NOVEL BIS (HYDROXY BENZYLIDENE) CYCLIC KETONE BASED TETRA-AZA CORAND

Abstract

A tetra-aza corand compound of formula (Ia) and compound of formula (Ib) and salts thereof. The tetra-aza corand of formula (Ia) and (Ib) of the present invention relates to novel corand entity having a substantially enclosed volume and a framework structure, the compounds are designed as therapeutic carriers for molecule therapeutics delivery and pharmaceutical compositions thereof.

Claims

1) A tetra-aza corand compound of formula (Ia); ##STR00020## Wherein, R.sub.1=—C.sub.1-C.sub.3 alkyl, —CH.sub.2NH— R.sub.2=—H, —CF.sub.3, C.sub.1-C.sub.4 alkyl, Halogen, haloalkyl, alkoxy R.sub.3=—H, C.sub.1-C.sub.10 alkyl, R.sub.4=—C.sub.1-C.sub.3 alkyl.

2) The tetra-aza corand as claimed in claim 1 wherein, method of preparing the tetra-aza corand compound of formula (Ia) comprises reaction of compound of formula-1 with cycloalkane-1,2-diamine ##STR00021## Wherein, R1=—C1-C3 alkyl, —CH2NH— R2=—H, —CF3, C1-C4 alkyl, Halogen, haloalkyl, alkoxy R3=—H, C1-C10 alkyl

3) The tetra-aza corand as claimed in claim 1 wherein, tetra-aza corand compound of formula (Ia) in isomeric form (1R, 2R) tetra-aza corand of formula (Ia′) ##STR00022## Wherein, R.sub.1=—C.sub.1-C.sub.3 alkyl, —CH.sub.2NH— R.sub.2=—H, —CF.sub.3, C.sub.1-C.sub.4 alkyl, Halogen, haloalkyl, alkoxy R.sub.3=—H, C.sub.1-C.sub.10 alkyl, R.sub.4=—C.sub.1-C.sub.3 alkyl.

4) The tetra-aza corand as claimed in claim 1 wherein, tetra-aza corand compound of formula (Ia) in isomeric form (1S, 2S) tetra-aza corand of formula (Ia″) ##STR00023## Wherein, R.sub.1=—C.sub.1-C.sub.3 alkyl, —CH.sub.2NH— R.sub.2=—H, —CF.sub.3, C.sub.1-C.sub.4 alkyl, Halogen, haloalkyl, alkoxy R.sub.3=—H, C.sub.1-C.sub.10 alkyl, R.sub.4=—C.sub.1-C.sub.3 alkyl.

5) A tetra-aza corand compound of formula (Ib); ##STR00024## Wherein, R.sub.1=—C.sub.1-C.sub.3 alkyl, —CH.sub.2NH— R.sub.2=—H, —CF.sub.3, C.sub.1-C.sub.4 alkyl, Halogen, haloalkyl, alkoxy R.sub.3=—H, C.sub.1-C.sub.10 alkyl, R.sub.4=—C.sub.1-C.sub.3 alkyl.

6) The tetra-aza corand as claimed in claim 1 wherein, tetra-aza corand compound of formula (Ib) in isomeric form is (1S, 2S) tetra-aza corand of formula (Ib′) ##STR00025## Wherein, R.sub.1=—C.sub.1-C.sub.3 alkyl, —CH.sub.2NH— R.sub.2=—H, —CF.sub.3, C.sub.1-C.sub.4 alkyl, Halogen, haloalkyl, alkoxy R.sub.3=—H, C.sub.1-C.sub.10 alkyl, R.sub.4=—C.sub.1-C.sub.3 alkyl.

7) The tetra-aza corand as claimed in claim 1 wherein, tetra-aza corand compound of formula (Ib) in isomeric form is (1S, 2S) tetra-aza corand of formula (Ib″) ##STR00026## Wherein, R.sub.1=—C.sub.1-C.sub.3 alkyl, —CH.sub.2NH— R.sub.2=—H, —CF.sub.3, C.sub.1-C.sub.4 alkyl, Halogen, haloalkyl, alkoxy R.sub.3=—H, C.sub.1-C.sub.10 alkyl, R.sub.4=—C.sub.1-C.sub.3 alkyl.

8) (canceled)

9) (canceled)

10) (canceled)

11) The tetra-aza corand as claimed in claim 1 wherein, method of preparing the tetra-aza corand compound of formula (Ib) comprises reduction of tetraimino corand compound of formula (Ia); ##STR00027## Wherein, R.sub.1=—C.sub.1-C.sub.3 alkyl, —CH.sub.2NH— R.sub.2=—H, —CF.sub.3, C.sub.1-C.sub.4 alkyl, Halogen, haloalkyl, alkoxy R.sub.3=—H, C.sub.1-C.sub.10 alkyl, R.sub.4=C.sub.1-C.sub.3 alkyl. in presences of mild reducing agent.

12) The tetra-aza corand as claimed in claim 11 wherein, reducing agent is Sodiumtriacetoxyborohydride/sodiumcyanoborohydride.

13) The tetra-aza corand as claimed in claim 1 wherein, Salts of corand of formula (Ic): ##STR00028## Wherein, R.sub.1=, C.sub.1-C.sub.3 alkyl, —CH.sub.2NH— R.sub.2=—H, —CF.sub.3, C.sub.1-C.sub.4 alkyl, Halogen, haloalkyl, alkoxy R.sub.3=—H, C.sub.1-C.sub.10 alkyl, R.sub.4=C.sub.1-C.sub.3 alkyl. X.sup.−=Folate, chloride, acetate.

14) The tetra-aza corand as claimed in claim 13 wherein, therapeutic agents are selected from group, Flutamide, Nilutamide, Gemcitabine, Methotrexate, Cis-platin, or Dasatinib.

15) The tetra-aza corand as claimed in claim 1 wherein, tetra-aza corand are attached to therapeutic agent by any non-covalent interaction including H bonding or ion-ion interaction or charge transfer interactions.

16) The tetra-aza corand as claimed in claim 1 wherein, the therapeutic agents are selected from group Flutamide, Nilutamide, Gemcitabine, Methotrexate Cis-platin, or Dasatinib.

17) The tetra-aza corand as claimed in claim 1 wherein, tetra-aza corand compound of formula (Ia) is attached to therapeutic agent by any non-covalent interaction including H bonding or ion-ion interaction or charge transfer interactions.

18) The tetra-aza corand as claimed in claim 1 wherein, therapeutic agent is cleaved from tetra-aza corand compound of formula (Ia) under acidic pH conditions or basic pH conditions or the change in temperature or by cell enzymes to release the therapeutic agents.

19) The tetra-aza corand as claimed in claim 8 wherein, the therapeutic agents are selected from group Flutamide, Nilutamide, Gemcitabine, Methotrexate Cis-platin, or Dasatinib.

20) The tetra-aza corand as claimed in claim 8 wherein, tetra-aza corand compound of formula (Ia) is attached to therapeutic agent by any non-covalent interaction including H bonding or ion-ion interaction or charge transfer interactions.

21) The tetra-aza corand as claimed in claim 8 wherein, therapeutic agent is cleaved from tetra-aza corand compound of formula (Ia) under acidic pH conditions or basic pH conditions or the change in temperature or by cell enzymes to release the therapeutic agents.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0062] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several examples of the disclosed subject matter and together with the description, serve to explain certain principles of the disclosed subject matter.

[0063] FIG. 1 NMR Titration to understand the interaction between the tetra iminocorand-3 and the drug Niluamide. FIG. 1a, 1b are expansions of FIG. 1

[0064] FIG. 2 NMR Titration to understand the interaction between the tetra amino corand-7 and the drug Gemcitabin. FIG. 2a, 2b are expansions of FIG. 2

[0065] FIG. 3 NMR Titration to understand the interaction between the tetra amino corand-7 and the drug Dasatinib. FIG. 3a, 3b are expansions of FIG. 1

[0066] FIG. 4 NMR Titration to understand the interaction between the tetra amino corand-7 and the drug Flutamide. FIG. 4a, 4b, 4c, 4d are expansions of FIG. 4

[0067] FIG. 5 NMR Titration to understand the interaction between the tetra amino corand-7 and the drug Nilutamide. FIG. 5a are expansions of FIG. 5

[0068] FIG. 6 NMR Titration to understand the interaction between the tetra amino folate corand and the drug Gemcitabin. FIG. 6a, 6b, 6c are expansions of FIG. 6

[0069] FIG. 7 NMR Titration to understand the interaction between the tetra amino folate corand and the drug Dasatinib. FIG. 7a, 7b are expansions of FIG. 7.

[0070] FIG. 8 NMR Titration to understand the interaction between the tetra amino corand-7 and the drug Capecitabine. a) Expansion of downfield region b) Expansion of Up-field region c) Complete NMR spectra

[0071] FIG. 9 Cumulative release of capecitabine at pH 7.4 and pH 5.5 from inclusion complex of tetra amino corand-7 with methotrexate

DETAILED DESCRIPTION OF THE INVENTION

[0072] The compounds, compositions, articles, devices, and methods described herein can be understood more readily by reference to the following detailed description of specific aspects of the disclosed subject matter and the Examples and Figures.

[0073] Likewise, many modifications and other embodiments of the compositions and methods described herein will come to mind to one of skill in the art to which the invention pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the invention is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0074] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art to which the invention pertains. Although any methods and materials similar to or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described herein.

[0075] Moreover, reference to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one element is present, unless the context clearly requires that there be one and only one element. The indefinite article “a” or “an” thus usually means “at least one.”

[0076] As used herein, “about” means within a statistically meaningful range of a value or values such as a stated concentration, length, molecular weight, pH, sequence identity, time frame, temperature or volume. Such a value or range can be within an order of magnitude, typically within 20%, more typically within 10%, and even more typically within 5% of a given value or range. The allowable variation encompassed by “about” will depend upon the particular system under study, and can be readily appreciated by one of skill in the art.

[0077] The term “pharmaceutically acceptable” as used herein includes reference to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. This term includes acceptability for both human and veterinary purposes.

[0078] The term “corands” refers to monocyclic compounds which contain electron donor atoms or acceptor atoms, which are electron rich or deficient, and which are capable of complexing with particular cations or anions or neutral molecule because of their unique structures. Because of the unique sizes and geometries of particular corands, they are adaptable to complexing with various ions or molecules.

[0079] The term “therapeutic/bioactive agents” is drugs such as Flutamide, Nilutamide, Gemcitabin, Dasatinib, Methotrexate, Cis-platin are intended to be coupled/attached non-covalently to corand of formula (Ia) and formula (Ib) as carriers for therapeutics drug delivery complexes. The therapeutic/bioactive agents can also be a drug molecule, which is intended to include both non-peptides and peptides.

[0080] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C.sub.1-C.sub.10 means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term “alkyl,” unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below, such as “heteroalkyl.” Alkyl groups that are limited to hydrocarbon groups are termed “homoalkyl”.

[0081] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C.sub.1-C.sub.4) alkyl” is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0082] Each of the above terms (e.g., “alkyl,” and “haloalkyl”) are meant to include both substituted and unsubstituted forms.

[0083] The present invention a tetra-aza corand of formula (Ia) and formula (Ib) i.e monocyclic macrocycle corands. The novel tetra-aza corand of formula (Ia) and formula (Ib) with cavity walls made up of bis-hydroxybenzylidene cyclic ketone and tetra imine/amine moieties. The novel tetra-aza corand of formula (Ia) and formula (Ib) has the properties somewhat similar to calixarene molecules. The novel tetra-aza corand of formula (Ia) and formula (Ib) encapsulate various drug molecules, further derivatisations by attachment of different functional groups to the proposed corands is done.

[0084] The tetra-aza corand of formula (Ia) and formula (Ib) are converted into their folate salts in order to develop a targeted drug delivery system. Cancer cells have folate receptors over expressed on their cell membrane where the folate salts of corands with the encapsulated drug are expected to be preferentially driven. The approach will deliver the drug to the tumor cells leaving the healthy cells unaffected.

[0085] The therapeutic/bioactive agents are attached to tetra-aza corand of formula (Ia) and formula (Ib) via non-covalent interaction. The therapeutic/bioactive agents may be attached to oligomer via an optional non-covalent interaction prior to the macromolecular complex step, or may be subsequently grafted onto the macromolecular complex via an optional non-covalent interaction, or may be attached to the macromolecular complex as an inclusion complex or host-guest interactions.

[0086] The present invention includes all salt forms of those molecules that contain ionisable functional groups, such as basic and acidic groups. The term “pharmaceutically acceptable salts” includes salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogen phosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, folic, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al., Journal of Pharmaceutical Science, 66: 1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0087] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.

[0088] The present invention relates to tetra-aza corand of formula (Ia) and formula (Ib) made up of bis-hydroxybenzylidene cyclic ketone moiety having a substantially enclosed volume and a framework structure, the compounds are designed as therapeutic carriers for molecule therapeutics delivery and pharmaceutical compositions thereof

##STR00012##

[0089] Wherein, [0090] R.sub.1=, C.sub.1-C.sub.3 alkyl, —CH.sub.2NH— [0091] R.sub.2=—H, —CF.sub.3, C.sub.1-C.sub.4 alkyl, Halogen, haloalkyl, alkoxy [0092] R.sub.3=—H, C.sub.1-C.sub.10 alkyl, [0093] R.sub.4=C.sub.1-C.sub.3 alkyl.

[0094] According to one embodiment of the present invention isomers of tetra-aza corand of formula (Ia) are (1R, 2R) tetra-aza corand of formula (Ia′) and (1S, 2S) tetra-aza corand of formula (Ia″) made up of bis-hydroxybenzylidene cyclic ketone moiety having a substantially enclosed volume and a framework structure, the compounds are designed as therapeutic carriers for molecule therapeutics delivery and pharmaceutical compositions thereof

##STR00013##

[0095] Wherein, [0096] R.sub.1=, C.sub.1-C.sub.3 alkyl, —CH.sub.2NH— [0097] R.sub.2=—H, —CF.sub.3, C.sub.1-C.sub.4 alkyl, Halogen, haloalkyl, alkoxy [0098] R.sub.3=—H, C.sub.1-C.sub.10 alkyl, [0099] R.sub.4=C.sub.1-C.sub.3 alkyl.

[0100] According to one embodiment of the present invention isomers of tetra-aza corand of formula (Ib) are (1R, 2R) tetra-aza corand of formula (Ib′) and (1S, 2S) tetra-aza corand of formula (Ib″) made up of bis-hydroxybenzylidene cyclic ketone moiety having a substantially enclosed volume and a framework structure, the compounds are designed as therapeutic carriers for molecule therapeutics delivery and pharmaceutical compositions thereof

##STR00014##

[0101] Wherein, [0102] R.sub.1=, C.sub.1-C.sub.3 alkyl, —CH.sub.2NH— [0103] R.sub.2=—H, —CF.sub.3, C.sub.1-C.sub.4 alkyl, Halogen, haloalkyl, alkoxy [0104] R.sub.3=—H, C.sub.1-C.sub.10 alkyl, [0105] R.sub.4=C.sub.1-C.sub.3 alkyl.

[0106] According to one embodiment of the present invention isomers of tetra-aza corand of formula (Ia) Racemic isomer comprises of

##STR00015##

[0107] According to one embodiment of the present invention isomers of tetra-aza corand of formula (Ib) Racemic isomer comprises of

##STR00016##

[0108] According to one embodiment of the present invention tetra-aza corand of formula (Ia) and formula (Ib) having a substantially enclosed volume and a framework structure, the compounds are designed as therapeutic carriers for molecule therapeutics delivery and pharmaceutical compounds such as Flutamide, Nilutamide, Gemcitabine, Methotrexate, Cis-platin, Bicalutamide, Topilutamide, Oxaliplatin, Carboplatin, Busulfan that were dissolved into various solvents like Dichloromethane, Ethanol, Methanol, Dimethyl formamide, Dimethyl sulphoxide, Ether, Toluene, Anisole, Trifluoroacetic acid, Benzene, Water.

[0109] According to one embodiment of the present invention the tetra-aza corand of formula (Ia) and formula (Ib) made up of bis-hydroxybenzylidene cyclic ketone moiety wherein therapeutic molecule is attached to the macrocycle compound of formula (Ia) or Formula (Ib) by non-covalent interaction. The corand may also employ targeting agents. By selecting from a variety of linker groups and targeting ligands the corand present methods for controlled delivery of the therapeutic agents. On reaching a targeted site in the body of a patient, the therapeutic molecule can then be cleaved onto the site. The methods provide reduced toxicity and local delivery of therapeutics. The invention also relates to methods of treating subjects with the therapeutic compositions described herein. The invention further relates to methods for conducting a pharmaceutical business comprising manufacturing, licensing, or distributing kits containing or relating to the polymeric compounds described herein.

[0110] In one embodiment, the reactive functional group is a member selected from amines, such as a primary or secondary amine, hydrazines, hydrazides, and sulfonyl hydrazides. Amines can, for example, be acylated, alkylated or oxidized. Useful non-limiting examples of amino-reactive groups include N-hydroxysuccinimide (NHS) esters, sulfo-NHS esters, imidoesters, isocyanates, isothiocyanates, acyl halides, arylazides, p-nitrophenyl esters, aldehydes, sulfonyl chlorides and carboxyl groups.

[0111] According to one embodiment of the present invention the corand of Formula (Ia) and Formula (Ib) wherein therapeutic molecule is attached to the corand of Formula (Ia) or Formula (Ib) by non-covalent interaction; H bonding; ion-ion interaction or charge transfer between corand and therapeutic molecule.

[0112] According to one embodiment of the present invention the tetra-aza corand of formula (Ia) and formula (Ib) are prepared by bis-hydroxybenzylidene cyclic ketone moiety of formula (I). The compound of formula (I) is reacted a cycloalkane-1,2-diamine to obtain tetra-aza corand of formula (Ia) and formula (Ib).

##STR00017##

[0113] Wherein, [0114] R.sub.1=, C.sub.1-C.sub.3 alkyl, —CH.sub.2NH— [0115] R.sub.2=—H, —CF.sub.3, C.sub.1-C.sub.4 alkyl, Halogen, haloalkyl, alkoxy [0116] R.sub.3=—H, C.sub.1-C.sub.10 alkyl,

[0117] According to one embodiment of the present invention process for preparation of corand of formula (Ia)

##STR00018##

[0118] Wherein, [0119] R.sub.1=, C.sub.1-C.sub.3 alkyl, —CH.sub.2NH— [0120] R.sub.2=—H, —CF.sub.3, C.sub.1-C.sub.4 alkyl, Halogen, haloalkyl, alkoxy [0121] R.sub.3=—H, C.sub.1-C.sub.10 alkyl, [0122] R.sub.4=C.sub.1-C.sub.3 alkyl.

Example 1: Process for Synthesis of Corand (Ia)

[0123] 2 L DCM was placed in a 5 L 3-necked round bottom flask equipped with 2 dropping funnels. One dropping funnel contained (0.003327 moles) of (1R, 2R)-cycloalkane-1,2-diamine dissolved in 750 ml of DCM and another dropping funnel contained (0.0028 moles) of 5,5′-((1E,1′E)-(2-oxocyclicketone-1,3-diylidene)bis(methanylylidene))bis(2-hydroxybenzaldehyde) or its derivatives dissolved in 750 ml of DCM. Both solutions were added drop wise to mechanically stirred 2 L DCM over 7 to 8 hours. The reaction mixture was concentrated to 100 ml and kept for 12 to 15 hours at room temperature to obtain orange crystalline product. The crystallined product was filtered and dried in vacuum oven to obtain free flowing product.

Example 2: Process for Synthesis of Tetra Iminocorand-1

[0124] 2 L DCM was placed in a 5 L 3-necked round bottom flask equipped with 2 dropping funnels. One dropping funnel contained (0.331 g, 0.00331 moles) of (1R,2R)-cyclopentane-1,2-diamine dissolved in 750 ml of DCM and another dropping funnel contained (1 g, 0.00276 moles) of 5,5′-((1E,1′E)-(2-oxocyclohexane-1,3-diylidene)bis(methanylylidene))bis(2-hydroxybenzaldehyde) dissolved in 750 ml of DCM. Both solutions were added drop wise to mechanically stirred 2 L DCM over 7 to 8 hours. The reaction mixture was concentrated to 100 ml and kept for 12 to 15 hours at room temperature to obtain orange crystalline product in 68% yield.

Example 3: Process for Synthesis of Tetra Iminocorand-1′

[0125] 2 L DCM was placed in a 5 L 3-necked round bottom flask equipped with 2 dropping funnels. One dropping funnel contained (0.378 g, 0.0033 moles) of (1S,2S)-cyclohexane-1,2-diamine dissolved in 750 ml of DCM and another dropping funnel contained (1 g, 0.0027 moles) of 5,5′-((1E,1′E)-(2-oxocyclohexane-1,3-diylidene)bis(methanylylidene))bis(2-hydroxybenzaldehyde) dissolved in 750 ml of DCM. Both solutions were added drop wise to mechanically stirred 2 L DCM over 7 to 8 hours. The reaction mixture was concentrated to 100 ml and kept for 12 to 15 hours at room temperature to obtain orange crystalline product in 60% yield.

Example 4: Process for Synthesis of Tetra Iminocorand-1″

[0126] 2 L DCM was placed in a 5 L 3-necked round bottom flask equipped with 2 dropping funnels. One dropping funnel contained (0.378 g, 0.0033 moles) of Trans-cyclohexane-1,2-diamine dissolved in 750 ml of DCM and another dropping funnel contained (1 g, 0.0027 moles) of 5,5′-((1E,1′E)-(2-oxocyclohexane-1,3-diylidene)bis(methanylylidene))bis(2-hydroxybenzaldehyde) dissolved in 750 ml of DCM. Both solutions were added drop wise to mechanically stirred 2 L DCM over 7 to 8 hours. The reaction mixture was concentrated to 100 ml and kept for 12 to 15 hours at room temperature to obtain orange product as mixture of three isomers in 52% yield.

Example 5: Process for Synthesis of Tetra Iminocorand-2

[0127] 2 L DCM was placed in a 5 L 3-necked round bottom flask equipped with 2 dropping funnels. One dropping funnel contained (0.23 g, 0.0023 moles) of (1R,2R)-cyclopentane-1,2-diamine dissolved in 750 ml of DCM and another dropping funnel contained (1 g, 0.0019 moles) of 5,5′-((1E,1′E)-(2-oxocyclohexane-1,3-diylidene)bis(methanylylidene))bis(3-bromo-2-hydroxybenzaldehyde) dissolved in 750 ml of DCM. Both solutions were added drop wise to mechanically stirred 2 L DCM over 7 to 8 hours. The reaction mixture was concentrated to 100 ml and kept for 12 to 15 hours at room temperature to obtain orange crystalline product in 52% yield.

Example 6: Process for Synthesis of Tetra Iminocorand-3

[0128] 2 L DCM was placed in a 5 L 3-necked round bottom flask equipped with 2 dropping funnels. One dropping funnel contained (0.378 g, 0.0033 moles) of (1R,2R)-cyclohexane-1,2-diamine dissolved in 750 ml of DCM and another dropping funnel contained (1 g, 0.0027 moles) of 5,5′-((1E,1′E)-(2-oxocyclohexane-1,3-diylidene)bis(methanylylidene))bis(2-hydroxybenzaldehyde) dissolved in 750 ml of DCM. Both solutions were added drop wise to mechanically stirred 2 L DCM over 7 to 8 hours. The reaction mixture was concentrated to 100 ml and kept for 12 to 15 hours at room temperature to obtain orange crystalline product in 75% yield.

Example 7: Process for Synthesis of Tetra Iminocorand-4

[0129] 2 L DCM was placed in a 5 L 3-necked round bottom flask equipped with 2 dropping funnels. One dropping funnel contained (0.26 g, 0.0023 moles) of (1R,2R)-cyclohexane-1,2-diamine dissolved in 750 ml of DCM and another dropping funnel contained (1 g, 0.0019 moles) of 5,5′-((1E,1′E)-(2-oxocyclohexane-1,3-diylidene)bis(methanylylidene))bis(3-bromo-2-hydroxybenzaldehyde) dissolved in 750 ml of DCM. Both solutions were added drop wise to mechanically stirred 2 L DCM over 7 to 8 hours. The reaction mixture was concentrated to 100 ml and kept for 12 to 15 hours at room temperature to obtain orange crystalline product in 40% yield.

Example 8: Drug Encapsulation Study with the Above Synthesized Tetraiminocorand NMR Titration

[0130] -NMR titrations were recorded on 400 MHz Bruker instrument to study the encapsulation of drug in the corand. 0.6 ml 1×10.sup.−2M solution of standard drugs (Flutamide, Nilutamideetc) were prepared in CDCl.sub.3 and placed in the NMR tubes. NMR titrations were carried out by adding 30 μl, 2×10.sup.−2M solution of tetraiminocorand.

[0131] FIG. 1 NMR Titration to understand the interaction between the tetra iminocorand-3 and the drug Niluamide. The NMR titration experiment revealed complete encapsulation of drug Niluamide in the tetra iminocorand-3. In case of Niluamide the double doublet of aromatic proton at 8.078 δ was shifted upfield at 8.075δ. The doublet of aromatic proton at 8.211δ and 8.325 δ was shifted upfield at 8.206δ and 8.322 δ.

Example 9: Process for Synthesis of Corand (Ib)

[0132] The tetra iminocorand-(Ia) (0.001135 moles) was dissolved in 20 ml DCM (Dichloromethane) and 50 ml methanol. Added sodiumtriacetoxyborohydride (0.0090 moles) to magnetically stirred solution of tetra imino corand. The solution was stirred for 30 minutes. Methanol was evaporated under vacuum completely. Residue was quenched in liquor ammonia and extracted with DCM. The DCM layer was dried over sodium sulphate and evaporated to obtain the desired product. The formed tetra amino corand was dried under high vacuum to obtain red free flowing solid.

Example 8: Process for Synthesis of Tetra Amino Corand-5

[0133] The tetra iminocorand-1 (1 g, 0.00117 moles) was dissolved in 10 ml DCM (Dichloromethane) and 50 ml methanol. Added sodiumtriacetoxyborohydride (1.98 g, 0.0094 moles) to magnetically stirred solution of tetra iminocorand-1. The solution was stirred for 30 minutes. Methanol was evaporated under vacuum completely. Residue was quenched in liquor ammonia and extracted with DCM. The DCM layer was dried over sodium sulphate and evaporated to obtain the desired product. The formed tetra amino corand-5 was dried under high vacuum to obtain red free flowing solid in 80% yield.

Example 9: Process for Synthesis of Tetra Amino Corand-5′

[0134] The tetra iminocorand-1′ (1 g, 0.001135 moles) was dissolved in 10 ml DCM (Dichloromethane) and 50 ml methanol. Added sodiumtriacetoxyborohydride (1.98 g, 0.0094 moles) to magnetically stirred solution of tetra iminocorand-5. The solution was stirred for 30 minutes. Methanol was evaporated under vacuum completely. Residue was quenched in liquor ammonia and extracted with DCM. The DCM layer was dried over sodium sulphate and evaporated to obtain the desired product. The formed tetra amino corand-5′ was dried under high vacuum to obtain red free flowing solid in 64% yield.

Example 10: Process for Synthesis of Tetra Amino Corand-5″

[0135] The mixture of isomers of tetra iminocorand-1″ (1 g, 0.001135 moles) was dissolved in 10 ml DCM (Dichloromethane) and 50 ml methanol. Added sodiumtriacetoxyborohydride (1.925 g, 0.00908 moles) to magnetically stirred solution of tetra iminocorand-6. The solution was stirred for 30 minutes. Methanol was evaporated under vacuum completely. Residue was quenched in liquor ammonia and extracted with DCM. The DCM layer was dried over sodium sulphate and evaporated to obtain the desired product. The formed mixture of isomers of tetra amino corand-5″ was dried under high vacuum to obtain red free flowing solid in 50% yield.

Example 11: Process for Synthesis of Tetraaminocorand-6

[0136] The tetra iminocorand-2 (1 g, 0.000855 moles) was dissolved in 10 ml DCM (Dichloromethane) and 50 ml methanol. Added sodiumtriacetoxyborohydride (1.45 g, 0.0068 moles) to magnetically stirred solution of tetraiminocorand-2. The solution was stirred for 30 minutes. Methanol was evaporated under vacuum completely. Residue was quenched in liquor ammonia and extracted with DCM. The DCM layer was dried over sodium sulphate and evaporated to obtain the desired product. The formed tetra amino corand-6 was dried under high vacuum to obtain red free flowing solid in 85% yield.

Example 12: Process for Synthesis of Tetra Amino Corand-7

[0137] The tetra iminocorand-3 (1 g, 0.001135 moles) was dissolved in 10 ml DCM (Dichloromethane) and 50 ml methanol. Added sodiumtriacetoxyborohydride (1.925 g, 0.00908 moles) to magnetically stirred solution of tetraiminocorand-3. The solution was stirred for 30 minutes. Methanol was evaporated under vacuum completely. Residue was quenched in liquor ammonia and extracted with DCM. The DCM layer was dried over sodium sulphate and evaporated to obtain the desired product. The formed tetra amino corand-7 was dried under high vacuum to obtain red free flowing solid in 76% yield.

Example 13: Process for Synthesis of Tetra Amino Corand-8

[0138] The tetra iminocorand-4 (1 g, 0.000835 moles) was dissolved in 10 ml DCM (Dichloromethane) and 50 ml methanol. Added sodiumtriacetoxyborohydride (1.416 g, 0.00668 moles) to magnetically stirred solution of tetraiminocorand-4. The solution was stirred for 30 minutes. Methanol was evaporated under vacuum completely. Residue was quenched in liquor ammonia and extracted with DCM. The DCM layer was dried over sodium sulphate and evaporated to obtain the desired product. The formed tetra amino corand-8 was dried under high vacuum to obtain red free flowing solid in 73% yield.

Example 14: Drug Encapsulation Study with the Above Synthesized Tetra Amino Corand

[0139] NMR titration: -NMR titrations were recorded on 400 MHz Bruker instrument to study the encapsulation of drug in the corand. 0.6 ml 1×10.sup.−2M solution of standard drugs (Flutamide, Nilutamide, Gemcitabin, Dasatinibetc) were prepared in DMSO-d.sub.6 and placed in the NMR tubes. NMR titrations were carried out by adding 30 μl, 2×10.sup.−2M solution of tetra aminocorand.

[0140] FIG. 2, NMR Titration to understand the interaction between the tetra amino corand-7 and the drug Gemcitabin. The NMR titration experiment revealed complete encapsulation of drug in the tetra amino corand-7. In case of Gemcitabin the signal of aliphatic OH group at 9.728δ and 8.672δ were shifted upfield to 8.15δ and 7.952δ respectively. The doublet of aromatic proton at 8.113 and 6.19 was shifted to upfield 7.828 δ and 5.898 δ respectively. The triplet of aliphatic proton at 6.088 δ was shifted dowfield to 6.119 δ

[0141] FIG. 3, NMR Titration to understand the interaction between the tetra amino corand-7 and the drug Dasatinib. The NMR titration experiment revealed complete encapsulation of drug in the tetra amino corand-7. In case of Dasatinib the singlet of aromatic proton at 8.220 δ was shifted upfield to 8.218δ. The singlet of secondary amine at 9.867δ was shifted to downfield at 9.887δ.

[0142] FIG. 4, NMR Titration to understand the interaction between the tetra amino corand-7 and the drug Flutamide. The NMR titration experiment revealed complete encapsulation of drug in the tetra amino corand-7. In case of Flutamide the signal of aromatic doublet at 8.311δ and 8.199δ were shifted to 8.313δ and 8.196δ respectively. The singlet of secondary amide group at 10.650 δ was shifted downfield to 10.680δ. The doublet of methyl proton at 1.138δ was shifted upfield to 1.136δ. FIG. 5, NMR Titration to understand the interaction between the tetra amino corand-7 and the drug Nilutamide. The NMR titration experiment revealed complete encapsulation of drug in the tetra amino corand-7. In case of Nilutamide the double doublet of aromatic proton at 8.328δ and doublet at 8.2135 δ was shifted upfield to 8.322 δ and 8.209 δ.

[0143] According to One Embodiment of the Present Invention Process for Preparation of Salts of Corand of Formula (Ic):

##STR00019##

[0144] Wherein, [0145] R.sub.1=, C.sub.1-C.sub.3 alkyl, —CH.sub.2NH— [0146] R.sub.2=—H, —CF.sub.3, C.sub.1-C.sub.4 alkyl, Halogen, haloalkyl, alkoxy [0147] R.sub.3=—H, C.sub.1-C.sub.10 alkyl, [0148] R.sub.4=C.sub.1-C.sub.3 alkyl. [0149] X.sup.−=Folate, chloride, acetate

Example 15: General Process for Formation of Folate Salt

[0150] The solution of folic acid (0.001125 moles) dissolved in N, N-Dimethylformamid (5 ml) was added dropwise to the solution of tetraaminocorand dissolved in N, N-Dimethylformamide (5 ml). The folate salt gets precipitated instantly. The precipitates were filtered, washed with the N, N-Dimethylformamide, methanol, dichloromethane and dried under vacuum. The free flowing salt was obtained.

Example 16: Process for Formation of Folate Salt of Tetraaminocorand-5

[0151] The solution of folic acid (0.001162 moles, 0.512 g) dissolved in N, N-Dimethylformamid (5 ml) was added dropwise to the solution of tetraaminocorand-5 (0.500 g) dissolved in N, N-Dimethylformamide (5 ml). The folate salt gets precipitated instantly. The precipitates were filtered, washed with the N, N-Dimethylformamide, methanol, dichloromethane and dried under vacuum. The free flowing salt was obtained with 68% yield.

Example 17: Process for Formation of Folate Salt of Tetraaminocorand-6

[0152] The solution of folic acid (0.00085 moles, 0.375 g) dissolved in N, N-Dimethylformamid (5 ml) was added dropwise to the solution of tetraaminocorand-6 (0.500 g) dissolved in N, N-Dimethylformamide (5 ml). The folate salt gets precipitated instantly. The precipitates were filtered, washed with the N, N-Dimethylformamide, methanol, dichloromethane and dried under vacuum. The free flowing salt was obtained with 67% yield.

Example 18: Process for Formation of Folate Salt of Tetra Aminocorand-7

[0153] The solution of folic acid (0.001125 moles, 0.49680 g) dissolved in N, N-Dimethylformamide (5 ml) was added dropwise to the solution of tetraaminocorand-7 (0.500 g) dissolved in N, N-Dimethylformamide (5 ml). The folate salt gets precipitated instantly. The precipitates were filtered, washed with the N, N-Dimethylformamide, methanol, dichloromethane and dried under vacuum. The free flowing salt was obtained with 70% yield.

Example 19: Process for Formation of Folate Salt of Tetraaminocorand-8

[0154] The solution of folic acid (0.00083 moles, 0.366 g) dissolved in N, N-Dimethylformamid (5 ml) was added dropwise to the solution of tetraaminocorand-8 (0.500 g) dissolved in N, N-Dimethylformamide (5 ml). The folate salt gets precipitated instantly. The precipitates were filtered, washed with the N, N-Dimethylformamide, methanol, dichloromethane and dried under vacuum. The free flowing salt was obtained with 66% yield.

Example 20: Process for Formation of Hydrochloride Salt

[0155] The solution of tetraaminocorand (0.00056 moles) was dissolved in methanol (25 ml). HCl gas was passed for around 10 minutes to precipitate out the hydrochloride salt. The salt was filtered, washed with the methanol followed by dichloromethane and dried under vacuum. The free flowing salt was obtained.

Example 21: Process for Formation of Hydrochloride Salt of Tetraaminocorand-5

[0156] The solution of tetraaminocorand-5 (0.00058 moles, 0.500 g) was dissolved in methanol (25 ml). HCl gas was passed for around 10 minutes to precipitate out the hydrochloride salt.

[0157] The salt was filtered, washed with the methanol followed by dichloromethane and dried under vacuum. The free flowing salt was obtained with 64% yield.

Example 22: Process for Formation of Hydrochloride Salt of Tetraaminocorand-6

[0158] The solution of tetraaminocorand-6 (0.000424 moles, 0.500 g) was dissolved in methanol (25 ml). HCl gas was passed for around 10 minutes to precipitate out the hydrochloride salt. The salt was filtered, washed with the methanol followed by dichloromethane and dried under vacuum. The free flowing salt was obtained with 63% yield.

Example 23: Process for Formation of Hydrochloride Salt of Tetraaminocorand-7

[0159] The solution of tetraaminocorand-7 (0.00056 moles, 0.500 g) was dissolved in methanol (25 ml). HCl gas was passed for around 10 minutes to precipitate out the hydrochloride salt. The salt was filtered, washed with the methanol followed by dichloromethane and dried under vacuum. The free flowing salt was obtained with 62% yield.

Example 24: Process for Formation of Hydrochloride Salt of Tetraaminocorand-8

[0160] The solution of tetraaminocorand-8 (0.000415 moles, 0.500 g) was dissolved in methanol (25 ml). HCl gas was passed for around 10 minutes to precipitate out the hydrochloride salt. The salt was filtered, washed with the methanol followed by dichloromethane and dried under vacuum. The free flowing salt was obtained with 60% yield.

Example 25: General Process for Formation of Acetate Salt

[0161] The solution of tetra-aminocorand (0.00056 moles) was dissolved in methanol (25 ml). Acetic acid was added drop wise. The reaction mixture was stirred for 4 h at 30-40° C. The products, which were obtained after removal of methanol, was washed with the methanol followed by dichloromethane and dried under vacuum. The free flowing salt was obtained.

Example 26: Process for Formation of Acetate Salt of Tetraaminocorand-5

[0162] The solution of tetraaminocorand-5 (0.00058 moles, 0.500 g) was dissolved in methanol (25 ml). Acetic acid (0.00116 moles) was added drop wise. The reaction mixture was stirred for 4 h at 30-40° C. The products, which were obtained after removal of methanol, was washed with the methanol followed by dichloromethane and dried under vacuum. The free flowing salt was obtained with 70% yield.

Example 27: Process for Formation of Acetate Salt of Tetraaminocorand-6

[0163] The solution of tetraaminocorand-6 (0.000424 moles, 0.500 g) was dissolved in methanol (25 ml). Acetic acid (0.000848 moles) was added drop wise. The reaction mixture was stirred for 4 h at 30-40° C. The products, which were obtained after removal of methanol, was washed with the methanol followed by dichloromethane and dried under vacuum. The free flowing salt was obtained with 73% yield.

Example 28: Process for Formation of Acetate Salt of Tetraaminocorand-7

[0164] The solution of tetraaminocorand-7 (0.00056 moles, 0.500 g) was dissolved in methanol (25 ml). Acetic acid (0.00112 moles) was added drop wise. The reaction mixture was stirred for 4 h at 30-40° C. The products, which were obtained after removal of methanol was washed with the methanol followed by dichloromethane and dried under vacuum. The free flowing salt was obtained with 80% yield.

Example 29: Process for Formation of Acetate Salt of Tetraaminocorand-8

[0165] The solution of tetraaminocorand-8 (0.000415 moles, 0.500 g) was dissolved in methanol (25 ml). Acetic acid (0.00083 moles) was added drop wise. The reaction mixture was stirred for 4 h at 30-40° C. The products, which were obtained after removal of methanol, was washed with the methanol followed by dichloromethane and dried under vacuum. The free flowing salt was obtained with 78% yield.

Example 30: Drug Encapsulation Study with the Above Synthesized Salts of Tetra Amino Corand

[0166] NMR titration: -NMR titrations were recorded on 400 MHz Bruker instrument to study the encapsulation of drug in the folate salt of corand. 0.6 ml 1×10.sup.−2M solution of standard drugs (Gemcitabin, Dasatinibetc) were prepared in DMSO-d.sub.6 and placed in the NMR tubes. NMR titrations were carried out by adding 15 μl, 2×10.sup.−2M solution of folate salt of tetraaminocorand.

[0167] FIG. 6 NMR Titration to understand the interaction between the tetra amino folate corand and the drug Gemcitabin. The NMR titration experiment revealed complete encapsulation of drug in the tetra amino folate corand. In case of Gemcitabin the doublet of aromatic proton at 8.095δ and 6.164δ was shifted upfield to 7.691 δ and 5.786δ. The triplet of aliphatic proton was shifted down field from 6.092δ to 6.131δ. In case of Gemcitabin titration aliphatic e proton at 3.661 δ and 3.629δ were shifted upfield at 3.631δ and 3.601δ.

[0168] FIG. 7 NMR Titration to understand the interaction between the tetra amino folate corand and the drug Dasatinib. The NMR titration experiment revealed complete encapsulation of drug in the tetra amino folate corand. In case of Dasatinib the doublet of aromatic proton at 7.282δ and double doublet at 7.402δ were shifted upfield to 7.278δ and 7.396δ respectively The singlet of secondary amine at 9.867 δ was shifted downfield at 9.877δ.

Example 31: Drug Encapsulation Study with the Above Synthesized Tetra Amino Corand-5′

[0169] NMR titration: -NMR titrations were recorded on 400 MHz Bruker instrument to study the encapsulation of drug in the folate salt of corand. 0.6 ml 1×10.sup.−2M solution of standard drugs (Gemcitabin, Dasatinibetc) were prepared in DMSO-d.sub.6 and placed in the NMR tubes. NMR titrations were carried out by adding 15 μl, 2×10.sup.−2M solution of tetra amino corand-5′.

[0170] FIG. 8 NMR Titration to understand the interaction between the tetra amino corand-5′ and the drug Capecitabine. a) Expansion of downfield region b) Expansion of Up-field region c) Complete NMR spectra

[0171] The cumulative release of methotrexate inclusion complex with tetra amino corand-5′ was studied in phosphate buffer at pH 7.4 and pH 5.5. The result reveals sustained release of methotrexate. The result also suggests that the release is more at pH 5.5 as compare to pH 7.7.

[0172] FIG. 9 Cumulative release of capecitabine at pH 7.4 and pH 5.5 from inclusion complex of tetra amino corand-5′ with methotrexate

[0173] Drug Binding Modes of Corands:

[0174] The corands will bind the drug molecules due to steric and interactional complementarity. The —OH (phenolic), —HC═N-(imino)/-NH-(Secondary amino) and —C═O (cyclic ketone) group will be responsible for making hydrogen bonding with the drug molecules. The benzylidene cyclic ketone group is also capable of establishing charge transfer interaction with the suitable drug molecule and making the stable host-guest complex.