# Patent

## Title
Thieno[2,3-D]-pyrimidin-4(3H)-one compounds with antifungal properties and process thereof

## Abstract

The present invention discloses novel compounds of the Formula (1), containing thieno-[2,3-d]pyrimidin-4(3H)-one moieties and pharmaceutically acceptable salts thereof, methods for preparing these compounds, the use of these compounds in prevention and treatment of fungal infections, and pharmaceutical preparations containing these novel compounds.

## Background
TECHNICAL FIELD
The present invention relates to novel compounds of the Formula (1), containing thieno-[2,3-d]pyrimidin-4(3H)-ones moieties and pharmaceutically acceptable salts thereof, methods for preparing these compounds, the use of these compounds in prevention and treatment of fungal infections, and to pharmaceutical preparations containing these novel compounds.
BACKGROUND AND PRIOR ART
Fungal infections are the major problem in the treatment of immuno-compromised patients and those suffering from AIDS. The current antifungal agents belong to various groups like polyenes, allylamines, antimetabolites, azoles, glucan synthesis inhibitors etc. Fluconazole is a member of the family of azole antifungals. Fluconazole is orally active and has low toxicity but its extensive use has resulted in emergence of fluconazole-resistant fungal strains. Therefore, it is necessary to meet the long-felt need to develop novel fluconazole analogues which exert high anti-fungal activity against various fungi including Candida albicans, Aspergillus niger and Fusarium proliferatum with MIC values 2 to 8 fold lower than that of fluconazole.
The presence of one triazole ring, halogenated phenyl ring and tertiary alcoholic oxygen functionality in fluconazole is necessary for activity. The present invention seeks to provide novel azoles and process thereof as an effort to come up with antifungal agents with broad spectrum of antifungal activity. Fluconazole analogues have been reported having antifungal activity in the literature.
A series of fluconazole analogues incorporating azaindole and indole moieties were described in “Synthesis and anti-fungal activities of new fluconazole analogues with azoheterocycle moiety”, Bioorg Med Chem Lett 2007 Jul. 1; 17(13), 3686-9.
OBJECTS OF THE INVENTION
The primary objective of the present invention is to provide compounds of Formula (1), containing thieno-[2,3-d]pyrimidin-4(3H)-one moieties with high anti-fungal activity against various fungi including C. albicans, Aspergillus. niger and F. proliferatum and the process for the preparation of said antifungal compounds.
SUMMARY OF THE INVENTION
Accordingly, to meet the above stated objective, the present invention discloses novel fluconazole analogues of Formula (1) containing thieno-[2,3-d]pyrimidin-4(3H)-one moieties, which are useful as antifungal compounds with MIC values 2 to 8 fold lower than that of fluconazole.
In one aspect, the invention provides novel compounds of formula (1), wherein, R1 is hydrogen or halogen selected from fluorine, chlorine, bromine or iodine;
R2 is hydrogen or halogen selected from fluorine, chlorine, bromine and iodine; and R3 and R4 which may be the same or different and each represents a hydrogen, alkyl group of linear or branched chain of 1 to 20 carbon atoms optionally substituted with aryl group, hydroxyl group, alkanoate group, acetoxy group, amino acetyloxy group, N-Boc-amino acetyloxy group, alkoxy(—OR) group (wherein R=alkyl group with 1 to 4 carbon atoms), benzyloxy, arylalkyl group (wherein the aryl group is phenyl which is either unsubstituted or substituted with alkyl group of 1 to 3 carbon atoms) or cycloalkyl group with 3 to 10 carbon atoms.




In another aspect, the invention provides a process for the preparation of the compounds of Formula (1) using various synthetic methods. Accordingly, the present invention describes a general process for the preparation of compounds of the Formula (1) wherein R1, R2, R3 and R4 are as defined above, which comprises reacting substituted 2-aminothiophene-3-carboxylates of the Formula (3) with formamide and ammonium acetate to collect the thienopyrimidinones of the Formula (4), followed by reacting the compounds of the Formula (4) with epoxide of the Formula (5) in presence of a suitable base to obtain the compounds of the Formula 1.
The said suitable base may be selected from various organic or inorganic bases well described in the art.
In yet another aspect, the invention discloses a pharmaceutical preparation which comprises a compound of formula (1) in association with at least one pharmaceutical excipient.


DETAILED DESCRIPTION
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
According to the present invention, there are provided novel antifungal compounds of Formula (1). These compounds are analogues of fluconazole that are active against fungi and used in pharmaceutical preparations as active agents.
In a preferred embodiment, there are provided the novel compounds of Formula 1,




wherein,

R1 is hydrogen, halogen selected from fluorine, chlorine, bromine or iodine;
R2 is hydrogen, halogen selected from fluorine, chlorine, bromine or iodine,
R3 and R4 which may the same or different and each represents a hydrogen, alkyl group of linear or branched chain of 1 to 20 carbon atoms optionally substituted with aryl group, hydroxyl group, alkanoate group, acetoxy group, amino acetyloxy group, N-Boc-amino acetyloxy group, alkoxy(—OR) group (wherein R=alkyl group with 1 to 4 carbon atoms), benzyloxy, arylalkyl group (wherein the aryl group is phenyl which is either unsubstituted or substituted with alkyl group of 1 to 3 carbon atoms) or cycloalkyl group with 3 to 10 carbon atoms.
The present invention encompasses all the novel compounds and their stereochemically isomeric forms or their pharmaceutically acceptable salts.
In another preferred embodiment, the invention describes process for preparation of the compounds of formula (1). The compounds of the present invention may be prepared by adapting the route depicted in Scheme 1. As depicted in Scheme 1, the compounds of Formula (3) are converted to the compounds of Formula (4), wherein R3 and R4 are as defined above. In a further step, the compounds of Formula (4) are converted to the compounds of Formula (1) by reacting with the compounds of Formula (5), wherein R1 is hydrogen or a halogen selected from fluorine, chlorine, bromine and iodine; R2 is hydrogen or a halogen selected from fluorine, chlorine, bromine and iodine.




Accordingly, the general process for the preparation of compounds of Formula 1, comprises steps of

    
    
        a) preparing 2-amino-4 and/or 5-substituted thiophene-3-carboxylate of formula (3), wherein R1 is methyl or ethyl; and R3 and R4 are as defined above by Gewald synthesis;
        b) contacting 2-amino-4 and/or 5-substituted thiophene-3-carboxylate of Formula (3) with formamide and ammonium acetate to obtain the thieno-[2,3-d]-pyrimidin-4(3H)-one of Formula (4), wherein R3 and R4 are as defined above, and
        c) treating the compound of Formula (4) with epoxide of Formula (5), wherein R1 and R2 are as defined above, in presence of a base to obtain the compound of Formula (1).
    
    


The said suitable base may be selected from various organic or inorganic bases well described in the art.
In another preferred embodiment, the invention discloses a pharmaceutical preparation which comprises a compound of formula (1) in association with at least one pharmaceutical excipient known in art.
The invention further provides a method for treating or preventing a fungal infection in a subject, which comprises administering an effective amount of the compound of formula (1) in association with pharmaceutical excipients.
The compounds of formula (1) can be conveniently administered to a patient in oral unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
Dosage forms include solid dosage forms like tablets, powders, capsules, sachets, troches and lozenges as well as liquid syrups, suspensions and elixirs. The active ingredient(s) and excipients can be formulated into compositions and dosage forms according to methods known in the art.
Accordingly, the compounds of formula (1) or their pharmaceutically acceptable salt can be milled into a powder and be used in a pharmaceutical product/composition or physically modified such as by granulation to produce larger granules. The compounds of formula (1) or their pharmaceutically acceptable salt can also be used to prepare a liquid pharmaceutical composition by dissolving or dispersing or suspending/emulsifying it in a pharmaceutically acceptable liquid medium such as water, glycerin, vegetable oil and the like as discussed in greater detail below.
When a dosage form such as a tablet is made by compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or to facilitate patient identification of the product and unit dosage level.
In liquid pharmaceutical compositions of the present invention, the compounds of formula (1) or their pharmaceutically acceptable salt and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin. Liquid pharmaceutical compositions can contain emulsifying agents to disperse an active ingredient or other excipient that is not soluble in the liquid carrier uniformly throughout the composition.
Selection of particular excipients and the amounts to use can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field. The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
The compounds of formula (1) or their pharmaceutical salt can also be used to prepare topical preparations such as shampoos, lotions, gels, foams, creams, transdermal patches and greasy ointments.
Still in another object, the use of the compounds of formula (1) for the preparation of medicament useful for the treatment or prevention of fungal infections is provided by the invention.
The invention is further illustrated with the following examples and should not be construed to limit the scope of the present invention. The features of the present invention will become more apparent from the following description of the inventive concept and the description of the preferred embodiments and appended claims.
Example 1
General Synthetic Procedure for Preparation of Compounds of the Formula 1
Procedure A:
Thienopyrimidinones of the Formula (4) (1 mmol), epoxide of formula (5) (1 mmol) and sodium methoxide (1.2 mmol) were taken in 2-neck RB flask under inert atmosphere, dry t-butanol (5-10 ml) was added to the above reaction mixture and the mixture was stirred under reflux for 10 to 30 hrs. Upon completion of the reaction, t-butanol was removed on rotavapor, water was added to the reaction mixture, the compound from the reaction mixture was extracted with ethyl acetate, dried and concentrated. Purification by column chromatography afforded the pure compounds of the Formula (1).
Procedure B:
Thienopyrimidinone of the Formula (4) (1 mmol) and epoxide of formula (5) (1 mmol) were taken in 2-neck RB flask under inert atmosphere, dry ethyl acetate (10-15 ml) was added followed by flame dried potassium carbonate (2 mmol) and tetrabutylammonium bromide (1.2 mmol). The mixture was stirred under reflux for 2 to 10 hrs, cooled, diluted with water, extracted with ethyl acetate, dried and concentrated. Purification by column chromatography afforded the pure compounds of the Formula (1).
Some functional group transformations like debenzylation, deacetylation, protection of hydroxyl functionality etc provided more number of compounds. The following novel compounds of formula (1) were prepared by using the above synthetic methods (see Table 1).
Example 2
6-(3-Benzyloxypropyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-ylpropyl]-thieno[2,3-d]pyrimidin-4(3H)-one (1-A02)
6-(3-Benzyloxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one of Formula (4-A02) (3.0 g, 0.01 mole), 1[[2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole of the Formula (5) (2.82 g, 0.012 mole) and sodium methoxide (0.65 g, 0.012 mole), were taken in two neck round bottom flask under inert atmosphere, dry t-butanol (70 ml) was added to the above reaction mixture and the mixture was stirred under reflux for 12 hours. t-Butanol was removed on rotavapor, water (50 ml) was added to the reaction mixture, the compound from the reaction mixture was extracted with ethyl acetate (3×50 ml), dried, concentrated and purified by column chromatography to obtain the pure 6-(3-benzyloxypropyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-ylpropyl]-thieno[2,3-d]pyrimidin-4(3H)-one (1-A02) (0.8 gm, 14%). 1HNMR (CDCl3, 200 MHz):: 1.91-2.06 (m, 2H), 2.95 (t, J=6 Hz, 2H), 3.51 (t, J=6 Hz, 2H), 4.21 (d, J=14 Hz, 1H), 4.49 (s, 2H), 4.52 (d, J=14 Hz, 1H), 4.72 (d, J=14 Hz, 1H), 4.79 (d, J=14 Hz, 1H), 6.22 (s, 1H), 6.72-6.88 (m, 2H), 7.08 (s, 1H), 7.31 (bs, 5H), 7.49-7.62 (m, 1H), 7.83 (s, 1H), 7.91 (s, 1H), 8.09 (s, 1H).
Example 3
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one (1-A09)
5,6,7,8-Tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one of Formula (4-A09) (1.0 g, 4.8 mmole), 1[[2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole of the Formula (5) (1.38 g, 5.8 mmole) and sodium methoxide (0.31 g, 5.8 mmole), were taken in two neck round bottom flask under inert atmosphere, dry t-butanol (30 ml) was added to the above reaction mixture and the mixture was stirred under reflux for 12 hours. t-Butanol was removed on rotavapor, water (20 ml) was added to the reaction mixture, the compound from the reaction mixture was extracted with ethyl acetate (3×20 ml), dried, concentrated and purified by column chromatography to obtain the pure 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one (1-A09) (1.29 gm, 60%). 1HNMR (CDCl3, 200 MHz): 1.74-1.96 (m, 4H), 2.71-2.81 (m, 2H), 2.90-3.02 (m, 2H), 4.18 (d, J=14 Hz, 1H), 4.55 (d, J=14 Hz, 1H), 4.70 (d, J=14 Hz, 1H), 4.77 (d, J=14 Hz, 1H), 6.29 (bs, 1H), 6.72-6.92 (m, 2H), 7.51-7.62 (m, 1H), 7.85 (s, 2H), 8.13 (s, 1H).
Example 4
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-6-(3-acetoxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one (1-A26)
6-(3-Acetoxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one of Formula (4-A26) (0.5 g, 2 mmole) and 1[[2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole of the Formula (5) (0.47 g, 2 mmole) were taken in two neck round bottom flask under inert atmosphere, dry ethyl acetate (5 ml) was added followed by flame dried potassium carbonate (0.55 g, 4 mmole) and tetrabutylammonium bromide (0.76 g, 2.4 mmole) the mixture was stirred under reflux for 12 hours, Cooled, diluted with water (15 ml), extracted with ethyl acetate (3×10 ml), dried, concentrated and purified by column chromatography afforded the pure 3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(3-acetoxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one (1-A26) (0.3 gm, 31%). 1HNMR (CDCl3, 200 MHz): 1.96-2.10 (m, 2H), 2.06 (s, 3H), 2.92 (t, J=8 Hz, 2H), 4.11 (t, J=6 Hz, 2H), 4.27 (d, J=14 Hz, 1H), 4.60 (d, J=14 Hz, 1H), 4.73 (d, J=14 Hz, 1H), 4.85 (d, J=14 Hz, 1H), 6.74-6.92 (m, 2H), 7.10 (s, 1H), 7.45-7.59 (m, 1H), 7.91 (bs, 1H), 7.95 (s, 1H), 8.36 (bs, 1H).
Following compounds were prepared by following either of the general procedures described above.
5) 6-(4-Benzyloxybutyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-ylpropyl]-thieno[2,3-d]pyrimidin-4(3H)-one (1-A01)
This compound was prepared by procedure B using 6-(4-benzyloxybutyl)-thieno[2,3-d]pyrimidin-4(3H)-one and 1[[2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole of the Formula (5). 1HNMR (CDCl3, 200 MHz): 1.61-1.86 (m, 4H), 2.84 (t, J=6 Hz, 2H), 3.49 (t, J=6 Hz, 2H), 4.23 (d, J=16 Hz, 1H), 4.49 (s, 2H), 4.53 (d, J=16 Hz, 1H), 4.72 (d, J=16 Hz, 1H), 4.80 (d, J=16 Hz, 1H), 6.22 (s, 1H), 6.72-6.90 (m, 2H), 7.08 (s, 1H), 7.32 (bs, 5H), 7.50-7.62 (m, 1H), 7.84 (s, 1H), 7.92 (s, 1H), 8.10 (s, 1H).
6) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-6-(n-hexyl)-thieno[2,3-d]pyrimidin-4(3H)-one (1-A03)
1HNMR (CDCl3, 200 MHz):: 0.88 (t, J=6 Hz, 3H), 1.21-1.48 (m, 6H), 1.61-1.76 (m, 2H), 2.82 (t, J=8 Hz, 2H), 4.22 (d, J=15 Hz, 1H), 4.52 (d, J=15 Hz, 1H), 4.72 (d, J=15 Hz, 1H), 4.80 (d, J=15 Hz, 1H), 6.24 (s, 1H), 6.75-6.89 (m, 2H), 7.07 (s, 1H), 7.48-7.62 (m, 1H), 7.83 (s, 1H), 7.91 (s, 1H), 8.10 (s, 1H).
7) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-6-n-pentylthieno[2,3-d]pyrimidin-4(3H)-one (1-A04)
1HNMR (CDCl3, 200 MHz):: 0.90 (t, J=6 Hz, 3H), 1.27-1.42 (m, 4H), 1.64-1.76 (m, 2H), 2.82 (t, J=8 Hz, 2H), 4.21 (d, J=15 Hz, 1H), 4.52 (d, J=15 Hz, 1H), 4.71 (d, J=15 Hz, 1H), 4.78 (d, J=15 Hz, 1H), 6.24 (s, 1H), 6.76-6.88 (m, 2H), 7.06 (s, 1H), 7.50-7.64 (m, 1H), 7.81 (s, 1H), 7.90 (s, 1H), 8.09 (s, 1H).
8) 5-n-Butyl-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-6-n-propyl-thieno[2,3-d]pyrimidin-4(3H)-one (1-A05)
1HNMR (CDCl3, 200 MHz):: 0.93 (t, J=6 Hz, 3H), 0.99 (t, J=6 Hz, 3H), 1.30-1.48 (m, 2H), 1.58-1.76 (m, 4H), 2.73 (t, J=6 Hz, 2H), 2.78-2.96 (m, 2H), 4.29 (d, J=14 Hz, 1H), 4.59 (d, J=14 Hz, 1H), 4.64 (d, J=14 Hz, 1H), 4.76 (d, J=14 Hz, 1H), 6.40 (bs, 1H), 6.72-6.89 (m, 2H), 7.48-7.60 (m, 1H), 7.86 (s, 2H), 8.18 (s, 1H).
9) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-6-n-heptylthieno[2,3-d]pyrimidin-4(3H)-one (1-A06)
1HNMR (CDCl3, 200 MHz):: 0.86 (t, J=6 Hz, 3H), 1.21-1.32 (m, 8H), 1.62-1.72 (m, 2H), 2.81 (t, J=8 Hz, 2H), 4.23 (d, J=15 Hz, 1H), 4.53 (d, J=15 Hz, 1H), 4.72 (d, J=15 Hz, 1H), 4.80 (d, J=15 Hz, 1H), 6.24 (bs, 1H), 6.74-6.89 (m, 2H), 7.06 (s, 1H), 7.48-7.60 (m, 1H), 7.84 (s, 1H), 7.91 (s, 1H), 8.13 (s, 1H).
10) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-3,5,6,7-tetrahydrocyclopenta[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (1-A07)
1HNMR (CDCl3, 200 MHz): 2.39-2.55 (m, 2H), 2.95 (t, J=7 Hz, 2H), 3.02 (t, J=7 Hz, 2H), 4.18 (d, J=14 Hz, 1H), 4.55 (d, J=14 Hz, 1H), 4.73 (d, J=14 Hz, 1H), 4.80 (d, J=14 Hz, 1H), 6.26 (bs, 1H), 6.74-6.92 (m, 2H), 7.51-7.63 (m, 1H), 7.85 (s, 2H), 8.15 (s, 1H).
11) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-methyl-5-npentyl-thieno[2,3-d]pyrimidin-4(3H)-one (1-A08)
1HNMR (CDCl3, 200 MHz):: 0.89 (t, J=6 Hz, 3H), 1.22-1.50 (m, 6H), 2.39 (s, 3H), 2.71-2.93 (m, 2H), 4.27 (d, J=14 Hz, 1H), 4.58-4.81 (m, 6H), 6.41 (bs, 1H), 6.72-6.88 (m, 2H), 7.48-7.62 (m, 1H), 7.85 (bs, 2H), 8.18 (bs, 1H).
12) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-6-n-hexyl-5-methyl-thieno[2,3-d]pyrimidin-4(3H)-one (1-A10)
1HNMR (CDCl3, 200 MHz):: 0.88 (t, J=6 Hz, 3H), 1.20-1.43 (m, 6H), 1.55-1.68 (m, 2H), 2.44 (s, 3H), 2.74 (t, J=8 Hz, 2H), 3.20 (bs, 1H), 4.22 (d, J=14 Hz, 1H), 4.59-4.88 (m, 6H), 6.74-6.92 (m, 2H), 7.48-7.62 (m, 1H), 7.89 (bs, 2H), 8.39 (bs, 1H).
13) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-5-methyl-6-npentyl-thieno[2,3-d]pyrimidin-4(3H)-one (1-A11)
1HNMR (CDCl3, 200 MHz):: 0.90 (bt, J=6 Hz, 3H), 1.30-1.45 (m, 4H), 1.56-1.69 (m, 2H), 2.43 (s, 3H), 2.74 (t, J=8 Hz, 2H), 4.24 (d, J=14 Hz, 1H), 4.66 (d, J=14 Hz, 1H), 4.74 (d, J=14 Hz, 1H), 4.86 (d, J=14 Hz, 1H), 6.72-6.92 (m, 2H), 7.46-7.59 (m, 1H), 7.92 (s, 1H), 7.95 (s, 1H), 8.55 (bs, 1H).
14) 6-(7-Acetoxyheptyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-ylpropyl]-thieno[2,3-d]pyrimidin-4(3H)-one (1-A12)
1HNMR (CDCl3, 200 MHz):: 1.21-1.36 (m, 6H), 1.51-1.80 (m, 4H), 2.03 (s, 3H), 2.81 (t, J=8 Hz, 2H), 4.03 (t, J=6 Hz, 2H), 4.25 (d, J=14 Hz, 1H), 4.56 (d, J=14 Hz, 1H), 4.72 (d, J=14 Hz, 1H), 4.82 (d, J=14 Hz, 1H), 6.72-6.88 (m, 2H), 7.06 (s, 1H), 7.47-7.61 (m, 1H), 7.87 (bs, 1H), 7.92 (s, 1H), 8.23 (bs, 1H).
15) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(7-hydroxy heptyl)-thieno[2,3-d]pyrimidin-4(3H)-one (1-A13)
6-(7-Acetoxyheptyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-ylpropyl]-thieno[2,3-d]pyrimidin-4(3H)-one (3.00 g, 5.5 mmol) was dissolved in the mixture of methanol (10 ml) and water (2 ml). Then potassium carbonate (760 mg, 5.5 mmol) was added and the mixture was stirred at RT for 2 hours. Methanol was then removed on rotavapor, water (10 ml) was added to the reaction mixture and extracted with ethyl acetate (2×5 ml), dried, concentrated and purified by column chromatography to obtain the pure 3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(7-hydroxyheptyl)-thieno[2,3-d]pyrimidin-4(3H)-one (2.5 gm, 90.57%).
1HNMR (CDCl3, 200 MHz): 1.25-1.42 (m, 6H), 1.49-1.80 (m, 4H), 2.81 (t, J=8 Hz, 2H), 3.62 (t, J=6 Hz, 2H), 4.25 (d, J=14 Hz, 1H), 4.57 (d, J=14 Hz, 1H), 4.72 (d, J=14 Hz, 1H), 4.82 (d, J=14 Hz, 1H), 6.27 (bs, 1H), 6.72-6.89 (m, 2H), 7.06 (s, 1H), 7.42-7.61 (m, 1H), 7.87 (bs, 1H), 7.92 (s, 1H), 8.25 (bs, 1H).
16) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-5(2-phenylethyl)-thieno[2,3-d]pyrimidin-4(3H)-one (1-A14)
1HNMR (CDCl3, 200 MHz):: 2.90 (t, J=8 Hz, 3H), 3.22 (t, J=8 Hz, 3H), 4.30 (d, J=14 Hz, 1H), 4.63 (d, J=14 Hz, 1H), 4.72 (d, J=14 Hz, 1H), 4.86 (d, J=14 Hz, 1H), 6.70-6.90 (m, 3H), 7.15-7.31 (m, 5H), 7.40-7.61 (m, 1H), 7.90 (bs, 1H), 7.99 (s, 1H), 8.33 (bs, 1H).
17) 6-Benzyl-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-5-methyl-thieno[2,3-d]pyrimidin-4(3H)-one (1-A15)
1HNMR (CDCl3, 200 MHz):: 2.51 (s, 3H), 4.09 (s, 2H), 4.21 (d, J=14 Hz, 1H), 4.61 (d, J=14 Hz, 1H), 4.74 (d, J=14 Hz, 1H), 4.84 (d, J=14 Hz, 1H), 6.65-6.91 (m, 2H), 7.15-7.34 (m, 5H), 7.45-7.61 (m, 1H), 7.89 (s, 1H), 7.90 (s, 1H), 8.36 (bs, 1H).
18) 6-n-Decyl-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]thieno[2,3-d]pyrimidin-4(3H)-one (1-A16)
1HNMR (CDCl3, 200 MHz):: 0.87 (t, J=6 Hz, 3H), 1.14-1.44 (m, 14H), 1.55-1.77 (m, 2H), 2.81 (t, J=8 Hz, 2H), 4.27 (d, J=14 Hz, 1H), 4.61 (d, J=14 Hz, 1H), 4.72 (d, J=14 Hz, 1H), 4.84 (d, J=14 Hz, 1H), 6.73-6.92 (m, 2H), 7.06 (s, 1H), 7.44-7.61 (m, 1H), 7.90 (bs, 1H), 7.93 (s, 1H), 8.35 (bs, 1H).
19) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-6-n-nonylthieno[2,3-d]pyrimidin-4(3H)-one (1-A17)
1HNMR (CDCl3, 200 MHz):: 0.86 (t, J=6 Hz, 3H), 1.13-1.42 (m, 12H), 1.54-1.80 (m, 2H), 2.80 (t, J=8 Hz, 2H), 4.26 (d, J=14 Hz, 1H), 4.57 (d, J=14 Hz, 1H), 4.72 (d, J=14 Hz, 1H), 4.82 (d, J=14 Hz, 1H), 6.27 (bs, 1H), 6.73-6.92 (m, 2H), 7.06 (s, 1H), 7.44-7.61 (m, 1H), 7.87 (bs, 1H), 7.92 (s, 1H), 8.25 (bs, 1H).
20) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-6-(n-propyl)-thieno[2,3-d]pyrimidin-4(3H)-one (1-A18)
1HNMR (CDCl3, 200 MHz):: 0.99 (t, J=7 Hz, 3H), 1.61-1.83 (m, 2H), 2.80 (t, J=8 Hz, 2H), 4.27 (d, J=14 Hz, 1H), 4.59 (d, J=14 Hz, 1H), 4.73 (d, J=14 Hz, 1H), 4.84 (d, J=14 Hz, 1H), 6.28 (bs, 1H), 6.74-6.90 (m, 2H), 7.08 (s, 1H), 7.46-7.61 (m, 1H), 7.88 (s, 1H), 7.92 (s, 1H), 8.28 (s, 1H).
21) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]3,5,6,7,8,9,10,11,12,13,14-undecahydrocyclododeca[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (1-A19)
1HNMR (CDCl3, 200 MHz):: 1.10-1.57 (m, 12H), 1.59-1.83 (m, 4H), 2.66-2.97 (m, 4H), 4.27 (d, J=14 Hz, 1H), 4.58 (d, J=14 Hz, 1H), 4.66 (d, J=14 Hz, 1H), 4.79 (d, J=14 Hz, 1H), 6.33 (bs, 1H), 6.72-6.90 (m, 2H), 7.46-7.90 (m, 1H), 7.86 (s, 1H), 7.89 (s, 1H), 8.20 (s, 1H).
22) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-5-methyl-6-n-octyl-thieno[2,3-d]pyrimidin-4(3H)-one (1-A20)
1HNMR (CDCl3, 200 MHz):: 0.91 (t, J=6 Hz, 3H), 1.18-1.49 (m, 10H), 1.56-1.75 (m, 2H), 2.48 (s, 3H), 2.78 (t, J=8 Hz, 2H), 4.22 (d, J=14 Hz, 1H), 4.59 (d, J=14 Hz, 1H), 4.77 (d, J=14 Hz, 1H), 4.84 (d, J=14 Hz, 1H), 6.31 (bs, 1H), 6.80-6.92 (m, 2H), 7.54-7.72 (m, 1H), 7.90 (bs, 2H), 8.20 (bs, 1H).
23) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-6-n-butyl-5-methyl-thieno[2,3-d]pyrimidin-4(3H)-one (1-A21)
1HNMR (CDCl3, 200 MHz):: 0.93 (t, J=6 Hz, 3H), 1.28-1.45 (m, 2H), 1.52-1.69 (m, 2H), 2.43 (s, 3H), 2.74 (t, J=8 Hz, 2H), 4.20 (d, J=14 Hz, 1H), 4.60 (d, J=14 Hz, 1H), 4.74 (d, J=14 Hz, 1H), 4.84 (d, J=14 Hz, 1H), 6.72-6.90 (m, 2H), 7.48-7.59 (m, 1H), 7.88 (bs, 2H), 8.34 (bs, 1H).
24) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-ethylthieno[2,3-d]pyrimidin-4(3H)-one (1-A22)
1HNMR (CDCl3, 200 MHz):: 1.35 (t, J=7 Hz, 3H), 2.87 (q, J=7 Hz, 2H), 4.27 (d, J=14 Hz, 1H), 4.60 (d, J=14 Hz, 1H), 4.72 (d, J=14 Hz, 1H), 4.83 (d, J=14 Hz, 1H), 6.26 (bs, 1H), 6.77-6.91 (m, 2H), 7.08 (s, 1H), 7.48-7.61 (m, 1H), 7.89 (s, 1H), 7.92 (s, 1H), 8.31 (s, 1H).
25) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-6-(4-hydroxybutyl)-thieno[2,3-d]pyrimidin-4(3H)-one (1-A23)
1HNMR (CDCl3, 200 MHz):: 1.50-1.90 (m, 4H), 2.87 (t, J=6 Hz, 2H), 3.59 (t, J=6 Hz, 2H), 4.26 (d, J=14 Hz, 1H), 4.56 (d, J=14 Hz, 1H), 4.77 (d, J=14 Hz, 1H), 4.89 (d, J=14 Hz, 1H), 6.22 (bs, 1H), 6.72-6.92 (m, 2H), 7.07 (s, 1H), 7.35-7.50 (m, 1H), 7.76 (bs, 1H), 8.00 (s, 1H), 8.22 (bs, 1H).
26) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(4-N-Bocaminoacetyloxybutyl)-thieno[2,3-d]pyrimidin-4(3H)-one (1-A24)
A mixture of -[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-6-(4-hydroxybutyl)-thieno[2,3-d]pyrimidin-4(3H)-one (500 mg, 0.895 mmol), Boc-glycine (188 mg, 1.073 mmol), DMAP (10 mg) in DCM (10 ml) was taken at 0° C. and added EDCI (257 mg, 1.34 mmol) to it and stirred for 2 hours. It was then diluted with water (10 ml), extracted with DCM (2×5 ml), dried, concentrated and purified by column chromatography to obtain the pure 3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(4-N-Bocaminoacetyloxybutyl)-thieno[2,3-d]pyrimidin-4(3H)-one (300 mg, 46.87%).
1HNMR (CDCl3, 200 MHz):: 1.47 (s, 9H), 1.62-1.90 (m, 4H), 2.80-2.96 (m, 2H), 3.78-3.98 (m, 2H), 4.05-4.32 (m, 3H), 4.55-4.91 (m, 3H), 5.05 (bs, 1H), 6.29 (bs, 1H), 6.73-6.89 (m, 2H), 7.12 (s, 1H), 7.50-7.65 (m, 1H), 7.92 (bs, 1H), 7.98 (s, 1H), 8.35 (bs, 1H).
27) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-6-(4-aminoacetyloxybutyl)-thieno[2,3-d]pyrimidin-4(3H)-one (1-A25)
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(4-N-Bocaminoacetyloxybutyl)-thieno[2,3-d]pyrimidin-4(3H)-one (200 mg, 0.28 mmol) was dissolved in DCM (6 ml) at 0° C. Trifluoroacetic acid (0.129 ml, 191 mg, 1.68 mmol) was added to it and stirred for 4 hours. It was then diluted with water (10 ml), extracted with DCM (2×5 ml), dried, concentrated and purified by column chromatography to obtain the pure 3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(4-aminoacetyloxy butyl)-thieno[2,3-d]pyrimidin-4(3H)-one (100 mg, 56.81%).
1HNMR (CDCl3, 200 MHz): 1.45-1.80 (m, 4H), 2.68-2.90 (m, 2H), 4.05-4.29 (m, 4H), 4.32-4.61 (m, 3H), 4.65-4.90 (m, 3H), 5.81 (bs, 1H), 6.68-6.91 (m, 2H), 7.03 (s, 1H), 7.39-7.58 (m, 1H), 7.74 (s, 1H), 7.91 (s, 1H), 8.08 (s, 1H).
28) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-6-(3-hydroxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one (1-A27)
1HNMR (CDCl3+DMSOd6, 200 MHz): 1.68-1.84 (m, 2H), 2.77 (t, J=8 Hz, 2H), 3.47 (t, J=6 Hz, 2H), 4.12 (d, J=14 Hz, 1H), 4.47 (d, J=14 Hz, 1H), 4.61 (d, J=14 Hz, 1H), 4.83 (d, J=14 Hz, 1H), 6.54-6.76 (m, 2H), 6.93 (s, 1H), 7.12-7.35 (m, 3H), 7.86 (s, 1H).
29) 3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (1-A28)
1HNMR (CDCl3, 200 MHz):: 2.51 (s, 3H), 4.23 (d, J=12 Hz, 1H), 4.53 (d, J=12 Hz, 1H), 4.69 (d, J=12 Hz, 1H), 4.77 (d, J=12 Hz, 1H), 6.22 (bs, 1H), 6.70-6.85 (m, 2H), 7.04 (s, 1H), 7.45-7.60 (m, 1H), 7.83 (s, 1H), 7.90 (s, 1H), 8.10 (s, 1H).
The pharmaceutical salts of the compounds of Formula (1) can be prepared by known methods and obvious modifications.







TABLE 1







Analogues of fluconazole of Formula (1)












Compound




Sample


No.
R1
R2
R3
R4
No.















1
2-F
4-F
CH3
H
1-A28


2
2-Cl
4-Cl
CH3
H


3
2-Br
4-Br
CH3
H


4
2-F
H
CH3
H


5
2-Cl
H
CH3
H


6
2-Br
H
CH3
H


7
H
4-F
CH3
H


8
H
4-Cl
CH3
H


9
H
4-Br
CH3
H


10
2-F
4-F
H
CH3


11
2-Cl
4-Cl
H
CH3


12
2-Br
4-Br
H
CH3


13
2-F
H
H
CH3


14
2-Cl
H
H
CH3


15
2-Br
H
H
CH3


16
H
4-F
H
CH3


17
H
4-Cl
H
CH3


18
H
4-Br
H
CH3


19
2-F
4-F
CH2CH3
H
1-A22


20
2-Cl
4-Cl
CH2CH3
H


21
2-Br
4-Br
CH2CH3
H


22
2-F
H
CH2CH3
H


23
2-Cl
H
CH2CH3
H


24
2-Br
H
CH2CH3
H


25
H
4-F
CH2CH3
H


26
H
4-Cl
CH2CH3
H


27
H
4-Br
CH2CH3
H


28
2-F
4-F
H
CH2CH3


29
2-Cl
4-Cl
H
CH2CH3


30
2-Br
4-Br
H
CH2CH3


31
2-F
H
H
CH2CH3


32
2-Cl
H
H
CH2CH3


33
2-Br
H
H
CH2CH3


34
H
4-F
H
CH2CH3


35
H
4-Cl
H
CH2CH3


36
H
4-Br
H
CH2CH3


37
2-F
4-F
(CH2)2CH3
H
1-A18


38
2-Cl
4-Cl
(CH2)2CH3
H


39
2-Br
4-Br
(CH2)2CH3
H


40
2-F
H
(CH2)2CH3
H


41
2-Cl
H
(CH2)2CH3
H


42
2-Br
H
(CH2)2CH3
H


43
H
4-F
(CH2)2CH3
H


44
H
4-Cl
(CH2)2CH3
H


45
H
4-Br
(CH2)2CH3
H


46
2-F
4-F
H
(CH2)2CH3


47
2-Cl
4-Cl
H
(CH2)2CH3


48
2-Br
4-Br
H
(CH2)2CH3


49
2-F
H
H
(CH2)2CH3


50
2-Cl
H
H
(CH2)2CH3


51
2-Br
H
H
(CH2)2CH3


52
H
4-F
H
(CH2)2CH3


53
H
4-Cl
H
(CH2)2CH3


54
H
4-Br
H
(CH2)2CH3


55
2-F
4-F
(CH2)3CH3
H


56
2-Cl
4-Cl
(CH2)3CH3
H


57
2-Br
4-Br
(CH2)3CH3
H


58
2-F
H
(CH2)3CH3
H


59
2-Cl
H
(CH2)3CH3
H


60
2-Br
H
(CH2)3CH3
H


61
H
4-F
(CH2)3CH3
H


62
H
4-Cl
(CH2)3CH3
H


63
H
4-Br
(CH2)3CH3
H


64
2-F
4-F
H
(CH2)3CH3


65
2-Cl
4-Cl
H
(CH2)3CH3


66
2-Br
4-Br
H
(CH2)3CH3


67
2-F
H
H
(CH2)3CH3


68
2-Cl
H
H
(CH2)3CH3


69
2-Br
H
H
(CH2)3CH3


70
H
4-F
H
(CH2)3CH3


71
H
4-Cl
H
(CH2)3CH3


72
H
4-Br
H
(CH2)3CH3


73
2-F
4-F
(CH2)4CH3
H
1-A04


74
2-Cl
4-Cl
(CH2)4CH3
H


75
2-Br
4-Br
(CH2)4CH3
H


76
2-F
H
(CH2)4CH3
H


77
2-Cl
H
(CH2)4CH3
H


78
2-Br
H
(CH2)4CH3
H


79
H
4-F
(CH2)4CH3
H


80
H
4-Cl
(CH2)4CH3
H


81
H
4-Br
(CH2)4CH3
H


82
2-F
4-F
H
(CH2)4CH3


83
2-Cl
4-Cl
H
(CH2)4CH3


84
2-Br
4-Br
H
(CH2)4CH3


85
2-F
H
H
(CH2)4CH3


86
2-Cl
H
H
(CH2)4CH3


87
2-Br
H
H
(CH2)4CH3


88
H
4-F
H
(CH2)4CH3


89
H
4-Cl
H
(CH2)4CH3


90
H
4-Br
H
(CH2)4CH3


91
2-F
4-F
(CH2)5CH3
H
1-A03


92
2-Cl
4-Cl
(CH2)5CH3
H


93
2-Br
4-Br
(CH2)5CH3
H


94
2-F
H
(CH2)5CH3
H


95
2-Cl
H
(CH2)5CH3
H


96
2-Br
H
(CH2)5CH3
H


97
H
4-F
(CH2)5CH3
H


98
H
4-Cl
(CH2)5CH3
H


99
H
4-Br
(CH2)5CH3
H


100
2-F
4-F
H
(CH2)5CH3


101
2-Cl
4-Cl
H
(CH2)5CH3


102
2-Br
4-Br
H
(CH2)5CH3


103
2-F
H
H
(CH2)5CH3


104
2-Cl
H
H
(CH2)5CH3


105
2-Br
H
H
(CH2)5CH3


106
H
4-F
H
(CH2)5CH3


107
H
4-Cl
H
(CH2)5CH3


108
H
4-Br
H
(CH2)5CH3


109
2-F
4-F
(CH2)6CH3
H
1-A06


110
2-Cl
4-Cl
(CH2)6CH3
H


111
2-Br
4-Br
(CH2)6CH3
H


112
2-F
H
(CH2)6CH3
H


113
2-Cl
H
(CH2)6CH3
H


114
2-Br
H
(CH2)6CH3
H


115
H
4-F
(CH2)6CH3
H


116
H
4-Cl
(CH2)6CH3
H


117
H
4-Br
(CH2)6CH3
H


118
2-F
4-F
H
(CH2)6CH3


119
2-Cl
4-Cl
H
(CH2)6CH3


120
2-Br
4-Br
H
(CH2)6CH3


121
2-F
H
H
(CH2)6CH3


122
2-Cl
H
H
(CH2)6CH3


123
2-Br
H
H
(CH2)6CH3


124
H
4-F
H
(CH2)6CH3


125
H
4-Cl
H
(CH2)6CH3


126
H
4-Br
H
(CH2)6CH3


127
2-F
4-F
(CH2)7CH3
H


128
2-Cl
4-Cl
(CH2)7CH3
H


129
2-Br
4-Br
(CH2)7CH3
H


130
2-F
H
(CH2)7CH3
H


131
2-Cl
H
(CH2)7CH3
H


132
2-Br
H
(CH2)7CH3
H


133
H
4-F
(CH2)7CH3
H


134
H
4-Cl
(CH2)7CH3
H


135
H
4-Br
(CH2)7CH3
H


136
2-F
4-F
H
(CH2)7CH3


137
2-Cl
4-Cl
H
(CH2)7CH3


138
2-Br
4-Br
H
(CH2)7CH3


139
2-F
H
H
(CH2)7CH3


140
2-Cl
H
H
(CH2)7CH3


141
2-Br
H
H
(CH2)7CH3


142
H
4-F
H
(CH2)7CH3


143
H
4-Cl
H
(CH2)7CH3


144
H
4-Br
H
(CH2)7CH3


145
2-F
4-F
(CH2)8CH3
H
1-A17


146
2-Cl
4-Cl
(CH2)8CH3
H


147
2-Br
4-Br
(CH2)8CH3
H


148
2-F
H
(CH2)8CH3
H


149
2-Cl
H
(CH2)8CH3
H


150
2-Br
H
(CH2)8CH3
H


151
H
4-F
(CH2)8CH3
H


152
H
4-Cl
(CH2)8CH3
H


153
H
4-Br
(CH2)8CH3
H


154
2-F
4-F
H
(CH2)8CH3


155
2-Cl
4-Cl
H
(CH2)8CH3


156
2-Br
4-Br
H
(CH2)8CH3


157
2-F
H
H
(CH2)8CH3


158
2-Cl
H
H
(CH2)8CH3


159
2-Br
H
H
(CH2)8CH3


160
H
4-F
H
(CH2)8CH3


161
H
4-Cl
H
(CH2)8CH3


162
H
4-Br
H
(CH2)8CH3


163
2-F
4-F
(CH2)9CH3
H
1-A16


164
2-Cl
4-Cl
(CH2)9CH3
H


165
2-Br
4-Br
(CH2)9CH3
H


166
2-F
H
(CH2)9CH3
H


167
2-Cl
H
(CH2)9CH3
H


168
2-Br
H
(CH2)9CH3
H


169
H
4-F
(CH2)9CH3
H


170
H
4-Cl
(CH2)9CH3
H


171
H
4-Br
(CH2)9CH3
H


172
2-F
4-F
H
(CH2)9CH3


173
2-Cl
4-Cl
H
(CH2)9CH3


174
2-Br
4-Br
H
(CH2)9CH3


175
2-F
H
H
(CH2)9CH3


176
2-Cl
H
H
(CH2)9CH3


177
2-Br
H
H
(CH2)9CH3


178
H
4-F
H
(CH2)9CH3


179
H
4-Cl
H
(CH2)9CH3


180
H
4-Br
H
(CH2)9CH3


181
2-F
4-F
CH3
CH3


182
2-Cl
4-Cl
CH3
CH3


183
2-Br
4-Br
CH3
CH3


184
2-F
H
CH3
CH3


185
2-Cl
H
CH3
CH3


186
2-Br
H
CH3
CH3


187
H
4-F
CH3
CH3


188
H
4-Cl
CH3
CH3


189
H
4-Br
CH3
CH3


190
2-F
4-F
CH3
CH2CH3


191
2-Cl
4-Cl
CH3
CH2CH3


192
2-Br
4-Br
CH3
CH2CH3


193
2-F
H
CH3
CH2CH3


194
2-Cl
H
CH3
CH2CH3


195
2-Br
H
CH3
CH2CH3


196
H
4-F
CH3
CH2CH3


197
H
4-Cl
CH3
CH2CH3


198
H
4-Br
CH3
CH2CH3


199
2-F
4-F
CH3
(CH2)2CH3


200
2-Cl
4-Cl
CH3
(CH2)2CH3


201
2-Br
4-Br
CH3
(CH2)2CH3


202
2-F
H
CH3
(CH2)2CH3


203
2-Cl
H
CH3
(CH2)2CH3


204
2-Br
H
CH3
(CH2)2CH3


205
H
4-F
CH3
(CH2)2CH3


206
H
4-Cl
CH3
(CH2)2CH3


207
H
4-Br
CH3
(CH2)2CH3


208
2-F
4-F
CH3
(CH2)3CH3


209
2-Cl
4-Cl
CH3
(CH2)3CH3


210
2-Br
4-Br
CH3
(CH2)3CH3


211
2-F
H
CH3
(CH2)3CH3


212
2-Cl
H
CH3
(CH2)3CH3


213
2-Br
H
CH3
(CH2)3CH3


214
H
4-F
CH3
(CH2)3CH3


215
H
4-Cl
CH3
(CH2)3CH3


216
H
4-Br
CH3
(CH2)3CH3


217
2-F
4-F
CH3
(CH2)4CH3
1-A08


218
2-Cl
4-Cl
CH3
(CH2)4CH3


219
2-Br
4-Br
CH3
(CH2)4CH3


220
2-F
H
CH3
(CH2)4CH3


221
2-Cl
H
CH3
(CH2)4CH3


222
2-Br
H
CH3
(CH2)4CH3


223
H
4-F
CH3
(CH2)4CH3


224
H
4-Cl
CH3
(CH2)4CH3


225
H
4-Br
CH3
(CH2)4CH3


226
2-F
4-F
CH3
(CH2)5CH3


227
2-Cl
4-Cl
CH3
(CH2)5CH3


228
2-Br
4-Br
CH3
(CH2)5CH3


229
2-F
H
CH3
(CH2)5CH3


230
2-Cl
H
CH3
(CH2)5CH3


231
2-Br
H
CH3
(CH2)5CH3


232
H
4-F
CH3
(CH2)5CH3


233
H
4-Cl
CH3
(CH2)5CH3


234
H
4-Br
CH3
(CH2)5CH3


235
2-F
4-F
CH3
(CH2)6CH3


236
2-Cl
4-Cl
CH3
(CH2)6CH3


237
2-Br
4-Br
CH3
(CH2)5CH3


238
2-F
H
CH3
(CH2)6CH3


239
2-Cl
H
CH3
(CH2)6CH3


240
2-Br
H
CH3
(CH2)6CH3


241
H
4-F
CH3
(CH2)6CH3


242
H
4-Cl
CH3
(CH2)6CH3


243
H
4-Br
CH3
(CH2)6CH3


244
2-F
4-F
CH3
(CH2)7CH3


245
2-Cl
4-Cl
CH3
(CH2)7CH3


246
2-Br
4-Br
CH3
(CH2)7CH3


247
2-F
H
CH3
(CH2)7CH3


248
2-Cl
H
CH3
(CH2)7CH3


249
2-Br
H
CH3
(CH2)7CH3


250
H
4-F
CH3
(CH2)7CH3


251
H
4-Cl
CH3
(CH2)7CH3


252
H
4-Br
CH3
(CH2)7CH3


253
2-F
4-F
CH3
(CH2)8CH3


254
2-Cl
4-Cl
CH3
(CH2)8CH3


255
2-Br
4-Br
CH3
(CH2)8CH3


256
2-F
H
CH3
(CH2)3CH3


257
2-Cl
H
CH3
(CH2)8CH3


258
2-Br
H
CH3
(CH2)8CH3


259
H
4-F
CH3
(CH2)8CH3


260
H
4-Cl
CH3
(CH2)8CH3


261
H
4-Br
CH3
(CH2)8CH3


262
2-F
4-F
CH2CH3
CH3


263
2-Cl
4-Cl
CH2CH3
CH3


264
2-Br
4-Br
CH2CH3
CH3


265
2-F
H
CH2CH3
CH3


266
2-Cl
H
CH2CH3
CH3


267
2-Br
H
CH2CH3
CH3


268
H
4-F
CH2CH3
CH3


269
H
4-Cl
CH2CH3
CH3


270
H
4-Br
CH2CH3
CH3


271
2-F
4-F
(CH2)2CH3
CH3


272
2-Cl
4-Cl
(CH2)2CH3
CH3


273
2-Br
4-Br
(CH2)2CH3
CH3


274
2-F
H
(CH2)2CH3
CH3


275
2-Cl
H
(CH2)2CH3
CH3


276
2-Br
H
(CH2)2CH3
CH3


277
H
4-F
(CH2)2CH3
CH3


278
H
4-Cl
(CH2)2CH3
CH3


279
H
4-Br
(CH2)2CH3
CH3


280
2-F
4-F
(CH2)3CH3
CH3


281
2-Cl
4-Cl
(CH2)3CH3
CH3


282
2-Br
4-Br
(CH2)3CH3
CH3


283
2-F
H
(CH2)3CH3
CH3


284
2-Cl
H
(CH2)3CH3
CH3


285
2-Br
H
(CH2)3CH3
CH3


286
H
4-F
(CH2)3CH3
CH3


287
H
4-Cl
(CH2)3CH3
CH3


288
H
4-Br
(CH2)3CH3
CH3


289
2-F
4-F
(CH2)4CH3
CH3
1-A11


290
2-Cl
4-Cl
(CH2)4CH3
CH3


291
2-Br
4-Br
(CH2)4CH3
CH3


292
2-F
H
(CH2)4CH3
CH3


293
2-Cl
H
(CH2)4CH3
CH3


294
2-Br
H
(CH2)4CH3
CH3


295
H
4-F
(CH2)4CH3
CH3


296
H
4-Cl
(CH2)4CH3
CH3


297
H
4-Br
(CH2)4CH3
CH3


298
2-F
4-F
(CH2)5CH3
CH3
1-A10


299
2-Cl
4-Cl
(CH2)5CH3
CH3


300
2-Br
4-Br
(CH2)5CH3
CH3


301
2-F
H
(CH2)5CH3
CH3


302
2-Cl
H
(CH2)5CH3
CH3


303
2-Br
H
(CH2)5CH3
CH3


304
H
4-F
(CH2)5CH3
CH3


305
H
4-Cl
(CH2)5CH3
CH3


306
H
4-Br
(CH2)5CH3
CH3


307
2-F
4-F
(CH2)6CH3
CH3


308
2-Cl
4-Cl
(CH2)6CH3
CH3


309
2-Br
4-Br
(CH2)6CH3
CH3


310
2-F
H
(CH2)6CH3
CH3


311
2-Cl
H
(CH2)6CH3
CH3


312
2-Br
H
(CH2)6CH3
CH3


313
H
4-F
(CH2)6CH3
CH3


314
H
4-Cl
(CH2)6CH3
CH3


315
H
4-Br
(CH2)6CH3
CH3


316
2-F
4-F
(CH2)7CH3
CH3


317
2-Cl
4-Cl
(CH2)7CH3
CH3


318
2-Br
4-Br
(CH2)7CH3
CH3


319
2-F
H
(CH2)7CH3
CH3


320
2-Cl
H
(CH2)7CH3
CH3


321
2-Br
H
(CH2)7CH3
CH3


322
H
4-F
(CH2)7CH3
CH3


323
H
4-Cl
(CH2)7CH3
CH3


324
H
4-Br
(CH2)7CH3
CH3


325
2-F
4-F
(CH2)8CH3
CH3


326
2-Cl
4-Cl
(CH2)8CH3
CH3


327
2-Br
4-Br
(CH2)8CH3
CH3


328
2-F
H
(CH2)8CH3
CH3


329
2-Cl
H
(CH2)8CH3
CH3


330
2-Br
H
(CH2)8CH3
CH3


331
H
4-F
(CH2)8CH3
CH3


332
H
4-Cl
(CH2)8CH3
CH3


333
H
4-Br
(CH2)8CH3
CH3


334
2-F
4-F
—(CH2)3—
═R3
1-A07


335
2-Cl
4-Cl
—(CH2)3—
═R3


336
2-Br
4-Br
—(CH2)3—
═R3


337
2-F
H
—(CH2)3—
═R3


338
2-Cl
H
—(CH2)3—
═R3


339
2-Br
H
—(CH2)3—
═R3


340
H
4-F
—(CH2)3—
═R3


341
H
4-Cl
—(CH2)3—
═R3


342
H
4-Br
—(CH2)3—
═R3


343
2-F
4-F
—(CH2)4—
═R3
1-A09


344
2-Cl
4-Cl
—(CH2)4—
═R3


345
2-Br
4-Br
—(CH2)4—
═R3


346
2-F
H
—(CH2)4—
═R3


347
2-Cl
H
—(CH2)4—
═R3


348
2-Br
H
—(CH2)4—
═R3


349
H
4-F
—(CH2)4—
═R3


350
H
4-Cl
—(CH2)4—
═R3


351
H
4-Br
—(CH2)4—
═R3


352
2-F
4-F
—(CH2)5—
═R3


353
2-Cl
4-Cl
—(CH2)5—
═R3


354
2-Br
4-Br
—(CH2)5—
═R3


355
2-F
H
—(CH2)5—
═R3


356
2-Cl
H
—(CH2)5—
═R3


357
2-Br
H
—(CH2)5—
═R3


358
H
4-F
—(CH2)5—
═R3


359
H
4-Cl
—(CH2)5—
═R3


360
H
4-Br
—(CH2)5—
═R3


361
2-F
4-F
—(CH2)6—
═R3


362
2-Cl
4-Cl
—(CH2)6—
═R3


363
2-Br
4-Br
—(CH2)6—
═R3


364
2-F
H
—(CH2)6—
═R3


365
2-Cl
H
—(CH2)6—
═R3


366
2-Br
H
—(CH2)6—
═R3


367
H
4-F
—(CH2)6—
═R3


368
H
4-Cl
—(CH2)6—
═R3


369
H
4-Br
—(CH2)6—
═R3


370
2-F
4-F
—(CH2)7—
═R3


371
2-Cl
4-Cl
—(CH2)7—
═R3


372
2-Br
4-Br
—(CH2)7—
═R3


373
2-F
H
—(CH2)7—
═R3


374
2-Cl
H
—(CH2)7—
═R3


375
2-Br
H
—(CH2)7—
═R3


376
H
4-F
—(CH2)7—
═R3


377
H
4-Cl
—(CH2)7—
═R3


378
H
4-Br
—(CH2)7—
═R3


379
2-F
4-F
—(CH2)8—
═R3


380
2-Cl
4-Cl
—(CH2)8—
═R3


381
2-Br
4-Br
—(CH2)8—
═R3


382
2-F
H
—(CH2)8—
═R3


383
2-Cl
H
—(CH2)8—
═R3


384
2-Br
H
—(CH2)8—
═R3


385
H
4-F
—(CH2)8—
═R3


386
H
4-Cl
—(CH2)8—
═R3


387
H
4-Br
—(CH2)8—
═R3


388
2-F
4-F
—(CH2)9—
═R3


389
2-Cl
4-Cl
—(CH2)9—
═R3


390
2-Br
4-Br
—(CH2)9—
═R3


391
2-F
H
—(CH2)9—
═R3


392
2-Cl
H
—(CH2)9—
═R3


393
2-Br
H
—(CH2)9—
═R3


394
H
4-F
—(CH2)9—
═R3


395
H
4-Cl
—(CH2)9—
═R3


396
H
4-Br
—(CH2)9—
═R3


397
2-F
4-F
—(CH2)10—
═R3


398
2-Cl
4-Cl
—(CH2)10—
═R3


399
2-Br
4-Br
—(CH2)10—
═R3


400
2-F
H
—(CH2)10—
═R3


401
2-Cl
H
—(CH2)10—
═R3


402
2-Br
H
—(CH2)10—
═R3


403
H
4-F
—(CH2)10—
═R3


404
H
4-Cl
—(CH2)10—
═R3


405
H
4-Br
—(CH2)10—
═R3
1-A19


406
2-F
4-F
CH2OH
H


407
2-Cl
4-Cl
CH2OH
H


408
2-Br
4-Br
CH2OH
H


409
2-F
H
CH2OH
H


410
2-Cl
H
CH2OH
H


411
2-Br
H
CH2OH
H


412
H
4-F
CH2OH
H


413
H
4-Cl
CH2OH
H


414
H
4-Br
CH2OH
H


415
2-F
4-F
CH2CH2OH
H


416
2-Cl
4-Cl
CH2CH2OH
H


417
2-Br
4-Br
CH2CH2OH
H


418
2-F
H
CH2CH2OH
H


419
2-Cl
H
CH2CH2OH
H


420
2-Br
H
CH2CH2OH
H


421
H
4-F
CH2CH2OH
H


422
H
4-Cl
CH2CH2OH
H


423
H
4-Br
CH2CH2OH
H


424
2-F
4-F
(CH2)2CH2OH
H
1-A 27


425
2-Cl
4-Cl
(CH2)2CH2OH
H


426
2-Br
4-Br
(CH2)2CH2OH
H


427
2-F
H
(CH2)2CH2OH
H


428
2-Cl
H
(CH2)2CH2OH
H


429
2-Br
H
(CH2)2CH2OH
H


430
H
4-F
(CH2)2CH2OH
H


431
H
4-Cl
(CH2)2CH2OH
H


432
H
4-Br
(CH2)2CH2OH
H


433
2-F
4-F
(CH2)3CH2OH
H
1-A 23


434
2-Cl
4-Cl
(CH2)3CH2OH
H


435
2-Br
4-Br
(CH2)3CH2OH
H


436
2-F
H
(CH2)3CH2OH
H


437
2-Cl
H
(CH2)3CH2OH
H


438
2-Br
H
(CH2)3CH2OH
H


439
H
4-F
(CH2)3CH2OH
H


440
H
4-Cl
(CH2)3CH2OH
H


441
H
4-Br
(CH2)3CH2OH
H


442
2-F
4-F
(CH2)4CH2OH
H


443
2-Cl
4-Cl
(CH2)4CH2OH
H


444
2-Br
4-Br
(CH2)4CH2OH
H


445
2-F
H
(CH2)4CH2OH
H


446
2-Cl
H
(CH2)4CH2OH
H


447
2-Br
H
(CH2)4CH2OH
H


448
H
4-F
(CH2)4CH2OH
H


449
H
4-Cl
(CH2)4CH2OH
H


450
H
4-Br
(CH2)4CH2OH
H


451
2-F
4-F
(CH2)5CH2OH
H


452
2-Cl
4-Cl
(CH2)5CH2OH
H


453
2-Br
4-Br
(CH2)5CH2OH
H


454
2-F
H
(CH2)5CH2OH
H


455
2-Cl
H
(CH2)5CH2OH
H


456
2-Br
H
(CH2)5CH2OH
H


457
H
4-F
(CH2)5CH2OH
H


458
H
4-Cl
(CH2)5CH2OH
H


459
H
4-Br
(CH2)5CH2OH
H


460
2-F
4-F
(CH2)6CH2OH
H
1-A13


461
2-Cl
4-Cl
(CH2)6CH2OH
H


462
2-Br
4-Br
(CH2)6CH2OH
H


463
2-F
H
(CH2)6CH2OH
H


464
2-Cl
H
(CH2)6CH2OH
H


465
2-Br
H
(CH2)6CH2OH
H


466
H
4-F
(CH2)6CH2OH
H


467
H
4-Cl
(CH2)6CH2OH
H


468
H
4-Br
(CH2)6CH2OH
H


469
2-F
4-F
(CH2)7CH2OH
H


470
2-Cl
4-Cl
(CH2)7CH2OH
H


471
2-Br
4-Br
(CH2)7CH2OH
H


472
2-F
H
(CH2)7CH2OH
H


473
2-Cl
H
(CH2)7CH2OH
H


474
2-Br
H
(CH2)7CH2OH
H


475
H
4-F
(CH2)7CH2OH
H


476
H
4-Cl
(CH2)7CH2OH
H


477
H
4-Br
(CH2)7CH2OH
H


478
2-F
4-F
(CH2)nCH2OAc
H


479
2-Cl
4-Cl
(CH2)nCH2OAc
H


480
2-Br
4-Br
(CH2)nCH2OAc
H


481
2-F
H
(CH2)nCH2OAc
H


482
2-Cl
H
(CH2)nCH2OAc
H


483
2-Br
H
(CH2)nCH2OAc
H


484
H
4-F
(CH2)nCH2OAc
H


485
H
4-Cl
(CH2)nCH2OAc
H


486
H
4-Br
(CH2)nCH2OAc
H


487
2-F
4-F
(CH2)2CH2OAc
H
1-A26


488
2-Cl
4-Cl
(CH2)2CH2OAc
H


489
2-Br
4-Br
(CH2)2CH2OAc
H


490
2-F
H
(CH2)2CH2OAc
H


491
2-Cl
H
(CH2)2CH2OAc
H


492
2-Br
H
(CH2)2CH2OAc
H


493
H
4-F
(CH2)2CH2OAc
H


494
H
4-Cl
(CH2)2CH2OAc
H


495
H
4-Br
(CH2)2CH2OAc
H


496
2-F
4-F
(CH2)6CH2OAc
H
1-A12


497
2-Cl
4-Cl
(CH2)6CH2OAc
H


498
2-Br
4-Br
(CH2)6CH2OAc
H


499
2-F
H
(CH2)6CH2OAc
H


500
2-Cl
H
(CH2)6CH2OAc
H


501
2-Br
H
(CH2)6CH2OAc
H


502
H
4-F
(CH2)6CH2OAc
H


503
H
4-Cl
(CH2)6CH2OAc
H


504
H
4-Br
(CH2)6CH2OAc
H


505
2-F
4-F
(CH2)nCH2OCOR
H


506
2-Cl
4-Cl
(CH2)nCH2OCOR
H


507
2-Br
4-Br
(CH2)nCH2OCOR
H


508
2-F
H
(CH2)nCH2OCOR
H


509
2-Cl
H
(CH2)nCH2OCOR
H


510
2-Br
H
(CH2)nCH2OCOR
H


511
H
4-F
(CH2)nCH2OCOR
H


512
H
4-Cl
(CH2)nCH2OCOR
H


513
H
4-Br
(CH2)nCH2OCOR
H


514
2-F
4-F
(CH2)nCH2OR
H


515
2-Cl
4-Cl
(CH2)nCH2OR
H


516
2-Br
4-Br
(CH2)nCH2OR
H


517
2-F
H
(CH2)nCH2OR
H


518
2-Cl
H
(CH2)nCH2OR
H


519
2-Br
H
(CH2)nCH2OR
H


520
H
4-F
(CH2)nCH2OR
H


521
H
4-Cl
(CH2)nCH2OR
H


522
H
4-Br
(CH2)nCH2OR
H


523
2-F
4-F
(CH2)2CH2OBn
H
1-A02


524
2-Cl
4-Cl
(CH2)2CH2OBn
H


525
2-Br
4-Br
(CH2)2CH2OBn
H


526
2-F
H
(CH2)2CH2OBn
H


527
2-Cl
H
(CH2)2CH2OBn
H


528
2-Br
H
(CH2)2CH2OBn
H


529
H
4-F
(CH2)2CH2OBn
H


530
H
4-Cl
(CH2)2CH2OBn
H


531
H
4-Br
(CH2)2CH2OBn
H


532
2-F
4-F
(CH2)3CH2OBn
H
1-A01


533
2-Cl
4-Cl
(CH2)3CH2OBn
H


534
2-Br
4-Br
(CH2)3CH2OBn
H


535
2-F
H
(CH2)3CH2OBn
H


536
2-Cl
H
(CH2)3CH2OBn
H


537
2-Br
H
(CH2)3CH2OBn
H


538
H
4-F
(CH2)3CH2OBn
H


539
H
4-Cl
(CH2)3CH2OBn
H


540
H
4-Br
(CH2)3CH2OBn
H


541
2-F
4-F
(CH2)nCH2R
H


542
2-Cl
4-Cl
(CH2)nCH2R
H


543
2-Br
4-Br
(CH2)nCH2R
H


544
2-F
H
(CH2)nCH2R
H


545
2-Cl
H
(CH2)nCH2R
H


546
2-Br
H
(CH2)nCH2R
H


547
H
4-F
(CH2)nCH2R
H


548
H
4-Cl
(CH2)nCH2R
H


549
H
4-Br
(CH2)nCH2R
H


550
2-F
4-F
CH2Ph
(CH2)nCH2R


551
2-Cl
4-Cl
CH2Ph
(CH2)nCH2R


552
2-Br
4-Br
CH2Ph
(CH2)nCH2R


553
2-F
H
CH2Ph
(CH2)nCH2R


554
2-Cl
H
CH2Ph
(CH2)nCH2R


555
2-Br
H
CH2Ph
(CH2)nCH2R


556
H
4-F
CH2Ph
(CH2)nCH2R


557
H
4-Cl
CH2Ph
(CH2)nCH2R


558
H
4-Br
CH2Ph
(CH2)nCH2R


559
2-F
4-F
CH2Ph
CH3
1-A15


560
2-Cl
4-Cl
CH2Ph
CH3


561
2-Br
4-Br
CH2Ph
CH3


562
2-F
H
CH2Ph
CH3


563
2-Cl
H
CH2Ph
CH3


564
2-Br
H
CH2Ph
CH3


565
H
4-F
CH2Ph
CH3


566
H
4-Cl
CH2Ph
CH3


567
H
4-Br
CH2Ph
CH3


568
2-F
4-F
H
(CH2)nCH2Ph


569
2-Cl
4-Cl
H
(CH2)nCH2Ph


570
2-Br
4-Br
H
(CH2)nCH2Ph


571
2-F
H
H
(CH2)nCH2Ph


572
2-Cl
H
H
(CH2)nCH2Ph


573
2-Br
H
H
(CH2)nCH2Ph


574
H
4-F
H
(CH2)nCH2Ph


575
H
4-Cl
H
(CH2)nCH2Ph


576
H
4-Br
H
(CH2)nCH2Ph


577
2-F
4-F
H
CH2CH2Ph
1-A14


578
2-Cl
4-Cl
H
CH2CH2Ph


579
2-Br
4-Br
H
CH2CH2Ph


580
2-F
H
H
CH2CH2Ph


581
2-Cl
H
H
CH2CH2Ph


582
2-Br
H
H
CH2CH2Ph


583
H
4-F
H
CH2CH2Ph


584
H
4-Cl
H
CH2CH2Ph


585
H
4-Br
H
CH2CH2Ph


586
2-F
4-F
(CH2)nCH2OCOCH2NHBoc
H


587
2-Cl
4-Cl
(CH2)nCH2OCOCH2NHBoc
H


588
2-Br
4-Br
(CH2)nCH2OCOCH2NHBoc
H


589
2-F
H
(CH2)nCH2OCOCH2NHBoc
H


590
2-Cl
H
(CH2)nCH2OCOCH2NHBoc
H


591
2-Br
H
(CH2)nCH2OCOCH2NHBoc
H


592
H
4-F
(CH2)nCH2OCOCH2NHBoc
H


593
H
4-Cl
(CH2)nCH2OCOCH2NHBoc
H


594
H
4-Br
(CH2)nCH2OCOCH2NHBoc
H


595
2-F
4-F
(CH2)3CH2OCOCH2NHBoc
H
1-A24


596
2-Cl
4-Cl
(CH2)3CH2OCOCH2NHBoc
H


597
2-Br
4-Br
(CH2)3CH2OCOCH2NHBoc
H


598
2-F
H
(CH2)3CH2OCOCH2NHBoc
H


599
2-Cl
H
(CH2)3CH2OCOCH2NHBoc
H


600
2-Br
H
(CH2)3CH2OCOCH2NHBoc
H


601
H
4-F
(CH2)3CH2OCOCH2NHBoc
H


602
H
4-Cl
(CH2)3CH2OCOCH2NHBoc
H


603
H
4-Br
(CH2)3CH2OCOCH2NHBoc
H


604
2-F
4-F
(CH2)nCH2OCOCH2NHR
H


605
2-Cl
4-Cl
(CH2)nCH2OCOCH2NHR
H


606
2-Br
4-Br
(CH2)nCH2OCOCH2NHR
H


607
2-F
H
(CH2)nCH2OCOCH2NHR
H


608
2-Cl
H
(CH2)nCH2OCOCH2NHR
H


609
2-Br
H
(CH2)nCH2OCOCH2NHR
H


610
H
4-F
(CH2)nCH2OCOCH2NHR
H


611
H
4-Cl
(CH2)nCH2OCOCH2NHR
H


612
H
4-Br
(CH2)nCH2OCOCH2NHR
H


613
2-F
4-F
(CH2)3CH2OCOCH2NH2
H
1-A25


614
2-Cl
4-Cl
(CH2)3CH2OCOCH2NH2
H


615
2-Br
4-Br
(CH2)3CH2OCOCH2NH2
H


616
2-F
H
(CH2)3CH2OCOCH2NH2
H


617
2-Cl
H
(CH2)3CH2OCOCH2NH2
H


618
2-Br
H
(CH2)3CH2OCOCH2NH2
H


619
H
4-F
(CH2)3CH2OCOCH2NH2
H


620
H
4-Cl
(CH2)3CH2OCOCH2NH2
H


621
H
4-Br
(CH2)3CH2OCOCH2NH2
H


622
2-F
4-F
(CH2)nCH3
(CH2)nCH3


623
2-Cl
4-Cl
(CH2)nCH3
(CH2)nCH3


624
2-Br
4-Br
(CH2)nCH3
(CH2)nCH3


625
2-F
H
(CH2)nCH3
(CH2)nCH3


626
2-Cl
H
(CH2)nCH3
(CH2)nCH3


627
2-Br
H
(CH2)nCH3
(CH2)nCH3


628
H
4-F
(CH2)nCH3
(CH2)nCH3


629
H
4-Cl
(CH2)nCH3
(CH2)nCH3


630
H
4-Br
(CH2)nCH3
(CH2)nCH3


631
2-F
4-F
(CH2)2CH3
(CH2)3CH3
1-A05


632
2-Cl
4-Cl
(CH2)2CH3
(CH2)3CH3


633
2-Br
4-Br
(CH2)2CH3
(CH2)3CH3


634
2-F
H
(CH2)2CH3
(CH2)3CH3


635
2-Cl
H
(CH2)2CH3
(CH2)3CH3


636
2-Br
H
(CH2)2CH3
(CH2)3CH3


637
H
4-F
(CH2)2CH3
(CH2)3CH3


638
H
4-Cl
(CH2)2CH3
(CH2)3CH3


639
H
4-Br
(CH2)2CH3
(CH2)3CH3









Example 5
General Method of Preparation of Compounds of Formula 4
A mixture of compound of Formula (3) (1 mmol), ammonium acetate (1-10 mmol) and formamide (10-20 mmol) was stirred under reflux for 2 to 20 hrs, cooled, diluted with water, extracted with ethyl acetate, dried, concentrated and purified by column chromatography to obtain the compound of the Formula (4).
The following compounds were prepared by the method described above:
1) 6-(4-Benzyloxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one (4-A02)
A mixture of ethyl 2-amino-5-(3-benzyloxypropyl)-thiophene-3-carboxylate of Formula (3-A02): (5.5 g, 0.017 mole), ammonium acetate (10.6 g, 0.14 mole) and formamide (17.12 ml, 0.43 mole), was stirred under reflux at 145° C. for 12 hours. It was then cooled, diluted with water (50 ml), extracted with ethyl acetate (3×30 ml), dried, concentrated and purified by column chromatography to obtain the pure 6-(4-Benzyloxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one of Formula (4-A02) (4.5 gm, 87.2%).
1HNMR (CDCl3, 200 MHz): 1.91-2.12 (m, 2H), 3.01 (t, J=6 Hz, 2H), 3.53 (t, J=6 Hz, 2H), 4.51 (s, 2H), 7.17 (s, 1H), 7.33 (bs, 5H), 8.03 (s, 1H), 12.84 (bs, 1H).
2) 6-(3-Acetoxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one (4-A26)
A mixture of ethyl 2-amino-5-(3-acetyloxypropyl)-thiophene-3-carboxylate (2.6 g, 9.7 mmole), ammonium acetate (0.74 g, 9.7 mmole) and formamide (8.64 ml, 19.2 mmole), was stirred under reflux at 145° C. for 12 hours. It was then cooled, diluted with water (20 ml), extracted with ethyl acetate (3×25 ml), dried, concentrated and purified by column chromatography to obtain the pure 6-(3-Acetoxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one of Formula (4-A26) (1.8 gm, 75%).
1HNMR (CDCl3, 200 MHz): 1.94-2.18 (m including s at 2.07, 5H), 2.85-3.08 (m, 2H), 4.05-4.30 (m, 2H), 7.18 (s, 1H), 8.03 (s, 1H), 12.63 (bs, 1H).
3) 5,6,7,8-Tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one (4-A09)
A mixture of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.7 g, 3.1 mmole), ammonium acetate (0.31 g, 4.04 mmole) and formamide (0.67 ml, 16.8 mmole), was stirred under reflux at 140° C. for 13 hours. It was then cooled, diluted with water (20 ml), extracted with ethyl acetate (3×35 ml), dried, concentrated and purified by column chromatography to obtain the pure 5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one of Formula (4-A09) (0.53 gm, 82%).
1HNMR (CDCl3+DMSO-d6, 200 MHz): 1.36-1.52 (m, 4H), 2.31-2.40 (m, 2H), 2.51-2.62 (m, 2H), 7.45 (s, 1H).
4) 6-(4-Benzyloxybutyl)-thieno[2,3-d]pyrimidin-4(3H)-one (4-A01)
1HNMR (CDCl3, 200 MHz): 1.61-1.92 (m, 4H), 2.89 (t, J=6 Hz, 2H), 3.51 (t, J=6 Hz, 2H), 4.51 (s, 2H), 7.17 (s, 1H), 7.34 (bs, 5H), 8.02 (s, 1H), 12.54 (bs, 1H).
5) 6-(n-Hexyl)-thieno[2,3-d]pyrimidin-4(3H)-one (4-A03)
1HNMR (CDCl3, 200 MHz): 0.90 (t, J=6 Hz, 3H), 1.21-1.50 (m, 6H), 1.61-1.86 (m, 2H), 2.87 (t, J=8 Hz, 2H), 7.15 (s, 1H), 8.03 (s, 1H), 12.80 (bs, 1H).
6) 6-(n-Pentyl)-thieno[2,3-d]pyrimidin-4(31)-one (4-A04)
1HNMR (CDCl3, 200 MHz): 0.89 (t, J=6 Hz, 3H), 1.16-1.45 (m, 4H), 1.52-1.83 (m, 2H), 2.84 (t, J=8 Hz, 2H), 7.13 (s, 1H), 8.07 (s, 1H), 12.90 (bs, 1H).
7) 5-n-Butyl-6-(n-propyl)-thieno[2,3-d]pyrimidin-4(3H)-one (4-A05)
1HNMR (CDCl3, 200 MHz): 0.93 (t, J=6 Hz, 3H), 0.99 (t, J=6 Hz, 3H), 1.26-1.85 (m, 6H), 2.79 (t, J=6 Hz, 2H), 2.95 (t, J=6 Hz, 2H), 7.95 (s, 1H), 12.34 (bs, 1H).
8) 6-(n-Heptyl)-thieno[2,3-d]pyrimidin-4(3H)-one (4-A06)
1HNMR (CDCl3, 200 MHz): 0.89 (t, J=6 Hz, 3H), 1.26-1.38 (m, 8H), 1.60-1.78 (m, 2H), 2.87 (t, J=6 Hz, 2H), 7.17 (s, 1H), 8.05 (s, 1H), 12.82 (bs, 1H).
9) 3,5,6,7-Tetrahydrocyclopenta[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (4-A07)
The crude compound obtained was used as such for further reaction.
10) 6-Methyl-5-n-pentyl-thieno[2,3-d]pyrimidin-4(3H)-one (4-A08)
1HNMR (CDCl3, 200 MHz): 0.91 (bt, J=6 Hz, 3H), 1.25-1.50 (m, 4H), 1.52-1.68 (m, 2H), 2.43 (s, 3H), 2.93 (t, J=8 Hz, 2H), 7.96 (s, 1H), 12.32 (bs, 1H).
11) 6-n Hexyl-5-methyl-thieno[2,3-d]pyrimidin-4(3H)-one (4-A10)
1HNMR (CDCl3, 200 MHz): 0.90 (t, J=6 Hz, 3H), 1.22-1.46 (m, 6H), 1.52-1.76 (m, 2H), 2.52 (s, 3H), 2.78 (t, J=6 Hz, 2H), 7.96 (s, 1H), 12.32 (bs, 1H).
11) 5-Methyl-6-n-pentyl-thieno[2,3-d]pyrimidin-4(3H)-one (4-A11)
1HNMR (CDCl3, 200 MHz): 0.91 (t, J=6 Hz, 3H), 1.25-1.48 (m, 4H), 1.55-1.75 (m, 2H), 2.52 (s, 3H), 2.79 (t, J=8 Hz, 2H), 8.20 (s, 1H).
12) 6-(7-Acetoxyheptyl)-thieno[2,3-d]pyrimidin-4(3H)-one (4-A12)
1HNMR (CDCl3, 200 MHz): 1.24-1.42 (m, 6H), 1.48-1.77 (m, 4H), 1.97 (s, 3H), 2.79 (t, J=8 Hz, 2H), 3.98 (t, J=7 Hz, 2H), 7.08 (s, 1H), 8.03 (s, 1H).
13) 5-(2-Phenylethyl)-thieno[2,3-d]pyrimidin-4(3H)-one (4-A14)
1HNMR (CDCl3+DMSO-d6, 200 MHz): 3.05 (t, J=7 Hz, 2H), 3.34 (t, J=7 Hz, 2H), 6.84 (s, 1H), 7.30 (bs, 5H), 8.00 (s, 1H).
14) 6-Benzyl-5-methyl-thieno[2,3-d]pyrimidin-4(3H)-one (4-A15)
1HNMR (DMSOd6, 200 MHz):: 2.48 (s, 3H), 4.13 (s, 2H), 7.22-7.34 (m, 5H), 8.00 (s, 1H).
15) 6-(n-Decyl)-thieno[2,3-d]pyrimidin-4(3H)-one (4-A16)
1HNMR (CDCl3, 200 MHz): 0.88 (t, J=6 Hz, 3H), 1.18-1.42 (m, 14H), 1.62-1.83 (m, 2H), 2.86 (t, J=6 Hz, 2H), 7.17 (s, 1H), 8.15 (s, 1H).
16) 6-(n-Nonyl)-thieno[2,3-d]pyrimidin-4(3H)-one (4-A17)
1HNMR (CDCl3, 200 MHz): 0.91 (t, J=6 Hz, 3H), 1.14-1.55 (m, 12H), 1.65-1.92 (m, 2H), 2.89 (t, J=6 Hz, 2H), 7.19 (s, 1H), 8.09 (s, 1H), 12.96 (bs, 1H).
17) 6-(n-Propyl)-thieno[2,3-d]pyrimidin-4(3H)-one (4-A18)
1HNMR (CDCl3, 200 MHz): 1.01 (t, J=6 Hz, 3H), 1.67-1.85 (m, 2H), 2.84 (t, J=6 Hz, 2H), 7.16 (s, 1H), 8.05 (s, 1H), 12.74 (bs, 1H).
18) 7,8,9,10,11,12,13,14,15,16-Decahydrocyclododeca[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (4-A19)
1HNMR (CDCl3, 200 MHz): 1.21-1.58 (m, 12H), 1.68-2.01 (m, 4H), 2.79-2.99 (m, 4H), 7.98 (s, 1H), 12.08 (bs, 1H).
19) 5-Methyl-6-n-octyl-thieno[2,3-d]pyrimidin-4(3H)-one (4-A20)
1HNMR (CDCl3, 200 MHz): 0.92 (t, J=7 Hz, 3H), 1.20-1.52 (m, 10H), 1.60-1.75 (m, 2H), 2.55 (s, 3H), 2.82 (t, J=8 Hz, 2H), 8.19 (s, 1H).
20) 6-n-Butyl-5-methyl-thieno[2,3-d]pyrimidin-4(3H)-one (4-A21)
1HNMR (CDCl3, 200 MHz): 0.96 (t, J=6 Hz, 3H), 1.32-1.73 (m, 4H), 2.52 (s, 3H), 2.79 (t, J=8 Hz, 2H), 7.99 (s, 1H), 12.48 (bs, 1H).
21) 6-Ethyl-thieno[2,3-d]pyrimidin-4(3H)-one (4-A22)
1HNMR (CDCl3, 200 MHz): 1.39 (t, J=8 Hz, 3H), 2.92 (q, J=8 Hz, 2H), 7.17 (s, 1H), 8.02 (s, 1H).
Example 6
General Methods of Preparation of Compounds of Formula (3)
Method A:
A mixture of ethyl cyanoacetate (1 eq), sulphur (1 eq), triethyl amine (0.5 eq) and a ketone or aldehyde (1 eq) was stirred at 30 to 80° C. for 8 to 20 hrs, cooled, diluted with water, extracted with ethyl acetate, dried, concentrated and purified by column chromatography to obtain the pure compounds of the Formula (3).
Method B:
A mixture of ethyl cyanoacetate (1 eq), sulphur (1 eq), morpholine (1 eq) and ketone or aldehyde (1 eq) in ethanol was stirred at 30 to 60° C. for 5 to 20 hrs, ethanol was removed on rotavapor, the reaction mixture was extracted with ethyl acetate, dried, concentrated and purified by column chromatography to get the pure compounds of the Formula (3).
1. Ethyl 2-amino-5-(3-benzyloxypropyl)-thiophene-3-carboxylate (3-A02)
A mixture of ethyl cyanoacetate (2.77 ml, 26 mmol), sulphur (0.83 g, 26 mmol), triethyl amine (1.82 ml, 13 mmol) and 5-benzyloxy-1-pentanal (5.00 g, 26 mmol) in DMF (40 ml) was stirred at 45-50° C. for 12 hours. It was then cooled, diluted with water (100 ml), extracted with ethyl acetate (2×100 ml), dried, concentrated and purified by column chromatography to obtain the pure ethyl 2-amino-5-(3-benzyloxypropyl)-thiophene-3-carboxylate (4.5 gm, 54%).
1HNMR (CDCl3, 200 MHz): 1.34 (t, J=8 Hz, 3H), 1.80-1.96 (m, 2H), 2.70 (t, J=7 Hz, 2H), 3.51 (t, J=7 Hz, 2H), 4.25 (q, J=7 Hz, 2H), 4.51 (s, 2H), 5.80 (bs, 2H), 6.64 (s, 1H), 7.34 (bs, 5H).
2. Ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (3-A09)
A mixture of ethyl cyanoacetate (1.15 g, 0.01 mol), sulphur (0.32 g, 0.01 mol), triethyl amine (0.52 g, 0.005 mol) and cyclohexanone (1.0 g, 0.01 mol) in DMF (10 ml) was stirred at 55° C. for 12 hours. It was cooled, diluted with water (80 ml), extracted with ethyl acetate (2×100 ml), dried, concentrated and purified by column chromatography to obtain the pure ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate of Formula (3-A09) (1.13 gm, 50%).
1HNMR (CDCl3, 200 MHz): 1.27 (t, J=7 Hz, 3H), 1.62-1.78 (m, 4H), 2.35-2.50 (m, 2H), 2.54-2.70 (m, 2H), 4.19 (q, J=7 Hz, 2H).
3. Ethyl 5-(3-acetoxypropyl)-2-aminothiophene-3-carboxylate (3-A26)
A mixture of ethyl cyanoacetate (6.2 ml, 50 mmol), sulphur (4.6 g, 50 mmol), morpholine (4.3 ml, 50 mmol) and 5-acetoxy-1-pentanal (8 g, 50 mmol) in ethanol (25 ml) was stirred at 80° C. for 12 hours. Ethanol was removed on rotavapor, the reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (3×100 ml), dried, concentrated and purified by column chromatography to get the pure ethyl 5-(3-acetoxypropyl)-2-amino-thiophene-3-carboxylate (6.4 gm, 42.5%).
1HNMR (CDCl3, 200 MHz): 1.32 (t, J=7 Hz, 2H), 1.81-1.98 (m, 2H), 2.05 (s, 3H), 2.65 (t, J=7 Hz, 2H), 4.08 (t, J=7 Hz, 2H), 4.24 (q, J=7 Hz, 2H), 5.18 (bs, 2H), 6.64 (s, 1H).
The methods described above were used for preparing more compounds some of which are given below:
4. Ethyl 2-amino-5-(4-benzyloxybutyl)-thiophene-3-carboxylate (3-A01)
1HNMR (CDCl3, 200 MHz): 1.33 (t, J=8 Hz, 3H), 1.60-1.75 (m, 4H), 2.59 (bt, J=6 Hz, 2H), 3.48 (bt, J=6 Hz, 2H), 4.25 (q, J=8 Hz, 2H), 4.50 (s, 2H), 5.77 (bs, 2H), 6.62 (s, 1H), 7.33 (bs, 5H).
5. Ethyl 2-amino-5-n-hexyl-thiophene-3-carboxylate (3-A03)
1HNMR (CDCl3, 200 MHz): 0.90 (bt, J=6 Hz, 3H), 1.22-1.42 (m, 9H), 1.49-1.63 (m, 2H), 2.57 (t, J=7 Hz, 2H), 4.26 (q, J=7 Hz, 2H), 5.79 (bs, 2H), 6.61 (s, 1H).
6. Ethyl 2-amino-5-n-pentyl-thiophene-3-carboxylate (3-A04)
1HNMR (CDCl3, 200 MHz): 0.88 (bt, J=6 Hz, 3H), 1.21-1.40 (m, 7H), 1.49-1.71 (m, 2H), 2.55 (t, J=8 Hz, 2H), 4.24 (q, J=7 Hz, 2H), 5.65 (bs, 2H), 6.61 (s, 1H).
7. Ethyl 2-amino-5-n-heptyl-thiophene-3-carboxylate (3-A06)
1HNMR (CDCl3, 200 MHz): 0.89 (bt, J=6 Hz, 3H), 1.26-1.48 (m, 11H), 1.51-1.71 (m, 2H), 2.58 (t, J=8 Hz, 2H), 4.26 (q, J=7 Hz, 2H), 5.49 (bs, 2H), 6.63 (s, 1H).
8. Ethyl 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate (3-A07)
1HNMR (CDCl3, 200 MHz): 1.32 (t, J=7 Hz, 3H), 2.22-2.38 (m, 2H), 2.65-2.90 (m, 4H), 4.24 (q, J=7 Hz, 2H), 5.85 (bs, 2H).
9. Ethyl 2-amino-5-methyl-4-(n-pentyl)-thiophene-3-carboxylate (3-A08)
1HNMR (CDCl3, 200 MHz): 0.91 (t, J=6 Hz, 3H), 1.30-1.52 (m, 7H), 2.16 (s, 3H), 2.35-2.50 (m, 2H), 2.55-2.70 (m, 2H), 4.29 (q, J=7 Hz, 2H), 5.92 (bs, 2H).
10. Ethyl 2-amino-5-n-hexyl-4-methyl-thiophene-3-carboxylate (3-A10)
1HNMR (CDCl3, 200 MHz): 0.90 (bt, J=6 Hz, 3H), 1.22-1.40 (m, 9H), 1.45-1.63 (m, 2H), 2.18 (s, 3H), 2.54 (t, J=8 Hz, 2H), 4.28 (q, J=8 Hz, 2H), 5.01 (bs, 2H).
11. Ethyl 2-amino-5(7-acetoxy-n-heptyl)-thiophene-3-carboxylate (3-A12)
1HNMR (CDCl3, 200 MHz): 1.21-1.40 (m, 9H), 1.45-1.67 (m, 4H), 2.00 (s, 3H), 2.52 (t, J=8 Hz, 2H), 4.00 (t, J=6 Hz, 2H), 4.20 (q, J=8 Hz, 2H), 5.67 (bs, 2H), 6.57 (s, 1H).
12. Ethyl 2-amino-5-(2-phenylethyl)-thiophene-3-carboxylate (3-A14)
1HNMR (CDCl3, 200 MHz): 1.35 (t, J=8 Hz, 3H), 2.74-3.07 (m, 4H), 4.32 (q, J=8 Hz, 2H), 5.19 (bs, 2H), 7.15-7.26 (m, 6H).
13. Ethyl 2-amino-5-benzyl-4-methyl-thiophene-3-carboxylate (3-A15)
1HNMR (CDCl3, 200 MHz): 1.35 (t, J=8 Hz, 3H), 2.25 (s, 3H), 3.90 (s, 2H), 4.29 (q, J=7 Hz, 2H), 5.18 (bs, 2H), 7.19 (bs, 5H).
14. Ethyl 2-amino-5-n-decyl-thiophene-3-carboxylate (3-A16)
1HNMR (CDCl3, 200 MHz): 0.88 (bt, J=6 Hz, 3H), 1.18-1.40 (m including t at 1.33 with J=7 Hz, 17H), 1.49-1.65 (m, 2H), 2.56 (t, J=7 Hz, 2H), 4.25 (q, J=7 Hz, 2H), 5.40 (bs, 2H), 6.63 (s, 1H).
15. Ethyl 2-amino-5-n-nonyl-thiophene-3-carboxylate (3-A17)
1HNMR (CDCl3, 200 MHz): 0.88 (bt, J=7 Hz, 3H), 1.15-1.42 (m including t at 1.32 with J=7 Hz, 15H), 1.47-1.65 (m, 2H), 2.54 (t, J=7 Hz, 2H), 4.24 (q, J=7 Hz, 2H), 5.78 (bs, 2H), 6.61 (s, 1H).
16. Ethyl 2-amino-5-n-propyl-thiophene-3-carboxylate (3-A18)
1HNMR (CDCl3, 200 MHz): 0.95 (t, J=7 Hz, 3H), 1.34 (t, J=7 Hz, 3H), 1.51-1.71 (m, 2H), 2.56 (t, J=7 Hz, 2H), 4.26 (q, J=7 Hz, 2H), 4.75 (bs, 2H), 6.64 (s, 1H).
17. Ethyl 2-amino-4,5,6,7,8,9,10,11,12,13-decahydro-[1]cyclododeca[b]thiophene-3-carboxylate (3-A19)
1HNMR (CDCl3, 200 MHz): 1.21-1.50 (m, 15H), 1.55-1.71 (m, 4H), 2.54-2.71 (m, 4H), 4.27 (q, J=7 Hz, 2H).
18. Ethyl 2-amino-5-ethyl-thiophene-3-carboxylate (3-A22)
1HNMR (CDCl3, 200 MHz): 1.23 (t, J=7 Hz, 3H), 1.34 (t, J=7 Hz, 3H), 2.62 (q, J=7 Hz, 2H), 4.26 (q, J=7 Hz, 2H), 4.62 (bs, 2H), 6.64 (s, 1H).
Example 7
Antifungal Activity Testing
The compounds of Formula 1 are antifungal agents effective against Candida albicans. In vitro evaluation of antifungal activity was performed by determining the minimum inhibitory concentration (MIC). Anti-fungal susceptibility testing of these anti-fungal compounds was done by broth dilution method using RPMI 1640 medium with MOPS buffer. Known anti-fungal agents like fluconazole and amphotericin-B were used as positive control. End points were determined after 48 hours visually and by using spectrophotometer wherever necessary. Different dilutions were, tried and various sets of experiments performed. The activity parameters are enumerated in Table 1:







TABLE 1







MIC obtained by broth macro-dilution method









MIC against fungi in μg/ml














Structure
C. albicans
A. niger
F. proliferatum


No.
Code no.
R1 = R2 = 2,4-difluoro
(ATCC 24433)
(ATCC 16404)
(ATCC 10052)






Fluconazole

0.25-1  
  64-128
>128



Amphote

0.12-0.25
0.25-1
1-2



ricin B


01
1-A01
R3 = —(CH2)4OBn,
0.06-0.12
NI till 4
NI till 4




R4 = H


02
1-A02
R3 = —(CH2)3OBn,
0.06-0.12
NI till 4
NI till 4




R4 = H


03
1-A03
R3 = —(CH2)5Me, R4 = H
0.03-0.06
NI till 2
NI till 2


04
1-A04
R3 = —(CH2)4Me, R4 = H
0.03-0.06
NI till 4
NI till 4


05
1-A05
R3 = —(CH2)2Me, R4 = —(CH2)3Me
2-4
NI till 4
NI till 4


06
1-A06
R3 = —(CH2)6Me, R4 = H
0.06-0.12
NI till 2
NI till 2


07
1-A07
R3, R4 = —(CH2)3—
0.25-0.5 
NI till 2
NI till 2


08
1-A08
R3 = —Me, R4 = —(CH2)4Me
2-4
NI till 4
NI till 4


09
1-A09
R3, R4 = —(CH2)4—
0.25-0.5 
NI till 8
NI till 8


10
1-A10
R3 = —(CH2)5Me, R4 = —Me
1-2
NI till 2
NI till 2


11
1-A11
R3 = —(CH2)4Me, R4 = —Me
1-2
NI till 2
NI till 2


12
1-A12
R3 = —(CH2)7OAc, R4 = H
0.12-0.25
NI till 2
NI till 2


13
1-A13
R3 = —(CH2)7OH, R4 = H
0.12-0.25
NI till 16
NI till 16


14
1-A14
R3 = H, R4 = (CH2)2Ph
0.5-1  
NI till 2
NI till 2


15
1-A15
R3 = CH2Ph, R4 = CH3
1-2
NI till 4
NI till 4


16
1-A16
R3 = (CH2)9CH5, R4 = H
1-2
NI till 2
NI till 2


17
1-A17
R3 = (CH2)8CH5, R4 = H
0.25-0.5 
NI till 4
NI till 4


18
1-A18
R3 = (CH2)2CH5, R4 = H
0.06-0.12
NI till 32
NI till 32


19
1-A19
R3, R4 = (CH2)10
NI till 2
NI till 2
NI till 2


20
1-A22
R3 = CH2CH3, R4 = H
0.06-0.12
NI till 16
NI till 16


21
1-A23
R3 = —(CH2)4OH R4 = H
1-2
NI till 64
NI till 64


22
1-A24
R3 = —(CH2)4OCOCH2—NHBoc, R4 = H
0.5-1  
NI till 16
NI till 16


23
1-A25
R3 = —(CH2)4OCOCH2NH2,
4-8
NI till 8
NI till 8




R4 = H


24
1-A26
R3 = —(CH2)3OAc, R4 = H
1-2
NI till 64
NI till 64


25
1-A27
R3 = —(CH2)3OH R4 = H
2-4
NI till 128
NI till 128


26
1-A28
R3 = CH3R4 = H
0.25-0.5 
NI till 64
NI till 64









It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

## Claims

1. An antifungal compound, comprising:
a compound of the Formula (1):




wherein,
R1 is hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine;
R2 is hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine; and either
a) R3 and R4, which may be the same or different, each represents a hydrogen, alkyl group of linear or branched chain of 1 to 20 carbon atoms optionally substituted with aryl group, hydroxyl group, alkanoate group, amino acetyloxy group, N-Boc-amino acetyloxy group, alkoxy (—OR) group (wherein R=alkyl group with 1 to 4 carbon atoms), benzyloxy, arylalkyl group (wherein the aryl group is phenyl which is either unsubstituted or substituted with alkyl group of 1 to 3 carbon atoms), or cycloalkyl group with 3 to 10 carbon atoms; or
R3 and R4 together form an alkylene chain having between 3 and 10 carbon atoms;

a stereochemically isomeric form thereof; or
a pharmaceutically acceptable salt thereof.

2. A process of preparing an antifungal compound of Formula (1), comprising:



a) preparing a 2-amino-4 and/or 5-substituted thiophene-3-carboxylate of Formula (3) by Gewald synthesis, wherein:
R is methyl or ethyl, and either
i) R3 and R4, which may be the same or different, each represent a hydrogen, alkyl group of linear or branched chain of 1 to 20 carbon atoms optionally substituted with aryl group, hydroxyl group, alkanoate group, amino acetyloxy group, N-Boc-amino acetyloxy group, alkoxy (—OR) group (wherein R=alkyl group with 1 to 4 carbon atoms), benzyloxy, arylalkyl group (wherein the aryl group is phenyl which is either unsubstituted or substituted with alkyl group of 1 to 3 carbon atoms), or cycloalkyl group with 3 to 10 carbon atoms); or
ii) R3 and R4 together form an alkylene chain having between 3 and 10 carbon atoms;

b) contacting said 2-amino-4 and/or 5-substituted thiophene-3-carboxylate of Formula (3) with formamide and ammonium acetate to obtain the thieno-[2,3-d]-pyrimidin-4(3H)-one of Formula (4), wherein R3 and R4 are as defined above; and
c) treating the compound of Formula (4) with an epoxide of Formula (5) in the presence of a base to obtain an antifungal compound of the Formula (1), wherein:
R1 and R2 are each hydrogen or a halogen selected from fluorine, chlorine, bromine or iodine.

3. A compound according to claim 1 selected from the group consisting of:
6-(4-Benzyloxybutyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-ylpropyl]-thieno[2,3-d]pyrimidin-4(3H)-one:
6-(3-Benzyloxypropyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-ylpropyl]-thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(n-hexyl)-thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-n-pentylthieno[2,3-d]pyrimidin-4(3H)-one:
5-n-Butyl-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-n-propyl-thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-n-heptylthieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-3,5,6,7-tetrahydrocyelopenta[4,5]thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-methyl-5-n-pentyl-thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-n-hexyl-5-methyl-thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-5-methyl-6-n-pentyl-thieno[2,3-d]pyrimidin-4(3H)-one:
6-(7-Acetoxyheptyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(7-hydroxyheptyl)-thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-5(2-phenylethyl)-thieno[2,3-d]pyrimidin-4(3H)-one:
6-Benzyl-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-5-methyl-thieno[2,3-d]pyrimidin-4(3H)-one:
6-n-Decyl-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-n-nonylthieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(n-propyl)-thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-3,5,6,7,8,9,10,11,12,13,14-undecahydrocyclododeca[4,5]thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]-triazol-1-yl-propyl]-5-methyl-6-n-octyl-thieno[2,3-d]pyrimidin-4(3H)-one:
3,-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-n-butyl-5-methyl-thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-yl-propyl]-6-ethylthieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(4-hydroxybutyl)-thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(4-N-Bocaminoacetyloxybutyl)-thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(4-aminoacetyloxybutyl)-thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(3-acetoxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one:
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(3-hydroxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one: or
3-[2-(2,4-Difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one.

4. A pharmaceutical composition comprising an antifungal compound of formula (1) according to claim 1, with at least one pharmaceutical excipient.

5. A pharmaceutical composition comprising an antifungal compound prepared according to the process of claim 2, with at least one pharmaceutical excipient.

6. A pharmaceutical composition comprising a compound according to claim 3, with at least one pharmaceutical excipient.

7. A method for treating or preventing a fungal infection in a subject, which method comprises administering an effective amount of a compound according to claim 1, with pharmaceutical excipients.

8. A method for treating or preventing a fungal infection in a subject, which method comprises administering an effective amount of an antifungal compound prepared according to the process of claim 2, with pharmaceutical excipients.

9. A method for treating or preventing a fungal infection in a subject, which method comprises administering an effective amount of a compound according to claim 3, with pharmaceutical excipients.

10. A compound according to claim 1, wherein R3 and R4 together form an alkylene chain of formula —(CH2)n—, n being between 3 and 10.

11. A process according to claim 2, wherein R3 and R4 together form an alkylene chain of formula —(CH2)n—, n being between 3 and 10.