Claims:We Claim:
1. A Compound having the Formula (I):

(I)
wherein,
Z is selected from or
R1, is selected from selected from hydrogen, substituted or unsubstituted (C1-C3)alkyl and (C1-C6)haloalkyl;
R2, selected from hydrogen, substituted or unsubstituted (C1-C3)alkyl and (C1-C6)haloalkyl;
R3, selected from hydrogen, substituted or unsubstituted (C1-C3)alkyl, (C1-C6)haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycle;
R4, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, substituted or unsubstituted (C1-C3)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -X-C(O)-Y, -OR9, -NR10R11, -NR13C(O)R9, -S(O)2NR10R11 and –NR13S(O)2R12;
R5 is hydrogen or substituted or unsubstituted (C1-C3)alkyl;
R6 is selected from hydrogen, substituted or unsubstituted (C1-C3)alkyl and substituted or unsubstituted (C3-C7)cycloalkyl;
R7, is from hydrogen or substituted or unsubstituted (C1-C3)alkyl;
R8, is from hydrogen or substituted or unsubstituted (C1-C3)alkyl;
at each occurrence X is selected from a bond, -(CRaRb)1-3-, -NH- and -O-(CRaRb)1-3-;
Ra and Rb, which may be same or different at each occurrence, is independently selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted (C1-C3)alkyl and substituted or unsubstituted (C3-C7)cycloalkyl;
Y is –OR9 or –NR10R11;
R9 is selected from hydrogen, substituted or unsubstituted (C1-C3)alkyl, substituted or unsubstituted (C1-C6)alkoxyalkyl and substituted or unsubstituted (C3-C7)cycloalkyl;
R10 and R11, which may be same or different at each occurrence, is independently selected from hydrogen, substituted or unsubstituted (C1-C3)alkyl and substituted or unsubstituted (C3-C7)cycloalkyl;
R12 is selected from substituted or unsubstituted (C1-C3)alkyl, substituted or unsubstituted (C3-C7)cycloalkyl and substituted or unsubstituted (C6-C10)aryl;
R13 is hydrogen or substituted or unsubstituted (C1-C3)alkyl; and
‘m’ is integer ranging from 0 to 3, both inclusive;
or a pharmaceutically acceptable salt thereof.

2. The Compound of claim 1 having Formula (II):

(II)
or a pharmaceutically acceptable salt thereof;
wherein,
R1, R2, R3, R4, R5 and ‘m’ are as defined in claim-1.
3. The Compound of claim 1 having the Formula (III):

(III)
or a pharmaceutically acceptable salt thereof;
wherein,
R1, R2, R3, R4, R6, R7, R8 and ‘m’ are as defined in claim-1
4. The Compounds of claim 1 wherein Z is
or ;
R5 is hydrogen or substituted or unsubstituted (C1-C3)alkyl; R6 is selected from hydrogen, substituted or unsubstituted (C1-C3)alkyl and substituted or unsubstituted (C3-C7)cycloalkyl; R7, is from hydrogen or substituted or unsubstituted (C1-C3)alkyl; and R8, is from hydrogen or substituted or unsubstituted (C1-C3)alkyl.
5. The Compounds of claim 1 wherein, R1 is hydrogen, substituted or unsubstituted (C1-C3)alkyl and (C1-C6)haloalkyl.
6. The Compounds of claim 1 wherein R1 hydrogen, substituted or unsubstituted (C1-C3)alkyl and (C1-C6)haloalkyl.
7. The Compounds of claim 1 wherein R3, is hydrogen, substituted or unsubstituted (C1-C3)alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocycle.
8. The Compounds of claim 1 wherein R4, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, substituted or unsubstituted (C1-C3)alkyl and (C1-C6)haloalkyl; and ‘m’ is 0 or1 or 2.
9. A compound of which is selected from:
(E)-1-(2,5-Dimethylfuran-3-yl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)prop-2-en-1-one;
(E)-3-(3-(5-Bromothiophen-2-yl)-1-(4-fluorophenyl)-1H-pyrazol-4-yl)-1-(2,5-dimethylfuran-3-yl) prop-2-en-1-one;
(E)-3-(3-(5-Bromothiophen-2-yl)-1-phenyl-1H-pyrazol-4-yl)-1-(2,5-dimethylfuran-3-yl)prop-2-en-1-one;
(E)-1-(2,5-Dimethylfuran-3-yl)-3-(1-phenyl-3-(thiophen-2-yl)-1H-pyrazol-4-yl)prop-2-en-1-one;
4-(4,5-Dihydro-3-(2,5-dimethylfuran-3-yl)-1H-pyrazol-5-yl)-1,3-diphenyl-1H-pyrazole;
3-(5-Bromothiophen-2-yl)-1-(4-fluorophenyl)-4-(4,5-dihydro-3-(2,5-dimethylfuran-3-yl)-1H-pyrazol-5-yl)-1H-pyrazole;
3-(5-Bromothiophen-2-yl)-4-(4,5-dihydro-3-(2,5-dimethylfuran-3-yl)-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazole; and
4-(4,5-Dihydro-3-(2,5-dimethylfuran-3-yl)-1H-pyrazol-5-yl)-1-phenyl-3-(thiophen-2-yl)-1H-pyrazole or
a pharmaceutical acceptable salts thereof.
10. A Pharmaceutical composition comprising compounds of claim 1 and one or more pharmaceutical acceptable excipients.
11. A method of treating, malaria in a subject in need thereof wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to claim 1 or pharmaceutically acceptable salts thereof.

Dated this 9th day of May 2020
, Description:Field of Invention
The present invention relates to Pyrazolyl compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions for the treatment of malaria.
Background of Invention
A parasitic disease like malaria is among the most important disease. Four species of Plasmodium protozoan parasites are generally responsible for malaria, including Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae, and Plasmodium ovale. Of the four, Plasmodium falciparum is the most dangerous, accounting for half of all clinical cases of malaria and 90% of deaths from the disease.
The transmission of malaria begins when a female mosquito bites a human already infected with the malaria parasite. When the infected mosquito bites another human, sporozoites in the mosquito's saliva are transferred into the blood, which then travel to the liver. In the liver, the sporozoites divide rapidly, then enter the bloodstream where they invade red blood cells. Inside these blood cells, the merozoites multiply rapidly until they cause the red blood cells to burst, releasing into the blood stream a new generation of merozoites that then infect other red blood cells. The treatment of malaria has been especially difficult due to the ability of malaria parasites to develop resistance to drugs. The most effective known drugs against the diseases have many side effects for which reason it is not possible to maintain the treatment or prophylaxis of diseases for years. Malaria remains serious diseases despite the efforts to control the diseases and reduce their prevalence by vector eradication and drug treatment. Thus, the invention is related to compounds having anti-malarial activities. Chalcone is a natural pigment found in plant and is an important intermediate for the synthesis of flavonoids. Pyrazole compounds are known to possess various pharmacological activities. The present invention is related to pyrazolyl compounds as antimalarial agent.
A1Summary of Invention
In accordance with one aspect the invention provides compounds having the structure of Formula (I),

(I)
wherein,
Z is selected from or
R1, is selected from selected from hydrogen, substituted or unsubstituted (C1-C3)alkyl and (C1-C6)haloalkyl;
R2, selected from hydrogen, substituted or unsubstituted (C1-C3)alkyl and (C1-C6)haloalkyl;
R3, selected from hydrogen, substituted or unsubstituted (C1-C3)alkyl, (C1-C6)haloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycle;
R4, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, substituted or unsubstituted (C1-C3)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, -X-C(O)-Y, -OR9, -NR10R11, -NR13C(O)R9, -S(O)2NR10R11 and –NR13S(O)2R12;
R5 is hydrogen or substituted or unsubstituted (C1-C3)alkyl;
R6 is selected from hydrogen, substituted or unsubstituted (C1-C3)alkyl and substituted or unsubstituted (C3-C7)cycloalkyl;
R7, is from hydrogen or substituted or unsubstituted (C1-C3)alkyl;
R8, is from hydrogen or substituted or unsubstituted (C1-C3)alkyl;
at each occurrence X is selected from a bond, -(CRaRb)1-3-, -NH- and -O-(CRaRb)1-3-;
Ra and Rb, which may be same or different at each occurrence, is independently selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted (C1-C3)alkyl and substituted or unsubstituted (C3-C7)cycloalkyl;
Y is –OR9 or –NR10R11;
R9 is selected from hydrogen, substituted or unsubstituted (C1-C3)alkyl, substituted or unsubstituted (C1-C6)alkoxyalkyl and substituted or unsubstituted (C3-C7)cycloalkyl;
R10 and R11, which may be same or different at each occurrence, is independently selected from hydrogen, substituted or unsubstituted (C1-C3)alkyl and substituted or unsubstituted (C3-C7)cycloalkyl;
R12 is selected from substituted or unsubstituted (C1-C3)alkyl, substituted or unsubstituted (C3-C7)cycloalkyl and substituted or unsubstituted (C6-C10)aryl;
R13 is hydrogen or substituted or unsubstituted (C1-C3)alkyl; and
‘m’ is integer ranging from 0 to 3, both inclusive;
or a pharmaceutically acceptable salt thereof.
The details of one or more embodiments of the invention set forth in below are only illustrative in nature and not intended to limit the scope of the invention. Other features, objects and advantages of the invention will be apparent from the description and claims.
In certain embodiments, Z is or .
In certain embodiments, R1, is hydrogen, substituted or unsubstituted (C1-C3)alkyl and (C1-C6)haloalkyl.
In certain embodiments, R2, is hydrogen, substituted or unsubstituted (C1-C3)alkyl and (C1-C6)haloalkyl.
In certain embodiments, R3, is hydrogen, substituted or unsubstituted (C1-C3)alkyl, Substituted or Unsubstituted aryl, Substituted or Unsubstituted heterocycle e.g. and .
In certain embodiments, R4, which may be same or different at each occurrence, is independently selected from the group consisting of halogen, substituted or unsubstituted (C1-C3)alkyl and (C1-C6)haloalkyl; and ‘m’ is 0 or 1 or 2.
In certain embodiments, R5 is hydrogen or substituted or unsubstituted (C1-C3)alkyl;
In certain embodiments, R6 is hydrogen, substituted or unsubstituted (C1-C3)alkyl, and substituted or unsubstituted (C3-C7)cycloalkyl;
According to one embodiment, the invention provides compounds having the structures of formula (II)

(II)
or a pharmaceutically acceptable salt thereof;
wherein,
R1, R2, R3, R4, R5 and ‘m’ are as described herein above.
According to another embodiment, the invention provides compounds having the structures of formula (III)

(III)
or a pharmaceutically acceptable salt thereof;
wherein,
R1, R2, R3, R4, R6, R7, R8 and ‘m’ are as described herein above.
According to another embodiment, there are provided compounds of Formula (I) to Formula (III) wherein the compound is a pharmaceutically acceptable salt.
According to another embodiment, the provided compounds of Formula (I) to Formula (III) structurally encompass stereoisomers including enantiomers and diastereomers.
The Examples given herein are the representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention.
In another aspect of the invention, there is provided a compound of Formula (I) to Formula (III) or a pharmaceutically acceptable salt thereof for use as a medicament.
In another aspect of the invention, there is provided a compound of Formula (I) to Formula (III) or a pharmaceutically acceptable salt thereof for use in treatment of malaria.
In another aspect, the invention provides a pharmaceutical composition comprising at least one compound of Formula (I) to Formula (III) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
In another aspect of the invention, there is provided use of a compound of Formula (I) to Formula (III) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament.
Detailed description of the invention
Definitions and Abbreviations:
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below.
For purposes of interpreting the specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.
The terms "halogen" or "halo" means fluorine, chlorine, bromine, or iodine.
The term "alkyl" refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molecule by a single bond, for example (C1-C6)alkyl or (C1-C4)alkyl, representative groups include e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1, 1 -dimethylethyl (t-butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched.
The term "alkenyl" refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Non-limiting Examples of alkenyl groups include, for example (C2-C6)alkenyl, (C2-C4)alkenyl, ethenyl, 1-propenyl, 2-propenyl (allyl), zso-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched.
The term "alkynyl" refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon- carbon triple bond. Non- limiting Examples of alkynyl groups include, for example (C2-C6)alkynyl, (C2-C4)alkynyl, ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched.
The term "alkoxy" refers to an alkyl group attached via an oxygen linkage. Non-limiting Examples of such groups include, for example (C1-C6)alkoxy,(C1-C4)alkoxy, methoxy, ethoxy and propoxy and the like. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.
The term "alkoxyalkyl" refers to an alkoxy group as defined above directly bonded to an alkyl group as defined above, for example (C1-C6)alkoxy-(C1-C6)alkyl,(C1-C4)alkoxy-(C1-C4)alkyl., -CH2-0-CH3, -CH2-0-CH2CH3, -CH2CH2-0-CH3 and the like.
The term "hydroxyalkyl" refers to an alkyl group, as defined above that is substituted by one or more hydroxy groups. Preferably, the hydroxyalkyl is monohydroxyalkyl or dihydroxyalkyl. Non-limiting examples of a hydroxyalkyl include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and the like.
The term "haloalkyl" refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above. For example (C1-C6)haloalkyl or (C1-C4)haloalkyl. Suitably, the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodine, bromine, chlorine or fluorine atom. Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms. Suitably, a polyhaloalkyl is substituted with up to 12 halogen atoms. Non-limiting Examples of a haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. A perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms. Unless set forth or recited to the contrary, all haloalkyl groups described or claimed herein may be straight chain or branched.
The term "cycloalkyl" refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, such as (C3-C10)cycloalkyl, (C3-C6)cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of multicycliccycloalkyl groups include, but are not limited to, perhydronaphththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl and the like.
The term "aryl" refers to an aromatic radical having 6- to 14- carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl and the like.
The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H4C6H5.
The term "heterocyclic ring" or "heterocyclyl ring" or "heterocyclyl", unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consists of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S. The heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bonds), and one or two carbon atoms in the heterocyclic ring or heterocyclyl may be interrupted with -CF2-, -C(O)-, -S(O)-, S(0)2 etc. In addition, heterocyclic ring may also be fused with aromatic ring. Non-limiting Examples of heterocyclic rings include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfoneindoline, benzodioxole, tetrahydroquinoline, tetrahydrobenzopyran and the like. The heterocyclic ring may be attached by any atom of the heterocyclic ring that results in the creation of a stable structure.
The term "heteroaryl" unless otherwise specified, refers to a substituted or unsubstituted 5- to 14- membered aromatic heterocyclic ring with one or more heteroatom independently selected from N, O or S. The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring may be attached by any atom of the heteroaryl ring that results in the creation of a stable structure. Non-limiting Examples of a heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazohnyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like.
Unless otherwise specified, the term "substituted" as used herein refers to a group or moiety having one or more substituents attached to the structural skeleton of the group or moiety; such substituents include, but are not limited to hydroxy, halogen, carboxyl, cyano, nitro, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, aryl(Ci-C6)alkyl, (C3-C7)cycloalkyl, heteroaryl, heterocyclic ring, heterocyclyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, -C(0)ORx, -C(0)Rx, -C(S)RX, -C(0)NRxRy, -NRxC(0)NRyRz, -NRxRy, -NRxC(0)Ry, - S(0)2NRxRy, -ORx, -OC(0)Rx, -OC(0)NRxRy, RxC(0)Ry, -SRX, and -S(0)2Rx; wherein each occurrence of Rx, Ry and Rz are independently selected from hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C7)cycloalkyl and aryl.
It is to be understood that the aforementioned "substituted" groups cannot be further substituted. For Example, when the substituent on "substituted alkyl" is "aryl" or "alkenyl", the aryl or alkenyl cannot be substituted aryl or substituted alkenyl respectively.
The compounds of the present invention may have one or more chiral centers. The absolute stereochemistry at each chiral center may be 'R' or 'S'. The compounds of the invention include all diastereomers and enantiomers and mixtures thereof. Unless specifically mentioned otherwise, reference to one stereoisomer applies to any of the possible stereoisomers. Whenever the stereoisomeric composition is unspecified, it is to be understood that all possible stereoisomers are included.
The term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" refers to stereoisomers which are not enantiomers. The terms "racemate" or "racemic mixture" refer to a mixture of equal parts of enantiomers.
A "tautomer" refers to a compound that undergoes rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula (I).
The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease, disorder, syndrome or condition, is sufficient to cause the effect in the subject which is the purpose of the administration. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
Pharmaceutically Acceptable Salts:
The compounds of the invention may form salts with acid or base. The compounds of invention may be sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic acid addition salts formed by addition of acids including hydrochloride salts. Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic base addition salts formed by addition of bases. The compounds of the invention may also form salts with amino acids. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for Example by reacting sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
Pharmaceutical Compositions:
The invention relates to pharmaceutical compositions containing the compounds of the Formula (I), or pharmaceutically acceptable salts thereof disclosed herein. In particular, pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula (I), Formula (II) and Formula (III) described herein and at least one pharmaceutically acceptable excipient (such as a carrier or diluent).
The subjects contemplated include, for example, a living cell and a mammal, including human mammal. The compound of the invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. The pharmaceutically acceptable excipient includes pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
Examples of suitable carriers or excipients include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
The pharmaceutical compositions described herein may be prepared by conventional techniques known in the art. For Example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for Example, in a sachet.
The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, caplets, orally disintegrating tablets, aerosols, solutions, suspensions or products for topical application.
The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
Solid oral Formulations include, but are not limited to, tablets, caplets, capsules (soft or hard gelatin), orally disintegrating tablets, dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Liquid Formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as pocketed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, caplet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
For administration to subject patients, the total daily dose of the compounds of the invention depends, of course, on the mode of administration. For example, oral administration may require a higher total daily dose, than an intravenous (direct into blood).
Suitable doses of the compounds for use in treatment described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in subject based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects for the patient.
Methods of Treatment
It is to be understood that the invention encompasses any of the compounds of Formulae (I), (II) and (III), or pharmaceutically acceptable salts thereof for use in the treatment or prevention of any of the conditions disclosed herein.
It is to be understood that the invention encompasses the use of any of the compounds of Formulae (I), (II) and (II), or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment or prevention of any of the conditions disclosed herein.
All of the patent, patent application and non-patent publications referred to in this specification are incorporated herein by reference in their entireties.
General Methods of Preparation
The compounds described herein may be prepared by techniques known in the art. In addition, the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme- 1. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the scope of the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the isomers of the compounds described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.

Scheme 1
A mixture of compound (a), compound (b) and 10% aqueous potassium hydroxide in ethanol was stirred at room temperature for 14 h. The process of completion of reaction was verified by TLC. Upon completion, the reaction mixture was poured into crushed ice and neutralized by using dilute hydrochloric acid (HCL). The precipitated solid was filtered, washed with water and dried. The product was crystallized from ethanol to get compound of Formula (II). The compound of formula (II) refluxed with hydrazine hydrate and glacial acetic acid for 6 hr. The mixture was then poured into crushed ice, filtered, dried and recrystallized from ethanol to obtained compound of Formula (III).
Example
Example 1: (E)-1-(2,5-Dimethylfuran-3-yl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)prop-2-en-1-one
A mixture of compound 1-(2,5-dimethylfuran-3-yl)ethanone and 1,3-diphenyl-1H-pyrazole-4-carbaldehyde stirred with 10% aqueous potassium hydroxide in ethanol to obtained Example 1. IR (? max, cm-1): 2921 (=C-H), 2855 (C-H), 1657 (C=O), 1454 (C=N); 1H-NMR (400 MHz, DMSO-d6, d, ppm): 9.31 (s, 1H, Pyrazole-H), 7.93 (d, 2H, J = 7.88 Hz), 7.38-7.68 (m, 10H, Ar-H), 6.60 (s, 1H, Furan-H), 2.53 (s, 3H, -CH3), 2.27 (s, 3H,-CH3); 13C NMR (100MHz, DMSO-d6, d, ppm): 184.41 (C=O), 159.89, 152.77, 149.67, 138.96, 132.19, 132.00, 129.64, 128.81, 128.52, 128.64, 128.40, 127.07, 123.83, 122.10, 118.63, 117.63, 105.91, 13.93 (CH3), 12.89 (CH3); MS (ESI-MS): m/z 369.11 (M+H)+.
Example 2: (E)-3-(3-(5-Bromothiophen-2-yl)-1-(4-fluorophenyl)-1H-pyrazol-4-yl)-1-(2,5-dimethylfuran-3-yl) prop-2-en-1-one
A mixture of compound 1-(2,5-dimethylfuran-3-yl)ethanone and 3-(5-bromothiophen-2-yl)-1-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde stirred with 10% aqueous potassium hydroxide in ethanol to obtained Example 2. IR (? max, cm-1): 2923 (=C-H), 2856 (C-H), 1656 (C=O), 1455 (C=N); 1H-NMR (400 MHz, DMSO-d6, d, ppm): 9.25 (s, 1H, Pyrazole-H), 7.90 (dd, 2H, J = 4.72 & 9.04 Hz, Ar-H), 7.64 (d, 1H, J = 15.44 Hz, olefinic-H), 7.39-7.45 (m, 3H, Ar-H), 7.34 (d, 1H, J = 3.88 Hz, Ar-H), 7.25 (d, 1H, J = 3.88 Hz, Ar-H), 6.61 (S, 1H, Furan-H), 2.55 (s, 3H, -CH3), 2.28 (s, 3H, -CH3); 13C NMR (100 MHz, DMSO-d6, d, ppm): 184.20, 162.04, 159.61, 157.05, 149.68, 145.65, 135.38, 135.13, 131.36, 130.83, 128.89, 127.26, 124.59, 122.01, 120.74, 120.60, 117.34, 116.55, 116.32, 112.47, 105.86, 13.95, 12.88; MS (ESI-MS): m/z 472.89 (M+H)+.
Example 3: (E)-3-(3-(5-Bromothiophen-2-yl)-1-phenyl-1H-pyrazol-4-yl)-1-(2,5-dimethylfuran-3-yl)prop-2-en-1-one
A mixture of compound 1-(2,5-dimethylfuran-3-yl)ethanone and 3-(5-bromothiophen-2-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde stirred with 10% aqueous potassium hydroxide in ethanol to obtained Example 3. IR (? max, cm-1): 2921 (=C-H), 2855 (C-H), 1699 (C=O), 1454 (C=N); 1H-NMR (400 MHz, DMSO-d6, d, ppm): 9.14 (s,1H, Pyrazole-H), 7.87 (d, 2H, J = 7.84 Hz, Ar-H), 7.70 (d, 1H, J = 15 Hz, olefinic-H), 7.52 (t, 2H, J = 8Hz, Ar-H), 7.36-7.40 (m, 2H, Ar-H), 7.20 (s, 2H, Ar-H), 6.55 (s, 1H, Furan-H), 2.57 (s, 3H,-CH3), 2.29 (s, 3H, -CH3); 13C NMR (100 MHz, DMSO-d6, d, ppm): 184.27, 157.06, 149.70, 145.67, 138.55, 135.47, 131.40, 130.92, 129.66, 128.79, 127.32, 127.29, 124.64, 122.04, 118.64, 117.35, 112.46, 105.90, 13.96, 12.89; MS(ESI-MS): m/z 454.57 (M+H)+.
Example 4: (E)-1-(2,5-Dimethylfuran-3-yl)-3-(1-phenyl-3-(thiophen-2-yl)-1H-pyrazol-4-yl)prop-2-en-1-one
A mixture of compound 1-(2,5-dimethylfuran-3-yl)ethanone and 1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4-carbaldehyde stirred with 10% aqueous potassium hydroxide in ethanol to obtained Example 4. IR (?max, cm-1): 2921 (=C-H), 2715 (C-H), 1652 (C=O), 1456 (C=N); 1H-NMR (400 MHz, DMSO-d6, d, ppm): 8.56 (s, 1H, Pyrazole-H), 7.91 (d, 2H, J = 7.84 Hz, Ar-H), 7.76 (d, 1H, J = 15.44 Hz, olefinic-H), 7.60 (d, 1H, J = 5.08 Hz, Ar-H), 7.54 (t, 2H, J = 8.24 Hz, Ar-H), 7.35-7.44 (m, 3H, Ar-H), 7.21 (dd, 1H, J = 5.04 & 3.72 Hz, Ar-H), 6.59 (s, 1H, Furan-H), 2.57 (s, 3H,-CH3), 2.29 (s, 3H, -CH3); 13C NMR (100MHz, DMSO-d6, d, ppm): 184.37, 157.01, 149.72, 146.84, 138.70, 133.46, 131.49, 129.68, 128.65, 128.10, 127.27, 127.22, 126.76, 124.32, 122.08, 118.63, 117.40, 105.97, 13.97, 12.90; MS(ESI-MS): m/z 375.10 (M+H)+.
Example 5: 4-(4,5-Dihydro-3-(2,5-dimethylfuran-3-yl)-1H-pyrazol-5-yl)-1,3-diphenyl-1H-pyrazole
Example 1 refluxed with hydrazine hydrate in presence of ethanol and glacial acetic acid to obtained Example 5. IR (?max, cm-1): 3306 (N-H), 3049 (Ar-H), 1592 (C=N); 1H-NMR (400 MHz, DMSO-d6, d, ppm): 8.56 (s, 1H, pyrazole-H), 7.90 (d, 2H, J = 7.8 Hz, Ar-H), 7.76 (d, 2H, J = 8.36 Hz, Ar-H), 7.47-7.52 (m, 4H, Ar-H), 7.41 (t, 1H, J = 7.28 Hz, Ar-H), 7.31 (t, 1H, J = 7.4 Hz, Ar-H), 7.20 (s, 1H, N-H), 6.19 (s, 1H, furan-H), 4.87 (t, 1H, J = 10.68 Hz, pyrazoline-H), 3.34 (dd, 1H, J = 10.54 & 15.64 Hz, pyrazoline-H), 2.88 (dd, 1H, J = 11.08 & 16.12 Hz, pyrazoline-H), 2.38 (s, 3H, CH3), 2.20 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, d, ppm): 150.42, 149.30, 147.59, 145.05, 139.46, 132.95, 129.51, 128.56, 127.94, 127.24, 126.17, 123.16, 118.12, 115.17, 105.87, 54.67, 41.97, 13.27, 12.96; MS (ESI-MS): m/z 383.04 (M+H)+.
Example 6: 3-(5-Bromothiophen-2-yl)-1-(4-fluorophenyl)-4-(4,5-dihydro-3-(2,5-dimethylfuran-3-yl)-1H-pyrazol-5-yl)-1H-pyrazole
Example 2 refluxed with hydrazine hydrate in presence of ethanol and glacial acetic acid to obtained Example 6. IR (? max, cm-1): 3310 (N-H), 3046 (Ar-H), 1594 (C=N); 1H NMR (400 MHz, DMSO-d6, d, ppm): 8.54 (s, 1H, pyrazole–H), 7.88 (m, 2H, Ar-H), 7.35 (t, 2H, J =8.72 Hz, Ar-H), 7.28 (dd, 2H, J = 3.84 Hz, Ar-H), 7.21 (s, 1H, N-H), 6.20 (s, 1H, furan-H), 4.93 (t, 1H, J = 10.68 Hz, pyrazoline-H), 3.37 (dd, 1H, J = 10.68 & 16.48 Hz, pyrazoline-H), 2.86 (dd, 1H, J = 10.96 & 16.12 Hz, pyrazoline-H), 2.38 (s, 3H, CH3), 2.20 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, d, ppm): 161.55, 159.13, 149.34, 147.70, 145.26, 144.06, 136.88, 135.62,131.18, 128.02, 126.57, 122.58, 120.24, 120.16, 116.42, 116.19, 115.07, 111.45, 105.88, 54.31, 41.13, 13.29, 12.96; MS (ESI-MS): m/z 486.93 (M+H)+.
Example 7: 3-(5-Bromothiophen-2-yl)-4-(4,5-dihydro-3-(2,5-dimethylfuran-3-yl)-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazole
Example 3 refluxed with hydrazine hydrate in presence of ethanol and glacial acetic acid to obtained Example 7. IR (? max, cm-1): 3303 (N-H), 3096 (Ar-H), 1593 (C=N), 1H NMR (400 MHz, DMSO-d6, d, ppm): 8.55 (s, 1H, pyrazole-H), 7.84 (d, 2H, J = 7.88 Hz, Ar-H), 7.51 (t, 2H, J = 7.6 Hz, Ar-H), 7.22-7.34 (m, 4H, Ar-H), 6.20 (s, 1H, furan-H), 4.94 (t, 1H, J = 10.6 Hz, pyrazoline-H), 3.38 (m, 1H, pyrazoline-H), 2.88 (dd, 1H, J = 12.12 & 16.08 Hz, pyrazoline-H), 2.39 (s, 3H, CH3), 2.20 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, d, ppm): 149.33, 147.69, 145.22, 144.03, 139.00, 137.01, 131.18, 129.58, 127.82, 126.56, 126.46, 122.53, 118.04, 115.09, 111.42, 105.89, 54.36, 41.11, 13.29, 12.97; MS (ESI-MS): m/z 468.95 (M+H)+ .
Example 8: 4-(4,5-Dihydro-3-(2,5-dimethylfuran-3-yl)-1H-pyrazol-5-yl)-1-phenyl-3-(thiophen-2-yl)-1H-pyrazole
Example 4 refluxed with hydrazine hydrate in presence of ethanol and glacial acetic acid to obtained Example 8. IR (? max, cm-1): 3336 (N-H), 3067 (Ar-H), 1501 (C=N); 1H NMR (400 MHz, DMSO-d6, d, ppm): 8.53 (s, 1H, pyrazole-H), 7.86 (d, 1H, J = 8 Hz, Ar-H), 7.58 (d, 1H, J = 4.96 Hz, Ar-H), 7.47-7.52 (m, 3H, Ar-H), 7.31 (t, 1H, J = 7.32 Hz, Ar-H), 7.15-7.20 (m, 2H, Ar-H), 6.21 (s, 1H, furan-H), 4.98 (t, 1H, J = 10.48 Hz, pyrazoline-H), 3.42 (m, 1H, pyrazoline-H), 2.89 (dd, 1H, J = 10.68 & 16.08 Hz, pyrazoline-H), 2.39 (s, 3H, CH3), 2.20 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, d, ppm): 149.33, 147.65, 145.11, 144.93, 139.16, 135.00, 129.55, 127.91, 127.42, 126.27, 126.00, 125.84, 122.60, 118.08, 115.13, 105.88, 54.53, 41.32, 13.29, 12.97; MS (ESI-MS): m/z 389.03 (M+H)+ .
Example 9: Pharmacological Activity
In vitro Antimalarial Screening
The in vitro antimalarial assay was carried out according to the microassay protocol of Rieckmann and co-workers with minor modifications. The results were recorded as the minimum inhibitory concentrations (MIC) (Table –1). Chloroquine and quinine were used as the reference drug.
Table-1: Antimalarial activity: (Minimum Inhibitory concentration in microgram/ mL)
Compound Plasmodium falciparum
(IC50 µg/ml)
1 0.54 µg/mL
2 1.86 µg/mL
3 0.98 µg/mL
4 1.15 µg/mL
5 2.42 µg/mL
6 0.23 µg/mL
7 0.10 µg/mL
8 0.25 µg/mL
Chloroquine 0.020 µg/mL
quinine 0.268 µg/mL