, 16-c] pyrazolines and their oxidized derivatives 29 have been synthesized using 3hydroxyandrostan-17-one as a starting material and evaluated for their anti-androgenic activity compared to that of cyproterone as a positive control. Some of the compounds exhibited better antiandrogenic activity than the reference drug [26].

The incidence of viral infections has been constantly emerging and re-emerging on a global scale. Effective antiviral drugs have been developed much more slowly than other types of anti-infective chemotherapy. One of the major limitations has been the absence of specific viral ‘targets’, because host cell pathways are used predominantly for viral replication. Pyrazoline derivatives have shown interesting antiviral properties, where El-Sabbagh et al. synthesized new N-acetyl and N-thiocarbamoyl derivatives of 4, 5-dihydropyrazoles starting from ,-unsaturated ketones. The antiviral activity for such novel compounds against a broad panel of viruses in different cell cultures revealed that some of compounds were the most active derivatives whereas Nacetyl 4,5-dihydropyrazole was the only active at subtoxic concentrations against vaccinia virus (Lederle strain) in HEL cell cultures with an EC50 value of 7μg/ml [29]. Pyrazoline derivatives derived from phenoxyacetic acid were reported by shaharyar et al. and tested for their in vitro cytotoxicity and antiviral activity. The most cytotoxic of the series was 2[4-[3-(2,4-dihydroxyphenyl)-1-(2-hydroxybenzoyl-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy] acetic acid with a minimum cytotoxic concentration of 0.16 μg/mL in human embryonic lung (HEL) cells [30]. Various triaryl pyrazolines 33 and compound 34 {[5-(4-chloro-phenyl)-3-thiophen-2-ylinhibited 4,5-dihydro-pyrazol-1-yl]-phenyl-methanone}

2.8. Antiviral Activity

2.7. Nitric Oxide Synthase Inhibitor Nitric oxide synthase (NOS) is an enzyme in the body that contributes to synaptic transmission from one neuron to another, to the immune system and to dilating blood vessels. It does so by synthesis of nitric oxide (NO) from the terminal nitrogen atom of L-arginine in the presence of NADPH. There are three known isoforms of NOS, two are constitutive (cNOS) i.e. neural (nNOS) & endothelial (eNOS) and the third is inducible (iNOS) which associated with biological functions brain and other parts of the body. Camacho et al. designed and synthesized 19 new nNOS inhibitors with a 4,5-dihydro-1H-pyrazole structure 30 in an attempt to find new compounds with neuroprotective activity. Compounds 1-cyclopropanecarbonyl-3-(2-amino-5chlorophenyl)-4,5-dihydro-1H-pyrazole and 1-cyclopropanecarbonyl-3-(2-amino-5-methoxyphenyl)- 4,5-dihydro-

R2

R2

CO2Et N

N

O

N

N

R1

N NH2 30

R2

R1

CO2Et N

O

R1

O

NH2 31 R1 = H, Cl, OMe R2 = Me, Et, Bu, Bn

NH2 32



O

X N N

R3

159

O

S N

(CH2)n

N

R1 R2 Cl 33

34

flavivirus infection in cell culture and was identified through high-throughput screening of a compound library using a luciferase-expressing West Nile (WN) virus infection assay. The compound inhibited an epidemic strain of WN virus without detectable cytotoxicity (IC50 of 28 M). Besides WN virus, the compound also inhibited other flaviviruses (dengue, yellow fever, and St. Louis encephalitis viruses), an alphavirus (Western equine encephalitis virus), a coronavirus (mouse hepatitis virus), and a rhabdovirus (vesicular stomatitis virus).

Cannabinoid CB1 receptor antagonists have also good prospects in other therapeutic areas, including smoking and alcohol addiction as well as cognitive impairment. Lange et al. reported novel 3,4-diarylpyrazolines 36 as potent CB1 receptor antagonists with lipophilicity lower than that of SLV319. The key change was the replacement of the arylsulfonyl group in the original series by a dialkylaminosulfonyl moiety. One of the compound exhibited the highest CB1 receptor affinity (Ki = 24 nM) in this series, as well as very potent CB1 antagonistic activity (pA2 = 8.8) and a high CB1/CB2 subtype selectivity ( 147-fold) [33].

Mode-of-action analyses in WN virus showed that the compound did not inhibit viral entry or virion assembly but specifically suppressed viral RNA synthesis [31]. The research group further worked these pyrazoline and developed preliminary SAR data that shows the aryl-rings are required for activity against WNV. They also investigate that pyrazolines inhibit RNA synthesis, pointing to viral RNA polymerase, RNA helicase, or other viral replication enzymes as potential targets [32].

Srivastava et al. prepared a number of analogues of diaryl dihydropyrazole-3-carboxamides 37 and evaluated them for appetite suppression and body weight reduction in animal models. The lead compounds bisulfate salt of (±)-5(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1Hpyrazole-3-carboxylic acid morpholin-4-ylamide and the bisulfate salt of (-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide showed significant body weight reduction in vivo, which is attributed to their CB1 antagonistic activity and exhibited a favorable pharmacokinetic profile [34]. Donohue et al. employed radio labeled ligands of ((-)-3-(4chlorophenyl)-N-[(4-cyanophenyl)sulfonyl]-4-phenyl-4,5dihydro-1H-pyrazole-1-carboxamidine) 38 for imaging of cannabinoid subtype-1 (CB1) receptors in vivo with positron emission tomography (PET) for understanding their role in neuropsychiatric disorders [35]. The list of patents on pyrazoline is discussed in Table 1 and 2 [36-84].

2.9. Cannabinoid CB1 Receptor Antagonists Cannabinoid CB1 receptor antagonists are currently the subject of intensive research due to their highly promising therapeutic prospects. NCEs having CB1 antagonistic properties have recently been disclosed by several pharmaceutical companies and some academic research groups, some of which are close structural analogs of the leading compound rimonabant 35 (SR-141716A). A considerable number of these CB1 antagonists are bioisosteres that are derived from rimonabant by the replacement of the pyrazole moiety with an alternative heterocycle like pyrazoline etc.

CN11 Cl O O

R1

S

N R2

N

Cl

Cl

R1

R5

N

N

N

N

N HN

CH3

R4

H2N

O

N N

NH

N

R3

N

N

R3

R2

O 35

36

37

Cl

38

S O

O


Table 1. S.

Kumar et al.

List of Patent on Pyrazoline Filed with World Intellectual Proprietary Organization (WIPO) Patent No.

Patent Date

Invention Disclosed

1.

WO2009037244

26.03.2009

This invention disclosed 5-(hetero)aryl-4,5-dihydro-(1H)-pyrazole (pyrazoline) derivatives as cannabinoid CB1 receptor agonists and also relates to the uses of such compounds particularly their use in administering them to patients to achieve a therapeutic effect in disorders in which CB1 receptors are involved [36]

2.

WO2008152086

18.12.2008

Disclosed invention related to 4, 5-dihydro-(1 H)-pyrazole (pyrazoline) derivatives as cannabinoid CB1 receptor modulators [37]

3.

WO2008146405

04.12.2008

Disclosed (bis)pyrazoline fluorescent material which is applicable to a resin laminate plate having a metal foil therein, which has excellent heat resistance and photostability [38]

4.

WO2008087030

24.07.2008

Invention related to substituted pyrazoline, synthesis medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans and animals, especially in dyslipidaemia [39]

5.

WO2008087029

24.07.2008

Substituted pyrazoline compounds with ACAT inhibition activity [40]

6.

WO2008079277

03.07.2008

The invention provides certain pyrazoline compounds useful as inhibitors of protein kinases and also provides pharmaceutical compositions and methods of using the compositions in the treatment of various diseases [41]

7.

WO2008053300

08.05.2008

Pyrazoline compounds as mineralocorticoid receptor antagonist [42]

8.

WO2008043544

17.04.2008

Sulphonamide substituted Pyrazoline compounds, their preparation and use as CB1 modulators [43]

9.

WO2007071662

28.06.2007

This invention is directed to 4, 5-dihydro -(1 H)-pyrazole (pyrazoline) derivatives as cannabinoid CB1 receptor modulators, pharmaceutical compositions, methods for the preparation and their use [44]

10.

WO2007017125

15.02.2007

CB1 Antagonist or inverse antagonist as therapeutical agents for the treatment of inflammation involving gene expression [45]

11.

WO2007009723

25.01.2007

Azepane-or azocane-substituted pyrazoline derivatives, their preparation and use as medicaments [46]

12.

WO2007009724

25.01.2007

Cycloalkane-substituted pyrazoline derivatives, their preparation and use as medicaments [47]

13.

WO2007009722

25.01.2007

Octahydropentalene-substituted pyrazoline derivatives, their preparation and use as medicaments [48]

14.

WO2007009721

25.01.2007

Indoline-substituted pyrazoline derivatives, their preparation and use as medicaments [49]

15.

WO2007009707

25.01.2007

Use of substituted pyrazoline compounds for the treatment of coagulation related diseases [50]

16.

WO2007009706

25.01.2007

Substituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood [51]

17.

WO2007009704

25.01.2007

Use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome in patients with developed diabetes [52]

18.

WO2007009702

25.01.2007

Substituted pyrazoline compounds, having predetermined stereochemistry, for reducing triglycerides in blood [53]

19.

WO2007009700

25.01.2007

Use of substituted pyrazoline compounds for the treatment of the lipid parameters of the metabolic syndrome [54]

20.

WO2007009698

25.01.2007

Combination of pyrazoline type cannabinoid receptor antagonist and statin [55]

21.

WO2007009697

25.01.2007

Quaternary ammonium salts of substituted pyrazoline compounds, their preparation and use as medicaments [56]

22.

WO2007009696

25.01.2007

Use of substituted pyrazoline compounds for the preparation of paediatric medicaments [57]

23.

WO2007009694

25.01.2007

Substituted pyrazoline compounds for the manufacture of a medicament and for the treatment of metabolic syndrome [58]

24.

WO2007009693

25.01.2007

Combination of a substituted pyrazoline compound and a drug used in food-related disorders [59]

25.

WO2007009692

25.01.2007

Use of substituted pyrazoline compounds for the treatment of food disorders, including obesity or metabolic syndrome in patients with developed diabetes [60]

26.

WO2007009691

25.01.2007

Combination of substituted pyrazolines and anti -addictive agent [61]

No.



161

(Table 1) Contd….

S.

Patent No.

Patent Date

Invention Disclosed

27.

WO2007009690

25.01.2007

Heterocyclyl-substituted pyrazoline compounds, their preparation and use as medicaments [62]

28.

WO2007009688

25.01.2007

Thiocarbonyl-substituted pyrazoline compounds, their preparation and use as cb1 modulators [63]

29.

WO2007009687

25.01.2007

Carbonyl substituted pyrazoline compounds, their preparation and use as cb1 receptor modulators [64]

30.

WO2006072353

13.07.2006

Use of azetidine-substituted pyrazolines as medicaments, novel azetidine-substituted pyrazolines, for the treatment and/or prophylaxis of diseases, especially cardiovascular diseases, preferably thromboembolic disease [65]

31.

WO2006072351

13.07.2006

Heteroaryl-substituited pyrazolines as par-1 antagonists and their use for treating and/or for the prophylaxis of illnesses, in particular cardiovascular diseases, preferably thromboembolic diseases [66]

32.

WO2006072350

13.07.2006

Cyanoguanidine-substituted pyrazolines and their use for treating and/or for the prophylaxis of illnesses, in particular cardiovascular diseases, preferably thromboembolic diseases [67]

33.

WO2005077910

25.08.2005

Pyrazoline derivatives useful for the treatment of cancer in particular for the treatment of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, especially for the treatment of colon cancer and/or bowel cancer and/or prostata cancer [68]

34.

WO2004052865

24.06.2004

Substituted pyrazoline carboxanilides for use as pesticides [69]

35.

WO20070724

28.08.2003

Substituted 4-pyrazolyl pyrazolines used for pest control [70]

36.

WO066625

14.08.2003

Substituted 4-hetaryl-pyrazolines as pest control agents [71]

37.

WO083128

24.10.2002

2,1-Oxazoline and 1,2-pyrazoline-based inhibitors of dipeptidyl peptidase IV and a method is also provided for treating diabetes and related diseases, especially Type II diabetes [72]

38.

WO080909

17.10.2002

Utilization of pyrazoline derivatives in the preparation of a medicament for the prevention and/or treatment of proliferative cell diseases [73]

39.

WO034264

02.05.2002

Novel drugs whereby motor neuron disease can be treated. Remedies for treating motor neuron disease which contain as the active ingredient 3-methyl-1-phenyl-2-pyrazolin-5-one or physiologically acceptable salts thereof [74]

40.

WO032173

10.05.2001

Kainic acid neurocytotoxicity inhibitors containing as the active ingredient acyl-nitrogen-containing 5membered heterocycle derivatives or pharmaceutically acceptable salts thereof; and 1-acyl-2-pyrazoline derivatives or pharmaceutically acceptable salts thereof [75]

No.

Table 2.

List of Patent on Pyrazoline Filed with United State Patent Trademark Office

S. No.

Patent No.

Patent Date

Invention Disclosed

1.

US20090082396

26.03.2009

5-(Hetero)aryl-4,5-dihydro-(1H)-pyrazole (pyrazoline) derivatives as cannabinoid CB.sub.1 receptor agonists and method for synthesis, pharmaceutical composition etc. Their use in patients to achieve a therapeutic effect in disorders in which CB.sub.1 receptors are involved [76]

2.

US20080177078

24.07.2008

This invention relates to a method for conversion of 2-pyrazolines to pyrazoles using Bromine [77]

3.

US20050119128

02.06.2005

The present invention relates to a plurality of processes for preparing novel substituted 4-hetarylpyrazolines as pest control agents [78]

4.

US20050107456

19.05.2005

Invention relates to novel substituted pyrazolines, processes for preparing these compounds and their use for controlling pests, and also to novel intermediates and processes for their preparation [79]

5.

US20050096474

05.05.2005

Patent disclosed a procedure for the preparation of racemic derivatives of 1,5-diaryl-3-trifluoromethyldelta 2-pyrazolines [80]

6.

US20050096373

05.05.2005

Procedure for the preparation of racemic and enantiomerically pure derivatives of 1,5 diaryl-3trifluorromethyl-delta 2-pyrazolines [81]


Kumar et al.

(Table 2) Contd….

S. No.

Patent No.

Patent Date

Invention Disclosed

7.

US20030105105

05.06.2003

Patent describe disubstituted pyrazolines and triazolines as factor Xa inhibitors [82]

8

US20020103381

01.07.2002

Method for the synthesis of pyrazolines and also claimed are novel intermediates and their methods of synthesis [83]

6.

US20010000179

05.04.2001

Patent describe disubstituted pyrazolines and triazolines having variety of N-containing groups, which are useful as inhibitors of factor Xa [84]

[12]

CURRENT & FUTURE DEVELOPMENTS Numerous pyrazoline derivatives have been found to possess considerable biological activities, which stimulated the research activity in this field. They have numerous prominent effects, such as antimicrobial, antimycobacterial, antifungal, antiamoebic, anti-inflammatory, analgesic, antidepressant and anticancer activities. Many new compounds have been made and patented, but still there are new aspects to explore and work on.

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[15] [16]

CONFLICT OF INTEREST Authors do not have any conflict of interest. [17]

REFERENCES [1]

[2] [3]

[4]

[5] [6]

[7]

[8]

[9] [10]

[11]

Zampieri D, Mamolo MG, Laurini E, Scialino G, Banfi E, Vio L. Antifungal and antimycobacterial activity of 1-(3, 5-diaryl-4,5dihydro-1H-pyrazol-4-yl)-1H-imidazole derivatives. Bioorg Med Chem 2008; 16: 4516-4522. Karthikeyan MS, Holla BS, Kumari NS. Synthesis and antimicrobial studies on novel chloro-fluorine containing hydroxy pyrazolines. Eur J Med Chem 2007; 42: 30-36. Shaharyar M, Siddiqui AA, Ali MA, Sriram D, Yogeeswari P. Synthesis and in vitro antimycobacterial activity of N1-nicotinoyl3-(4-hydroxy-3-methyl phenyl)-5-[(sub)phenyl]-2-pyrazolines. Bioorg Med Chem Lett 2006; 16: 3947-3949. Abdel-Wahab BF, Abdel-Aziz HA, Ahmed EM. Synthesis and antimicrobial evaluation of 1-(benzofuran-2-yl)-4-nitro-3arylbutan-1-ones and 3-(benzofuran-2-yl)-4,5-dihydro-5-aryl-1-[4(aryl)-1,3-thiazol-2-yl]-1H-pyrazoles. Eur J Med Chem 2009; 44: 2632-2635. Abid M, Azam A. Synthesis and antiamoebic activities of 1-Nsubstituted cyclised pyrazoline analogues of thiosemicarbazones. Bioorg Med Chem 2005; 13: 2213-2220. Budakoti A, Abid M, Azam A. Syntheses, characterization and in vitro antiamoebic activity of new Pd(II) complexes with 1-Nsubstituted thiocarbamoyl-3,5-diphenyl-2-pyrazoline derivatives. Eur J Med Chem 2007; 42: 544-551. Bhat AR, Athar F, Azam A. Bis-pyrazolines: Synthesis, characterization and antiamoebic activity as inhibitors of growth of Entamoeba histolytica. Eur J Med Chem 2009; 44: 426-431. Budakoti A, Bhat AR, Athar F, Azam A. Synthesis and evaluation of 3-(3-bromo phenyl)-5-phenyl-1-(thiazolo [4,5-b] quinoxaline-2yl)-2-pyrazoline derivatives. Eur J Med Chem 2008; 43: 17491757. Abid M, Bhat AR, Athar F, Azam A. Synthesis, spectral studies and antiamoebic activity of new 1-N-substituted thiocarbamoyl-3phenyl-2-pyrazolines. Eur J Med Chem 2009; 44: 417-425. Rathish IG, Javed K, Ahmad S, et al. Synthesis and antiinflammatory activity of some new 1,3,5-trisubstituted pyrazolines bearing benzene sulfonamide. Eur J Med Chem 2009; 19: 255-258. Reddy MVR, Billa VK, Pallela VR, et al. Design, synthesis, and biological evaluation of 1-(4-sulfamylphenyl)-3-trifluoromethyl-5indolyl pyrazolines as cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) inhibitors. Bioorg Med Chem 2008; 16: 3907-3916.

[18]

[19]

[20]

[21]

[22]

[23]

[24] [25]

[26]

[27]

[28]

Amir M, Kumar H, Khan SA. Synthesis and pharmacological evaluation of pyrazoline derivatives as new anti-inflammatory and analgesic agents. Bioorg Med Chem Lett 2008; 18: 918-922. Barsoum FF, Hosni HM, Girgis AS. Novel bis(1-acyl-2pyrazolines) of potential anti-inflammatory and molluscicidal properties. Bioorg Med Chem 2006; 14: 3929-3937. Havrylyuk D, Zimenkovsky B, Vasylenko O, Zaprutko L, Gzella A, Lesyk R. Synthesis of novel thiazolone-based compounds containing pyrazoline moiety and evaluation of their anticancer activity. Eur J Med Chem 2009; 44: 1396-1404. Johnson M, Younglove B, Lee L, et al. Design, synthesis, and biological testing of pyrazoline derivatives of combretastatin-A4. Bioorg Med Chem Lett 2007; 17: 5897-5901. Roecker AJ, Coleman PJ, Mercer SP, et al. Kinesin spindle protein (KSP) inhibitors. Part 8: Design and synthesis of 1,4-diaryl-4,5dihydro pyrazoles as potent inhibitors of the mitotic kinesin KSP. Bioorg Med Chem Lett 2007; 17: 5677-5682. José MG, Miguel del Corral M, Castro MA, et al. Synthesis and evaluation of pyrazolignans. A new class of cytotoxic agents. Bioorg Med Chem 1995; 3: 1203-1210. Manna F, Chimenti F, Fioravanti R, et al. Synthesis of some pyrazole derivatives and preliminary investigation of their affinity binding to P-glycoprotein. Bioorg Med Chem Lett 2005; 15: 46324635. Rostom SAF. Synthesis and in vitro antitumor evaluation of some indeno[1,2-c]pyrazol(in)es substituted with sulfonamide, sulfonylurea(-thiourea) pharmacophores, and some derived thiazole ring systems. Bioorg Med Chem 2006; 14: 6475-6485. Prasad YR, Rao AL, Prasoona L, Murali K, Kumar PR. Synthesis and antidepressant activity of some 1,3,5-triphenyl-2-pyrazolines and 3-(2-hydroxy naphthalen-1-yl)-1,5-diphenyl-2-pyrazolines. Bioorg Med Chem Lett 2005; 15: 5030-5034. Özdemir Z, Kandilci HB, Gümüel B, Çalı U, Bilgin AA. Synthesis and studies on antidepressant and anticonvulsant activities of some 3-(2-furyl)- pyrazoline derivatives. Eur J Med Chem 2007; 42: 373-379. Chimenti F, Fioravanti R, Bolasco A, et al. Synthesis, molecular modeling studies and selective inhibitory activity against MAO of N1-propanoyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives. Eur J Med Chem 2008; 43: 2262-2267. Chimenti F, Maccioni E, Secci D, et al. Synthesis, molecular modeling studies, and selective inhibitory activity against monoamine oxidase of 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro(1H)- pyrazole derivatives. J Med Chem 2005; 48: 7113-7122. Zhang X, Li X, Allan GF, et al. Design, synthesis, and in vivo SAR of a novel series of pyrazolines as potent selective androgen receptor modulators. J Med Chem 2007; 50: 3857-3869. Jones DG, Liang X, Stewart EL, et al. Discovery of non-steroidal mifepristone mimetics: Pyrazoline-based PR antagonists. Bioorg Med Chem Lett 2005; 15: 3203-3206. Amr AG, Abdel-Latif NA, Abdalla MM. Synthesis and antiandrogenic activity of some new 3-substituted androstano[17,16-c]5-aryl-pyrazoline and their derivatives. Bioorg Med Chem 2006; 14: 373-384. Camacho ME, León J, Entrena A, et al. 4,5-Dihydro-1H-pyrazole derivatives with inhibitory nNOS activity in rat brain: Synthesis and structure-activity relationships. J Med Chem 2004; 47: 56415650. Carrión MD, López CLC, Camacho ME, et al. Pyrazoles and pyrazolines as neural and inducible nitric oxide synthase (nNOS


[29]

[30]

[31] [32]

[33]

[34]

[35]

[36] [37] [38] [39] [40] [41] [42]

[43] [44] [45] [46] [47] [48] [49] [50]

and iNOS) potential inhibitors (III). Eur J Med Chem 2008; 43: 2579-2591. El-Sabbagh OI, Baraka MM, Ibrahim SM, et al. Synthesis and antiviral activity of new pyrazole and thiazole derivatives. Eur J Med Chem 2009 (in press). Yar MS, Bakht MA, Siddiqui AA, Abdullah MM, Clercq ED. Synthesis and evaluation of in vitro antiviral activity of novel phenoxy acetic acid derivatives. J Enzym Inhib Med Chem 2009; 24: 876-882. Puig-Basagoiti F, Tilgner M, Forshey BM, et al. Triaryl pyrazoline compound inhibits flavivirus rna replication. Antimicrob Agents Chemother 2006; 50: 1320-1329. Goodell JR, Puig-Basagoiti F, Forshey BM, Shi P-Y, Ferguson DM. Identification of compounds with anti-west nile virus activity. J Med Chem 2006; 49: 2127-2137. Lange JHM, Stuivenberg HH, Veerman W, et al. Novel 3,4diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower lipophilicity. Bioorg Med Chem Lett 2005; 15: 47944798. Srivastava BK, Joharapurkar A, Raval S, et al. Diaryl dihydropyrazole-3-carboxamides with significant in vivo antiobesity activity related to CB1 receptor antagonism: Synthesis, biological evaluation, and molecular modeling in the homology model. J Med Chem 2007; 50: 5951-5966. Donohue SR, Pike VW, Finnema SJ, et al. Discovery and labeling of high-affinity 3,4-diarylpyrazolines as candidate radioligands for in vivo imaging of cannabinoid subtype-1 (cb1) receptors. J Med Chem 2008; 51: 5608-5616. Lange, J.H.M., Zilaout, H., Van-vliet, B.: WO2009037244 (2009). Yildirim, M., Wals, H.C., Van vliet, B.J., Lange, J.H.M.: WO2008152086 (2008). Taguchi, Y., Inoue, K.: WO2008146405 (2008). Torrens-Jover, A.: WO2008087030 (2008). Yenes-Minguez, S., Torrens-Jover, A.: WO2008087029 (2008). Adams, R.S., Duffey, M., Gould, A. E., Greenspan, P.D., Kulkarni, B. A., Vos, T.J.: WO2008079277 (2008). Meyers, M.J., Arhancet, G.B., Chen, X., Hockerman, S., Long, S.A., Mahoney, M.W., Reitz, D.B., Rico, J.G.: WO2008053300 (2008). Buschmann, H.H., Torrens-Jover, A., Mas-Prio, J., YenesMinguez, S.: WO2008043544 (2008). Lange, J.H.M., Iwema B.W., Van Der Neut, M.A.W., Van Vliet, B. J.: WO2007071662 (2007). Buschmann, H. H.: WO2007017125 (2007). Yenes-Minguez, S., Torrens-Jover, A.: WO2007009723 ( 2007). Yenes-Minguez, S., Torrens-Jover, A.: WO2007009724 (2007). Yenes-Minguez, S., Torrens-Jover, A.: WO2007009722 (2007). Yenes-Minguez, S., Torrens-Jover, A.: WO2007009721 (2007). Buschmann, H.H., Erill Saez, S.: WO2007009707 (2007).

Recent Patents on Anti-Infective Drug Discovery, 2009, Vol. 4, No. 3 [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67]

[68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84]

163

Altisen, C.M.R.: WO2007009706 (2007). Buschmann, H. H.: WO2007009704 (2007). Altisen, C.M.R.: WO2007009702 (2007). Buschmann, H.H.: WO2007009700 (2007). Buschmann, H. H.: WO2007009698 (2007). Torrens-Jover, A., Mas-Prio, J.: WO2007009697 (2007). Buschmann, H.H.: WO2007009696 (2007). Buschmann, H.H.: WO2007009694 (2007). Buschmann, H.H.: WO2007009693 (2007). Buschmann, H.H.: WO2007009692 (2007). Buschmann, H.H.: WO2007009691 (2007). Buschmann, H.H., Torrens-Jover, A., Mas-Prio, J., Ruiz, Q.J.R., Yenes-Minguez, S.: WO2007009690 (2007). Buschmann, H.H., Torrens-Jover, A., Mas-Prio, J., YenesMinguez, S.: WO2007009688 (2007). Dordal, Z.A., Buschmann, H. H., Torrens-Jover, A., Mas-Prio, J., Quintana R.J.R.: WO2007009687 (2007). Brohm, D., Diedrichs, N., Hübsch, W., Schneider, D., Fröhlen, BN., Gerdes, C., Gnoth, M.J., Perzborn, E., Vöhringer, V.: WO2006072353 (2006). Brohm, D., Diedrichs, N., Hübsch, W., Fröhlen, B-N., Gerdes, C., Gnoth, M.J., Perzborn, E., Vöhringer, V.: WO2006072351 (2006). Allerheiligen, S., Brohm, D., Diedrichs, N., Hübsch, W., Fröhlen, B-N., Gerdes, C., Gnoth, M.J., Perzborn, E., Vöhringer, V.: WO2006072350 (2006). Cuberes, A.R., Frigola, C.J., Mangues, B.R., Casanova, R.I. WO2005077910 (2005). Fuchs, R., Maurer, F., Konze, J., Arnold, C.: WO2004052865 (2004). Maurer, F., Fuchs, R., Erdelen, C., Turberg, A., Konze, J.: WO03070724 (2003). Maurer, F., Fuchs, R., Erdelen, C., Turberg, A., Konze, J., Lösel, P.: WO03066625 (2003). Sulsky, R. B., Robl, J.A.: WO02083128 (2002). Cuberes-Altisent, M.R., Berrocal-Romero, J.M., Contijoch-Llobet, M.M., Frigola-Constansa, J.: WO02080909 (2002). Ikeda, K.: WO2002034264 (2002). Shishikura, J., Inami, H., Kaku, H., Tsutsumi, R., Yamashita, H., Ohno, K.: WO01032173 (2001). Lange, J. H.M.: US20090082396 (2009). Fagan, P. J.: US20080177078 (2008). Maurer, F.: US20080119128 (2008). Maurer, F.: US20050107456 (2005). Alcon-Marrugat, M.: US20050096474 (2005). Alcon-Marrugat, M.: US20050096373 (2005). Pinto, D.J.P.: US20030105105 (2003). Boldi, A.M.: US20020103381 (2002). Pinto, D.J.P.: US20010000179 (2001).