WO2023281552A1 - 2,4-disubstituted-thieno[2,3-d]pyrimidine derivatives, and uses thereof - Google Patents

2,4-disubstituted-thieno[2,3-d]pyrimidine derivatives, and uses thereof Download PDF

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Publication number
WO2023281552A1
WO2023281552A1 PCT/JO2021/050008 JO2021050008W WO2023281552A1 WO 2023281552 A1 WO2023281552 A1 WO 2023281552A1 JO 2021050008 W JO2021050008 W JO 2021050008W WO 2023281552 A1 WO2023281552 A1 WO 2023281552A1
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mixture
compound
pharmaceutical composition
cox
alkyl
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PCT/JO2021/050008
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French (fr)
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Pran Kishore Deb
Ruba Anwar SALOU
Wafa HOURANI
Abdulmuttaleb Yousef JABER
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Philadelphia University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to pyrimidine derivatives, and more particularly to substituted pyrimidine derivatives, methods of preparation thereof, and uses thereof as antiinflammatory agents.
  • Nonsteroidal anti-inflammatory drugs are among the most widely used therapeutics, primarily for the treatment of pain, rheumatic arthritis and various types of inflammatory conditions. However, their use is mainly restricted by their well-known serious gastrointestinal side effects such as gastroduodenal erosions, ulcerations and nephrotoxicity.
  • COX cyclooxygenase
  • COX-1 constitutive form
  • COX-2 inducible form
  • the constitutive COX-1 isozyme plays an important role in many physiological functions, such as cytoprotection of gastric mucosa, renal blood flow regulation and platelet aggregation.
  • the expression of COX-2 isozyme is mainly induced by several stimuli such as hormones, growth factors, mitogens, oncogenes and disorders of water-electrolyte homeostasis resulting in its involvement to pathological processes such as inflammation and various types of cancer.
  • NSAIDs such as aspirin, ibuprofen, flurbiprofen, naproxen, indomethacin, diclofenac, mefenamic acid, and piroxicam
  • side effects such as gastrointestinal ("GI") ulcer and renal toxicity due to their nonselective inhibition of COX- 1 pathway.
  • GI gastrointestinal
  • COX-2 selective inhibitors have been developed.
  • COX-2 selective inhibitors like celecoxib, rofecoxib and valdecoxib due to their adverse cardiovascular side effects which is also found to be associated with other classical NSAIDs.
  • COX-2 selective inhibitors are also evident to be involved in the aetiology of various other diseases such as cancers, Alzheimer's disease, Parkinson's disease, and diabetes.
  • n may be 0, 1 , or 2;
  • Ri may be an H atom, (C 1 - C 4 ) alkyl, phenyl, p-substituted phenyl, benzyl, or p- substituted benzyl group;
  • R2 may represent an H atom, (C 1 - C 4 ) alkyl, alkyl sulfonyl, aryl sulfonyl, p-substituted aryl sulfonyl, alkyl carbonamide, aryl carbonamie or p-substituted carbonamide group.
  • Ri may be a benzyl group.
  • R2 may be an aryl sulfonyl group.
  • the method may include the steps of: mixing cyclopentanone with powdered sulfur, malonitrile in ethanol to produce a first mixture; heating the first mixture; adding diethylamine dropwise to the heated first mixture with continuous stirring in order to produce a second mixture; cooling down the second mixture to room temperature and neutralizing it dropwise with HC1 till a brown solid precipitate is formed; collecting the brown solid precipitate, followed by filtering, drying, recrystallizing the collected precipitate using chloroform and methanol to obtain a first compound; dissolving the first compound in dioxane; adding benzonitrile and HC1 to the dioxane solution to produce a third mixture; cooling down the third mixture and neutralizing it dropwise with NaOH solution in ice till a second precipitate is formed; filtering, drying, and recrystallizing the second precipitate to obtain a second compound; dissolving the second compound in about pyridine to form
  • aspects of the present disclosure further provide a pharmaceutical composition including a compound of the general Formula (I) and/or a pharmaceutically acceptable salt thereof and a pharmaceutical acceptable carrier and/or excipient.
  • compositions as an anti-inflammatory agent for treating of pain.
  • the pharmaceutical composition is a selective inhibition to COX-2 isoenzyme.
  • FIG. 1 illustrates a flowchart of a method of preparing 2,4-disubstituted-thieno[2,3- d] pyrimidine derivative compounds in accordance with embodiments of the present disclosure.
  • FIG. 2 illustrates a column chart showing level of inhibition of catalytic activity of human COX-1 and COX-2 isoenzymes at IOOmM concentration of the compounds prepared in accordance with embodiments of the present disclosure and conventional compounds at the same concentration.
  • FIG. 3 illustrates a column chart showing level of inhibition of enzymatic activity of human COX-2 isoenzyme at different concentrations of the compounds prepared in accordance with embodiments of the present disclosure and a conventional compound.
  • FIG. 4 illustrates a line chart representation of percentage of inhibition of enzymatic activity of the compounds prepared in accordance with embodiments of the present disclosure and a conventional compound against COX-2 isoenzyme at different concentrations.
  • n may be 0, 1 , or 2;
  • Ri may be an H atom, (C 1 - C 4 ) alkyl, phenyl, p-substituted phenyl, benzyl, or p- substituted benzyl group;
  • R2 may represent an H atom, (C 1 - C 4 ) alkyl, alkyl sulfonyl, aryl sulfonyl, p-substituted aryl sulfonyl, alkyl carbonamide, aryl carbonamie or p-substituted carbonamide group.
  • Embodiments of the present disclosure further provide a pharmaceutical composition including a compound of general formula (I) and/or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier/excipient.
  • composition is intended to include a pharmaceutical active compound of general formula (I) and/or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition can be, for example, in a liquid form, e.g. a solution, syrup, emulsion and suspension, or in a solid form, e.g. a capsule, caplet, tablet, pill, powder and suppository. Granules, semi-solid forms and gel caps are also considered.
  • dosage unit optionally is to be measured, e.g. in the dosage unit of a teaspoon.
  • the pharmaceutical composition of this disclosure can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • the pharmaceutical composition can be administered to humans and other mammals orally, sublingually, rectally, parenterally, intracisternally, intraurethrally, intraperitoneally, topically (as powder, ointment or drop), as buccal or as an oral or nasal spray.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, subcutaneous, intra-articular injection and infusion.
  • compositions of this disclosure for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • pharmaceutically acceptable carrier/excipient means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; binding agents such as hypromellose; disintegrating agents such as crosscarmellose; water; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil; cottonseed oil; safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar
  • compositions have to be pharmaceutically acceptable.
  • pharmaceutically acceptable means at least non-toxic.
  • the therapeutically active component should preferably be present in the above-mentioned pharmaceutical composition, the concentration of about 0.1 to 99.5% by weight, preferably of about 0.5 to 95% by weight of the total mixture.
  • composition can further contain other pharmaceutical active compounds in addition to the compound of general formula (I) according to the disclosure.
  • the pharmaceutical composition is for use as anti-bacterial, anti-inflammatory, anti-diabetic, and anti-cancer agents.
  • the pharmaceutical composition is a COX-2 selective inhibitor.
  • FIG. 1 illustrates a flowchart of a method of preparing the compound of the general formula (I), or a derivative thereof, wherein the method may include the steps of mixing about 0.04 mol (3.63 ml) of cyclopentanone with about 0.04 mol (1.28 g) of powdered sulfur, and about 0.04 mol (1.06 g) of malonitrile in about 40 ml ethanol in a suitable flask to produce a first mixture (process block 1-1), followed by heating the first mixture to a temperature of about 40 °C (process block 1-2).
  • Compound (4) may have chemical characterization as follows:
  • Compound (5) may have chemical characterization as follows:
  • Compound (6) may have chemical characterization as follows: N-(2-phenyl-6, 7-dihydro- 5H - cyclopenta [4, 5] thieno[2, 3-d]pyrimidin-4- yl)benzenesulfonamide (6)
  • COX inhibition assay was performed by using COX (human) Inhibitor Screening Assay Kit (Cayman Item No. 701230) according to the manufacturer instructions. All the reagents and buffers were prepared in ultrapure water. COX-1 and COX-2 human Recombinant enzymes, heme were diluted with the reaction buffer, arachidonic acid was reconstituted with potassium hydroxide and stannous chloride SnCl 2 prepared in hydrochloric acid. All stock solutions of the compound (6) and the positive controls, commercially available Indomethacin and Celecoxib, were dissolved in dimethyl sulfoxide solution ("DMSO").
  • DMSO dimethyl sulfoxide solution
  • reaction buffer In every inhibitor sample tube, about 160 ⁇ L reaction buffer, about 10 ⁇ L of heme, about 10 ⁇ L of diluted COX-1 or COX-2 enzyme and about 10 ⁇ L of the diluted inhibitor were added to get a final concentration of about 100 ⁇ M.
  • the background samples were prepared for both COX-1 and COX-2 by heat to inactivate the enzymes (about 20 ⁇ L of each enzyme in separate test tubes) in boiling water for about 3 minutes; and about 10 ⁇ L of the inactive COX-1 or COX-2 were added to the background tubes. About 10 ⁇ L of the vehicle control, DMSO was added to the background tubes and the 100% initial activity of COX enzymes.
  • ELISA standards were prepared in test tubes SI to S8 and dilutions were prepared with the ELISA buffer. Firstly, the lyophilised prostaglandin screening standard (about 10 ng/mL) was dissolved in about lmL of ELISA buffer. About 800 ⁇ L of the ELISA buffer was added to SI and about 500 ⁇ L of the same was added to S1-S8. Then about 200 ⁇ L of prostaglandin standard (about 10 ng/mL) was added to tube SI and mixed thoroughly. The standards were diluted serially by transferring about 500 ⁇ L from tube SI to tube S2 and mixed; this was repeated until tube S8.
  • COX reaction dilutions background samples were diluted 100 times by adding about 10 ⁇ L of the background COX-1 and COX-2 to about 990 ⁇ L of ELISA buffer. Two dilutions were made for the 100% initial activity samples for COX-1 and COX-2 enzymes in test tubes designated as IAland IA2.
  • COX 100% initial activity samples and COX inhibitor samples were diluted 2000 times of the original sample by adding about 10 ⁇ L of the samples to about 990 ⁇ L of ELISA buffer (IA1), then transferring about 50 ⁇ L of the latter tubes to about 950 ⁇ L of ELISA buffer (IA2).
  • Diluted COX inhibitor samples were also prepared in the same way in test tubes designated as C1-C2.
  • NSB nonspecific binding
  • Bo maximum binding
  • AChE prostaglandin screening tracer
  • the plate was shielded with a foil, placed on an orbital shaker and incubated for about 60-90 minutes. After that, the plate was read at a wavelength of about 405 nm with Microplate reader from BioTek and data were collected using Gen5TM analysis software.
  • the normal cells dermal Fibroblasts were purchased from the American Type Culture Collection (ATCC, USA). Cells were cultured in high glucose Dulbecco's modified eagle medium (DMEM) (Invitrogen, USA) supplemented with 10% heat inactivated fetal bovine serum (HI-FBS) (Invitrogen), 2 mmol L-l of L-glutamine, 50 U mL-1 of penicillin and 50 ⁇ g mL-1 of streptomycin. Cell lines were maintained at 37 °C in a 5 % CO 2 atmosphere of 95% humidity.
  • DMEM Dulbecco's modified eagle medium
  • HI-FBS heat inactivated fetal bovine serum
  • compound (6) did not show any growth reduction of human dermal fibroblast cells (IC50 >300, Table 2), thereby indicating the safety or tolerability of the test compound.
  • the term "about”, when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.

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Abstract

There is provided a 2,4-disubstituted-thieno[2,3-d]pyrimidine derivative compounds of the general formula (I), a method of preparation, and its use as anti-microbial, anti-inflammatory, anti-diabetic, and anti-cancer agents: (I) Wherein n may be 0, 1, or 2; R1 may be an H atom, (C1 - C4) alkyl, phenyl, p-substituted phenyl, benzyl, or p- substituted benzyl group; and R2 may represent an H atom, (C1 - C4) alkyl, alkyl sulfonyl, aryl sulfonyl, p-substituted aryl sulfonyl, alkyl carbonamide, aryl carbonamie or p-substituted carbonamide group.

Description

2,4-DISUBSTITUTED-THIENO[2,3-D]PYRIMIDINE DERIVATIVES,
AND USES THEREOF
TECHNICAL FIELD
[01] The present disclosure relates to pyrimidine derivatives, and more particularly to substituted pyrimidine derivatives, methods of preparation thereof, and uses thereof as antiinflammatory agents.
BACKGROUND INFORMATION
[02] Nonsteroidal anti-inflammatory drugs ("NSAIDs") are among the most widely used therapeutics, primarily for the treatment of pain, rheumatic arthritis and various types of inflammatory conditions. However, their use is mainly restricted by their well-known serious gastrointestinal side effects such as gastroduodenal erosions, ulcerations and nephrotoxicity.
[03] There are two different isoforms of cyclooxygenase ("COX") isoenzymes, a constitutive form ("COX-1") and an inducible form ("COX-2"). The constitutive COX-1 isozyme plays an important role in many physiological functions, such as cytoprotection of gastric mucosa, renal blood flow regulation and platelet aggregation. The expression of COX-2 isozyme is mainly induced by several stimuli such as hormones, growth factors, mitogens, oncogenes and disorders of water-electrolyte homeostasis resulting in its involvement to pathological processes such as inflammation and various types of cancer. Conventional NSAIDs, such as aspirin, ibuprofen, flurbiprofen, naproxen, indomethacin, diclofenac, mefenamic acid, and piroxicam, are associated with side effects such as gastrointestinal ("GI") ulcer and renal toxicity due to their nonselective inhibition of COX- 1 pathway. The success of NSAIDs in the treatment of various inflammatory disorders depends on the selective inhibition of COX-2 over COX-1 isoenzyme. To overcome this problem, various COX-2 selective inhibitors have been developed. However, the market withdrawal of some potent COX-2 selective inhibitors like celecoxib, rofecoxib and valdecoxib due to their adverse cardiovascular side effects which is also found to be associated with other classical NSAIDs. Furthermore, in the last decade COX-2 selective inhibitors are also evident to be involved in the aetiology of various other diseases such as cancers, Alzheimer's disease, Parkinson's disease, and diabetes. These observations have imposed a big challenge to the researchers to fulfil the unmet need for the discovery and development of novel COX-2 selective inhibitors with alternate chemical scaffold and improved pharmacokinetics and pharmacodynamics properties.
SUMMARY
[04] Aspects of the present disclosure provide 2,4-disubstituted-thieno[2,3-d] pyrimidine derivative compounds of the general formula (I):
Figure imgf000004_0001
Formula (I)
Wherein n may be 0, 1 , or 2;
Ri may be an H atom, (C1 - C4) alkyl, phenyl, p-substituted phenyl, benzyl, or p- substituted benzyl group; and
R2 may represent an H atom, (C1 - C4) alkyl, alkyl sulfonyl, aryl sulfonyl, p-substituted aryl sulfonyl, alkyl carbonamide, aryl carbonamie or p-substituted carbonamide group.
[05] In some aspects, Ri may be a benzyl group.
[06] In some aspects, R2 may be an aryl sulfonyl group.
[07] Further aspects of the present disclosure provide a method for preparing the compound of the general Formula (I), the method may include the steps of: mixing cyclopentanone with powdered sulfur, malonitrile in ethanol to produce a first mixture; heating the first mixture; adding diethylamine dropwise to the heated first mixture with continuous stirring in order to produce a second mixture; cooling down the second mixture to room temperature and neutralizing it dropwise with HC1 till a brown solid precipitate is formed; collecting the brown solid precipitate, followed by filtering, drying, recrystallizing the collected precipitate using chloroform and methanol to obtain a first compound; dissolving the first compound in dioxane; adding benzonitrile and HC1 to the dioxane solution to produce a third mixture; cooling down the third mixture and neutralizing it dropwise with NaOH solution in ice till a second precipitate is formed; filtering, drying, and recrystallizing the second precipitate to obtain a second compound; dissolving the second compound in about pyridine to form a fourth mixture while stirring; adding benzenesufonyl chloride to the fourth mixture while stirring to form a fifth mixture; neutralizing the fifth mixture dropwise with HC1 in ice followed by treating the neutralized fifth mixture with water and extracting it with ethyl acetate; and collecting, drying and recrystallizing the ethyl acetate extract with chloroform and methanol to obtain a third compound.
[08] Aspects of the present disclosure further provide a pharmaceutical composition including a compound of the general Formula (I) and/or a pharmaceutically acceptable salt thereof and a pharmaceutical acceptable carrier and/or excipient.
[09] Further aspects of the present disclosure provide the use of the pharmaceutical composition for treating a microbial infection.
[010] Further aspects of the present disclosure provide the use of the pharmaceutical composition as an anti-inflammatory agent for treating of pain.
[011] Other aspects of the present disclosure provide the use of the pharmaceutical composition for treating inflammation and rheumatoid arthritis.
[012] Further aspects of the present disclosure provide the use of the pharmaceutical composition for treating diabetes. [013] Other aspects of the present disclosure provide the use of the pharmaceutical composition for treating cancer.
[014] In aspects of the present disclosure, the pharmaceutical composition is a selective inhibition to COX-2 isoenzyme.
BRIEF DESCRIPTION OF THE DRAWINGS
[015] The present disclosure will now be described with reference to the accompanying drawings, which illustrate embodiments of the present disclosure, without however limiting the scope of protection thereto, and in which:
[016] FIG. 1 illustrates a flowchart of a method of preparing 2,4-disubstituted-thieno[2,3- d] pyrimidine derivative compounds in accordance with embodiments of the present disclosure.
[017] FIG. 2 illustrates a column chart showing level of inhibition of catalytic activity of human COX-1 and COX-2 isoenzymes at IOOmM concentration of the compounds prepared in accordance with embodiments of the present disclosure and conventional compounds at the same concentration.
[018] FIG. 3 illustrates a column chart showing level of inhibition of enzymatic activity of human COX-2 isoenzyme at different concentrations of the compounds prepared in accordance with embodiments of the present disclosure and a conventional compound.
[019] FIG. 4 illustrates a line chart representation of percentage of inhibition of enzymatic activity of the compounds prepared in accordance with embodiments of the present disclosure and a conventional compound against COX-2 isoenzyme at different concentrations.
DETAILED DESCRIPTION
[020] It is an object of the present disclosure to provide 2,4-disubstituted-thieno[2,3-d ] pyrimidine derivative compounds of the general Formula (I):
Figure imgf000007_0001
Formula (I)
Wherein n may be 0, 1 , or 2;
Ri may be an H atom, (C1 - C4) alkyl, phenyl, p-substituted phenyl, benzyl, or p- substituted benzyl group; and
R2 may represent an H atom, (C1 - C4) alkyl, alkyl sulfonyl, aryl sulfonyl, p-substituted aryl sulfonyl, alkyl carbonamide, aryl carbonamie or p-substituted carbonamide group.
[021] Embodiments of the present disclosure further provide a pharmaceutical composition including a compound of general formula (I) and/or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier/excipient.
[022] The term "pharmaceutical composition", as used herein, is intended to include a pharmaceutical active compound of general formula (I) and/or a pharmaceutically acceptable salt thereof.
[023] The pharmaceutical composition can be, for example, in a liquid form, e.g. a solution, syrup, emulsion and suspension, or in a solid form, e.g. a capsule, caplet, tablet, pill, powder and suppository. Granules, semi-solid forms and gel caps are also considered. In case that the pharmaceutical composition is a liquid or a powder, dosage unit optionally is to be measured, e.g. in the dosage unit of a teaspoon.
[024] The pharmaceutical composition of this disclosure can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration. The pharmaceutical composition can be administered to humans and other mammals orally, sublingually, rectally, parenterally, intracisternally, intraurethrally, intraperitoneally, topically (as powder, ointment or drop), as buccal or as an oral or nasal spray. The term "parenterally", as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, subcutaneous, intra-articular injection and infusion.
[025] Pharmaceutical compositions of this disclosure for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[026] The term "pharmaceutical acceptable carrier/excipient", as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; binding agents such as hypromellose; disintegrating agents such as crosscarmellose; water; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil; cottonseed oil; safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgement of the formulator.
[027] All components of the pharmaceutical composition have to be pharmaceutically acceptable. The term "pharmaceutically acceptable" means at least non-toxic. The therapeutically active component should preferably be present in the above-mentioned pharmaceutical composition, the concentration of about 0.1 to 99.5% by weight, preferably of about 0.5 to 95% by weight of the total mixture.
[028] The above-mentioned pharmaceutical composition can further contain other pharmaceutical active compounds in addition to the compound of general formula (I) according to the disclosure.
[029] In embodiments of the present disclosure, the pharmaceutical composition is for use as anti-bacterial, anti-inflammatory, anti-diabetic, and anti-cancer agents.
[030] In embodiments of the present disclosure, the pharmaceutical composition is a COX-2 selective inhibitor.
[031] The disclosure is now further illustrated on the basis of Examples and a detailed description from which further features and advantages may be taken. It is to be noted that the following explanations are presented for the purpose of illustration and description only; they are not intended to be exhaustive or to limit the disclosure to the precise form disclosed.
Example 1
Preparation of 2,4-disubstituted-thieno[2,3-d]pyrimidine derivatives
Preparation Scheme
[032] Compounds of the general formula (I) may be prepared in accordance with the following scheme:
Figure imgf000010_0001
[033] Reference is now being made to FIG. 1, which illustrates a flowchart of a method of preparing the compound of the general formula (I), or a derivative thereof, wherein the method may include the steps of mixing about 0.04 mol (3.63 ml) of cyclopentanone with about 0.04 mol (1.28 g) of powdered sulfur, and about 0.04 mol (1.06 g) of malonitrile in about 40 ml ethanol in a suitable flask to produce a first mixture (process block 1-1), followed by heating the first mixture to a temperature of about 40 °C (process block 1-2). After that, adding about 0.04 mol (4.2 ml) of diethylamine dropwise to the heated first mixture while stirring at a temperature ranging from about 50 °C to about 70 °C with continuous stirring for about 8 hours in order to produce a second mixture (process block 1-3). Afterwards, cooling down the second mixture to room temperature and neutralizing it drop wise with HC1 having a concentration of about 6.0 M in ice till a brown solid precipitate is formed (process block 1-4), and collecting the brown solid precipitate by suction, followed by filtering, drying, recrystallizing the collected precipitate using chloroform and methanol to obtain a first compound (process block 1-5). After that, dissolving about 0.012 mol of the first compound in about 0.12 mol (12.2 ml) dioxane (process block 1-6), followed by an addition of about 0.12 mol (12.4 ml) of benzonitrile and about 0.12 mol (13.1 ml) HC1 having a concentration of 12.0 M to produce a third mixture (process block 1-7), wherein the third mixture can be kept under stirring with reflux for about 4 hours while maintaining it a temperature ranging from about 80 °C to about 90 °C. After that, cooling down the third mixture to about 25 °C and neutralizing it dropwise with about 6.0 M NaOH solution in ice till a second precipitate is formed (process block 1-8), followed by filtering, drying, and recrystallizing the second precipitate to obtain a second compound (process block 1-9). After that, dissolving about 0.002 mol (0.5 g) of the second compound in about 0.06 mol (5.00 ml) pyridine to form a fourth mixture while stirring for about 30 minutes (process block 1-10), followed by adding about 0.01 mol (1.2 ml) of benzenesufonyl chloride to the fourth mixture while stirring for about 3 hours at a temperature raging from about 20 °C to about 30 °C to form a fifth mixture (process block
1-11), neutralizing the fifth mixture dropwise with HC1 having a concentration of 6.0 M in ice followed by treating the neutralized fifth mixture with water and extracting it with ethyl acetate (process block 1-12), and collecting, drying and recrystallizing the ethyl acetate extract with chloroform and methanol to obtain a third compound (process block 1-13).
Example 2
Structure Elucidation Data
[034] Compound (4) may have chemical characterization as follows:
2-amino-5,6-dihydro-4H -cyclopenta[b ]thiophene-3-carbonitrile (4)
IR (cm-1): 3422, 3327 (NH2), 2966, 2917, 2855 (aliphatic C-H), 2195 (C≡N), 1613 (C=C).
1H NMR (500 MHz, DMSO-d6 ): δ = 7.00 (s, 2H, NH2), 2.63 (t, J = 6.3 Hz, 2H, H- 4), 2.54 (t, J= 6.3 Hz, 2H, H- 6), 2.25 (m, 2H, H- 5) ppm. 13C NMR (500 MHz, DMSO-d6 ): δ= 169.1 (C-2), 141.5 (C-6a), 121.8 (C-3a), 117.0 (C- CN), 79.3 (C-3), 29.4 (C-6), 28.5 (C-4), 27.2 (C-5) ppm.
HRMS (ESI) m/z: Calcd. forC8H9N2S [M+H]+ 165.04721, found 165.04810.
[035] Compound (5) may have chemical characterization as follows:
2-phenyl-6, 7-dihydro- 5H/-cyclopenta[4,5]thieno[2,3-d ]pyrimidin-4-amine (5)
IR (cm-1): 3477, 3294 (NH2), 3086 (aromatic C-H), 2973, 2910, 2847 (aliphatic C-H), 1637 (C=N), 1583, 1558, 1505 (C=C).
1H NMR (500 MHz, DMSO-d6 ): δ= 8.33 (dd, J= 7.9, 2.0 Hz, 2H, H- 2 , H- 6’), 7.44 (m, 3H, H-3 , H- 4 , H- 5 ), 6.91 (s, 2H, NH2), 3.05 (t, J= 7.0 Hz, 2H, H- 5), 2.92 (t, J= 7.1 Hz, 2H, H- 7) , 2.40 (m, 2H, H- 6) ppm.
13C NMR (500 MHz, DMSO-d6 ): δ= 172.6 (C-4), 158.6 (C-2), 158.2 (C-7b), 137.9 (C- 7a), 136.6 (C-1'), 136.3 (C-4a), 130.3 (C-4), 128.7 (C-3’, C-5), 128.0 {C-2 , C-6 ), 111.3 (C-4b), 29.7 (C-5), 29.2 (C-7), 27.7 (C-6) ppm.
HRMS (ESI) m/z : Calcd. for C15H14N3S [M+H]+ 268.09029, found 268.09132.
[036] Compound (6) may have chemical characterization as follows: N-(2-phenyl-6, 7-dihydro- 5H - cyclopenta [4, 5] thieno[2, 3-d]pyrimidin-4- yl)benzenesulfonamide (6)
IR (cm-1): 3426 (NH2), 3095, 3061 (aromatic C-H), 2972, 2952, 2917, 2844 (aliphatic C- H), 1640 (C=N), 1583, 1565, 1541 (C=C), 2336 (S02).
1H NMR (500 MHz, DMSO-d6 ): δ= 7.50 (s, 2H, NH2), 3.08 (t, J= 6.5 Hz, 2H, H-5), 2.38 (m, J= 6.2 Hz, 2H, H-6), 2.78 (t, J= 7.1 Hz, 2H, H-7) , 8.00 (d, J= 7.3 Hz, 2H, H-2', H- 6'), 7.53 (m, 3H, H-3',H-4', H-5'), 7.63 (d, J= 7.7 Hz, 2H, H-2", H-6"), 3.45 (m, 2H, H- 3", H4"), 7.78 (t, J= 7.2 Hz, 1H, H-5") ppm. 13C NMR (500 MHz, DMSO-d6 ): δ = 177.3 (C-4), 158.1 (C-2), 137.0 (C-4a), 126.5 (C- 4b), 30.6 (C-5), 27.4 (C-6), 28.3 (C-7), 147.5 (C-7a), 136.1 (C-7b), 137.7 (C-l'), 128.1 (C- 2', C-6'), 129.4 (C-3' C-5'), 135.9 (C-l"), 131.8 (C-4'), 129.9 (C-2", C-6"), 129.2 (C- 3", C-5"), 135.5 (C-4") ppm.
HRMS (ESI) m/z : Calcd. for C21H17N3O2S2 [M+H]- 406.06894, found 406.06010.
Example 3
Biological Assay
COX inhibition assay preparation
[037] COX inhibition assay was performed by using COX (human) Inhibitor Screening Assay Kit (Cayman Item No. 701230) according to the manufacturer instructions. All the reagents and buffers were prepared in ultrapure water. COX-1 and COX-2 human Recombinant enzymes, heme were diluted with the reaction buffer, arachidonic acid was reconstituted with potassium hydroxide and stannous chloride SnCl2 prepared in hydrochloric acid. All stock solutions of the compound (6) and the positive controls, commercially available Indomethacin and Celecoxib, were dissolved in dimethyl sulfoxide solution ("DMSO"). In every inhibitor sample tube, about 160 μL reaction buffer, about 10 μL of heme, about 10 μL of diluted COX-1 or COX-2 enzyme and about 10 μL of the diluted inhibitor were added to get a final concentration of about 100 μM. The background samples were prepared for both COX-1 and COX-2 by heat to inactivate the enzymes (about 20 μL of each enzyme in separate test tubes) in boiling water for about 3 minutes; and about 10 μL of the inactive COX-1 or COX-2 were added to the background tubes. About 10 μL of the vehicle control, DMSO was added to the background tubes and the 100% initial activity of COX enzymes.
[038] All the reaction tubes were incubated for about 10 minutes at a temperature of about 37 °C. Following incubation, about 10 μL of the substrate, arachidonic acid, was added to all test tubes, mixed, and incubated for exactly 30 seconds at a temperature of about 37 °C. Arachidonic acid is converted to PGH2 due to COX enzyme activity. This PGH2 was reduced by adding about 30 μL of SnCl2 solution to every reaction tube to stop the enzyme catalysis and incubated at a temperature of about 37 °C for about 5 minutes. The reaction tubes were stored at a temperature of about 4 °C to quantify the prostaglandin formation by competitive enzyme linked immunosorbent assay ("ELISA").
Competitive ELISA
[039] To carry out the competitive ELISA, ELISA standards were prepared in test tubes SI to S8 and dilutions were prepared with the ELISA buffer. Firstly, the lyophilised prostaglandin screening standard (about 10 ng/mL) was dissolved in about lmL of ELISA buffer. About 800 μL of the ELISA buffer was added to SI and about 500 μL of the same was added to S1-S8. Then about 200 μL of prostaglandin standard (about 10 ng/mL) was added to tube SI and mixed thoroughly. The standards were diluted serially by transferring about 500 μL from tube SI to tube S2 and mixed; this was repeated until tube S8. For the COX reaction dilutions, background samples were diluted 100 times by adding about 10 μL of the background COX-1 and COX-2 to about 990 μL of ELISA buffer. Two dilutions were made for the 100% initial activity samples for COX-1 and COX-2 enzymes in test tubes designated as IAland IA2. COX 100% initial activity samples and COX inhibitor samples were diluted 2000 times of the original sample by adding about 10 μL of the samples to about 990 μL of ELISA buffer (IA1), then transferring about 50 μL of the latter tubes to about 950 μL of ELISA buffer (IA2). Diluted COX inhibitor samples were also prepared in the same way in test tubes designated as C1-C2. After that, about 50 μL of the diluted standards, COX background, COX 100% initial activity and COX inhibitor samples were transferred to a 96-well ELISA plate to the corresponding wells. Blank (to assess the background absorbance produced by Ellman's reagent) and total activity, TA (to assess the enzymatic activity of the ACE- linked tracer) wells were left empty, about 100 μL and about 50 μL of the ELISA buffer were added to the nonspecific binding ("NSB") and maximum binding ("Bo"), respectively. NSB indicates the amount of tracer binds to the wells of the plate in the absence of any specific antibody while Bo is the maximum amount of the tracer that the antibody can bind in the absence of free analyte. About 50 μL of prostaglandin screening tracer ("AChE") was added to each well except TA and blank wells. Finally, about 50 μL of prostaglandin screening ELISA antiserum was added to each well except TA, NSB and blank wells. The plate was covered with a plastic film and covered with aluminium foil to avoid light exposure and incubated for about 18 hours at a temperature of about 25 °C on a shaker. Following incubation, the plate was washed 5 times with the wash buffer and developed with the addition of about 200 μL of Ellman's reagent to all wells, about 5 μL of tracer was added to TA well. The plate was shielded with a foil, placed on an orbital shaker and incubated for about 60-90 minutes. After that, the plate was read at a wavelength of about 405 nm with Microplate reader from BioTek and data were collected using Gen5™ analysis software.
[040] The absorbance readings were subtracted from the blank readings; the corrected maximum binding was calculated by subtracting the NSB average from the Bo average. To get the %B/Bo (% samples or standard bound/max bound) values for the standards by subtracting the average NSB absorbance from the Si to S8 absorbance and divided by the corrected max binding then multiplied by 100. %B/B0 values for the samples were calculated and identified on the standard curve to determine the sample concentration. Background values were subtracted from the 100% initial activity and COX inhibitor samples. To get the percent inhibition, each inhibitor sample was subtracted from the initial activity sample then divided by the initial activity sample and multiplied by 100.
[041] Initially, all the compounds were evaluated in vitro at about 100 μM concentrations in replicate to evaluate their percentage inhibition of the human COX-1 and COX-2 isoenzyme's catalytic activity, by using Cayman's human COX assay kit (Item No. 701230). Commercially available Indomethacin and Celecoxib were initially used as positive controls. Results are shown in Table 1 and FIG. 2. Based on the initial screening, the most selective COX-2 inhibitor, compound (6) was further screened against the COX- 2 isoenzyme at six different concentrations of 0.01, 0.1, 1.0, 10, 100, and 500 μM, to evaluate its IC50 value using Indomethacin as a reference standard as shown in Table 2, and FIGS. 3-4. Compound (6) was found to have little less potency but better selectivity for COX-2 over COX-1 enzyme as compared to the indomethacin. Table (1): In vitro COX-1 and COX-2 percentage inhibition results at a concentration of about IOOmM of compound 6 and positive controls.
Figure imgf000016_0001
Example 4
Cytotoxicity Assay (“MTT Assay”)
Cell line and culture conditions
[042] The normal cells dermal Fibroblasts were purchased from the American Type Culture Collection (ATCC, USA). Cells were cultured in high glucose Dulbecco's modified eagle medium (DMEM) (Invitrogen, USA) supplemented with 10% heat inactivated fetal bovine serum (HI-FBS) (Invitrogen), 2 mmol L-l of L-glutamine, 50 U mL-1 of penicillin and 50 μg mL-1 of streptomycin. Cell lines were maintained at 37 °C in a 5 % CO2 atmosphere of 95% humidity.
[043] In vitro evaluation of the cytotoxic effects related to the examined compound (6) was undertaken using the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay, as previously reported. Cells were plated at seeding density of 1x104 cells per well in 96-well plates and incubated for about 24 hours for attachment. The examined compound (6) was applied in three triplicates of each concentration and was evaluated in three independent assays for a total of 9 replicates. Cells were incubated for about 48 hours at a temperature pf about 37 °C in a 5 % CO2 incubator. At the end of the treatment period, MTT assay was carried out where viable cell count was determined based on the quantity of formazan product, as verified by the absorbance at 490 nm.
[044] However, compound (6) did not show any growth reduction of human dermal fibroblast cells (IC50 >300, Table 2), thereby indicating the safety or tolerability of the test compound.
Table (2): In vitro COX-2 percentage inhibition results at six different concentration levels of compound 6 and Indomethacin, and their cytotoxicity against fibroblast cells).
Figure imgf000017_0001
[045] While embodiments of the present disclosure have been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various additions, omissions, and modifications can be made without departing from the spirit and scope thereof.
[046] In describing and claiming the present invention, the following terminology was used.
[047] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.
[048] As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a defacto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.
[049] Concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub- range is explicitly recited. For example, a numerical range of approximately 1 to approximately 4.5 should be interpreted to include not only the explicitly recited limits of 1 to approximately 4.5, but also to include individual numerals such as 2, 3, 4, and sub- ranges such as 1 to 3, 2 to 4, etc. The same principle applies to ranges reciting only one numerical value, such as "less than approximately 4.5," which should be interpreted to include all of the above-recited values and ranges. Further, such an interpretation should apply regardless of the breadth of the range or the characteristic being described.
[050] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the presently disclosed subject matter belongs. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the presently disclosed subject matter, representative methods, devices, and materials are now described.
[051] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter.
[052] As used herein, the term "about", when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.

Claims

CLAIMS What is claimed is:
1. A compound of the general Formula (I), or a salt thereof:
Figure imgf000020_0001
Formula (I) wherein n is 0, 1 , or 2;
Ri is selected from a group containing an H atom, (C1 - C4) alkyl, phenyl, p-substituted phenyl, benzyl, or p-substituted benzyl group; and
R2 is selected from a group including an H atom, (C1 - C4) alkyl, alkyl sulfonyl, aryl sulfonyl, p-substituted aryl sulfonyl, alkyl carbonamide, aryl carbonamie or p- substituted carbonamide group.
2. The compound of claim 1, wherein Ri is a benzyl group.
3. The compound of claim 2, wherein R2 is an aryl sulfonyl group.
4. A method for preparing the compound of claim 1, the method comprises the steps of: mixing cyclopentanone with powdered sulfur, malonitrile in ethanol to produce a first mixture; heating the first mixture; adding diethylamine dropwise to the heated first mixture with continuous stirring in order to produce a second mixture; cooling down the second mixture to room temperature and neutralizing it dropwise with HC1 till a brown solid precipitate is formed; collecting the brown solid precipitate, followed by filtering, drying, recrystallizing the collected precipitate using chloroform and methanol to obtain a first compound; dissolving the first compound in dioxane; adding benzonitrile and HC1 to the dioxane solution to produce a third mixture; cooling down the third mixture and neutralizing it dropwise with NaOH solution in ice till a second precipitate is formed; filtering, drying, and recrystallizing the second precipitate to obtain a second compound; dissolving the second compound in about pyridine to form a fourth mixture while stirring; adding benzenesufonyl chloride to the fourth mixture while stirring to form a fifth mixture; neutralizing the fifth mixture dropwise with HC1 in ice followed by treating the neutralized fifth mixture with water and extracting it with ethyl acetate; and collecting, drying and recrystallizing the ethyl acetate extract with chloroform and methanol to obtain a third compound.
5. A pharmaceutical composition including the compound of claim 1 and/or a pharmaceutically acceptable salt thereof and a pharmaceutical acceptable carrier and/or excipient.
6. The pharmaceutical composition of claim 5, as a selective inhibitor to COX-2 isoenzyme.
7. Use of the pharmaceutical composition of claim 5 for treating a microbial infection.
8. Use of the pharmaceutical composition of claim 5 as an anti-inflammatory agent for treating of pain.
9. Use of the pharmaceutical composition of claim 5 for treating inflammation and rheumatoid arthritis.
10. Use of the pharmaceutical composition of claim 5 for treating diabetes.
11. Use of the pharmaceutical composition of claim 5 for treating cancer.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7566721B2 (en) * 2005-08-08 2009-07-28 Osi Pharmaceuticals, Inc. Substituted thienol[2,3-d]pyrimidines as kinase inhibitors
US20130338095A1 (en) * 2010-10-19 2013-12-19 Elcelyx Therapeutics, Inc. Chemosensory Receptor Ligand-Based Therapies

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7566721B2 (en) * 2005-08-08 2009-07-28 Osi Pharmaceuticals, Inc. Substituted thienol[2,3-d]pyrimidines as kinase inhibitors
US20130338095A1 (en) * 2010-10-19 2013-12-19 Elcelyx Therapeutics, Inc. Chemosensory Receptor Ligand-Based Therapies

Non-Patent Citations (1)

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Title
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