JPH10231296A - Tetrahydrofuran-based antifungal agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound consisting of a specific tetrahydrofuran derivative, having a high solubility and useful, e.g. as a broad spectrum antifungal agent having a favorable activity profile effective for treatment and prevention of a systemic fungus infection of mammals. SOLUTION: This compound is a new tetrahydrofuran derivative (salt) shown by formula I (2 Xs are both F or Cl, or one is F and the other Cl; R1 is a 4-5C alkyl substituted with 1 or 2 groups which are convertible in vivo into 1 or 2 hydroxy parts), and useful, e.g. as a broad spectrum antifungal agent having a favorable activity profile. The compound is obtained by reacting a tetrahyddofuran derivative shown by formula II (Ts is tosyl) with a hydroxy compound shown by the formula HOY (Y is a group shown by formula III) in an aprotic solvent in the presence of a strong base, e.g. NaH.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an antifungal agent for tetrahydrofuran, (2R-cis) -4- [4- [4- [4-
[[(5- (2,4-Dihalophenyl) -tetrahydro-5- ( 1H -1,2,4-triazol-1-ylmethyl) -tetrahydrofuran-3-yl] methoxy] phenyl] -2,4-dihydro 2- [mono - or di - substituted (C ₄ ~C ₅₎ esters of alkyl and ether]-3H-1,2,4-triazol-3-one substituted antifungals, and salts thereof, their And a method of treating and / or preventing an antifungal infection in a host, including warm-blooded animals, particularly humans having such a tetrahydrofuran antifungal agent.

[0002]

2. Description of the Related Art International publication No. 1 published on June 1, 1990
WO 89/04829 and US Pat. No. 5,039,676 (AKSaks
ena et al) is represented by the following formula (±) cis and (±) bets
Disclose Lance antifungal compounds:

[0003]

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Wherein X is F or Cl; Z is lower alkyl, 2-lower alkyl-3-oxo-1,2,4-triazol-4-yl (eg, (±) cis and (±) Trans -1- [4-[[2- (2,4-difluorophenyl) -2-[( 1H -1,2,4-triazol-1-yl) methyl] tetrahydro-4-furanyl] methoxy] phenyl ] -4- (1-Methylethyl)
Substituted by piperazine) (C ₂ -C ₈₎ alkanoyl or phenyl. However, WO 89/04829 does not disclose the compounds of the present invention.

[0005] issued May 5, 1993 European Patent Publication No. 05399381 (which is the same assignee as the present application owns), for example, [(5R) - cis -4- [4- [4-
[4-[[5- (2,4-dihalophenyl) -5- (1
H-1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-7yl] methoxy] phenyl]-
1-piperazinyl] phenyl) -2,4-dihydro-2
- (C ₁ -C ₁₀₎ alkyl)] - discloses a 3H-1,2,4-triazol-3-one anti-fungal agent, does not disclose the compounds of the present invention.

US Pat. No. 4,791,111 to Janssen discloses, for example, (+) cis -4- [4- [4- [4-[[2-2, useful as an antimicrobial agent and having high solubility.
4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] -2,4dihydro-2- (2-hydroxy-1-methylpropyl) -3H-1,2,4-triazole-3
-One but not the compounds of the invention.

[0007] International Publication No. WO95 / 17407 (June 1995
29th) is a tetrahydrofuran antifungal agent (2R-cis) -4- [4- [4- [4 [[(5- (2,4-dihalophenyl-tetrahydro-5- ( 1H- 1,2,2, 4-
Triazol-1-ylmethyl) - tetrahydrofuran-3-yl] methoxy] phenyl] -2,4-dihydro-2- [mono- - or dihydroxy - substituted (C ₃ -C ₈₎
Alkyl] -3H-1,2,4-triazol-3-one-substituted antifungal agents, pharmaceutically acceptable esters, ethers and salts thereof, pharmaceutical compositions containing them, and hosts (warm-blooded animals) (Including especially humans) are disclosed for the treatment and / or prevention of fungal infections with such tetrahydrofuran antifungal agents.

[0008] International Publication No. WO95 / 19983 (July 27, 1995)
Published azoles) disclose azole methyl substituted dioxolane and tetrahydrofuran and disclose that they have water solubility and antifungal activity.

[0009]

SUMMARY OF THE INVENTION Highly soluble and systemic fungal infections (especially Aspergillus , Candida , Cyrp
(Tococcus and opportunistic infections) to provide a broad spectrum antifungal agent with a favorable activity profile.

[0010]

The present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, which achieves the above objects:

[0011]

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Wherein X is independently both F or both Cl, or one X is independently F
And the other is independently Cl; R ₁ is a straight-chain or branched (C) substituted by one or two groups that can be converted in vivo to one or two hydroxy moieties. ₄ -C ₅₎ alkyl group.

Preferably, the R ₁ group of formula I, which can be converted to a hydroxy moiety (ie, OH) in vivo, is a polyetherester, phosphate, or amino acid ester.

Preferably, R of the formula I₁Are each in vivo
One or two compounds that can be converted to various hydroxy moieties
Straight or branched chain substituted by a amino acid ester group
(C _Four~ C_Five) An alkyl group.

Preferably, R ₁ of formula I is a hydroxy-substituted C ₄ -or C ₅ -alkyl group selected from:

[0016]

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Wherein R ₄ is an amino acid ester group which can be converted to OH in vivo or a pharmaceutically acceptable salt thereof, and the carbon having a star (*) is R or S
Has absolute configuration.

In a preferred aspect of the present invention, the following formula II
Or a pharmaceutically acceptable salt thereof is provided:

[0019]

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Wherein X is independently both F or both Cl, or one X is independently F
, And the and the other is independently a Cl; R ₂ is vivo is replaced with an amino acid ester group may be converted to hydroxy moiety is straight or branched chain (C ₄ ~C ₅₎
It is an alkyl group.

Preferably, R ₂ of formula II is a linear or branched C ₅ alkyl group substituted by an amino acid ester group that can be converted in vivo to a hydroxy moiety.

Preferably, R ₂ of formula II is a C ₅ alkyl group substituted by an amino acid ester group that can be converted in vivo to a hydroxy moiety, and each X is F.

In another preferred aspect, the present invention provides a compound of formula III
Or a pharmaceutically acceptable salt thereof, provided by:

[0024]

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Where R ₅ is

[0026]

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Wherein R ₁₁ is an amino acid ester.

In another aspect of the present invention, there is provided a compound according to Formula IV, or a pharmaceutically acceptable salt thereof:

[0029]

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Where R ₉ is

[0031]

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Where R ₆ is OH in vivo
Carbons that are amino acid ester groups that can be converted to and have a star ( ^* ) have the R or S absolute configuration.

Preferred R ₆ groups of formula IV that can be converted to OH in vivo are amino acid ester groups.

Preferably, R ₆ is a dipeptide ester group.

Preferably, the dipeptide ester group of formula IV above is an ester of glycylglycine (ie, -OC
OCH ₂ NHCOCH ₂ NH ₂ ).

Preferably, the amino acid ester group of Formula IV above is an ester of glycine (ie, —OCOCH ₂
NH ₂ ).

Preferably, the amino acid ester group of formula IV above is an ester of 2,4-diaminobutyric acid (ie, -OC
OCH (NH ₂ ) (CH ₂ CH ₂ ) NH ₂ ).

Preferably, the amino acid ester group of Formula IV above is an ester of leucine (ie, -OCOCH
(NH ₂ ) CH ₂ CH (CH ₃ ) ₂ ).

Preferably, the amino acid ester group of Formula IV above is an ester of isoleucine (ie, -OCOC
H (NH ₂ ) CH (CH ₃ ) CH ₂ CH ₃ ).

Preferably, the amino acid ester group of Formula IV above is an ester of valine (ie, -OCOCH (N
H ₂ ) CH (CH ₃ ) ₂ ).

Preferably, R ₉ of formula IV is

[0042]

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Is as follows.

Preferably, R ₉ is

[0045]

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Is as follows.

Preferably, the amino acid ester group of formula IV above is

[0048]

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Is as follows.

The present invention relates to a pharmaceutical composition for treating or preventing a fungal infection, which comprises, together with a pharmaceutically acceptable carrier thereof, the antifungal activity of a compound according to any of claims 1 to 20. Pharmaceutical compositions containing an effective amount are provided.

The present invention also provides a method for treating and / or preventing a fungal infection in a mammal suffering from a fungal infection, wherein the method is sufficient for such treatment or prevention.
20. A method comprising administering an antifungal effective amount of a compound according to any of 20.

Preferably, the mode of administration is oral or parenteral.

[0053]

DETAILED DESCRIPTION OF THE INVENTION As used herein,
The term “(C ₄ -C ₅ ) alkyl group substituted by one or two hydroxy moieties” refers to n- and iso- , n- , and <br> substituted by one or two hydroxy moieties. /> And sec-propyl , iso- and tert- butyl, and n
-, sec-, an iso-, tert and neo- including pentyl means four or five straight and branched chain alkyl group with a carbon but not limited to, and such (C ₄
-C ₅₎ include R and S stereoisomers of the alkyl group.

The term “hydroxy-substituted C ₄ or C ₅ alkyl group” as used herein refers to

[0055]

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Where each carbon bearing a star ( ^* ) has the R or S absolute configuration.

The term “group that can be converted to OH in vivo”
By means a group that can be converted to a hydroxyl group in vivo (eg, by hydrolysis and / or by an enzyme (eg, an esterase)). Such groups include polyether esters, phosphate esters,
Sulfates, heterocyclic esters, alkanoate esters, alkenoate esters, amino acid esters,
And acid esters. Preferred groups that can be converted to hydroxyl groups in vivo are polyether esters, phosphate esters, and amino acid esters.

The term "ether" refers to (a) straight and branched chain alkyloxy of 1 to 20 carbons, preferably 1 to 8 carbons, more preferably 1 to 6 carbons. Groups; (b) polyethylene glycol (for example, PEG200-
PEG10000, preferably PEG200-PEG5000) and (c)
A (C ₁ -C ₆ ) alkoxy or aryl (C ₁ -C ₆ ) alkoxy group of the formula —O— (CHR ₁₇ ) _g —Ar, wherein R ₁₇
Is (C ₁ -C ₆ ) straight and branched chain alkyl, and g is 0-6, preferably 1-3, and Ar is phenyl; halo (especially chloro and fluoro), or nitro , Phenyl substituted by cyano and trihalomethyl, especially trifluoromethyl.
(C ₁ ~C ₆₎ alkoxy or aryl (C ₁ ~C ₆₎ -
Alkoxy groups can be easily created by well-known Williamson ether synthesis methods. Typically suitable ether groups include methoxy and benzoxy.

The term "ester" refers to (a) polyether ester (b) phosphate ester (c) heterocyclic ester (d) alkanoate and alkenoate ester (e) amino acid ester (f) acid ester and (f) g) means sulfate ester.

As used herein, the term “polyetherester” means those polyetheresters of the formula:

[0061]

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Here, R ₇ is a straight-chain or branched (C _1-
C ₆ ) an alkyl group or hydrogen and s is 1-6
T is an integer of 1 to 6, preferably s is 1 to 3, and more preferably s is 1;
Preferably t is 1-3 and more preferably t
Is 2 or 3.

R ₈ is R ₇ or — (CHR ₇ ) _s —CO ₂ R ₇ ;
Preferably R ₈ is CH ₃ or C ₂ H ₅ or -CH ₂ CO ₂ H or -CH ₂ CO ₂ CH _3. Typically, suitable polyether _{esters, -COCH 2 O (CH 2 CH} 2 O) 1 CH 3; -COCH 2 O (CH 2 C
H ₂ O) ₂ CH _3, and the like _{-COCH 2 O (CH 2 CH 2} O) 3 CH 3.

As used herein, the term “phosphate ester” means those phosphate esters of the formula:

[0065]

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Wherein z is 0 or 1; R ₇ is as hereinbefore defined and preferably is H; n and f are independently integers from 0 to 6; M is 0 or 1 and W is H, CH ₂ Ar or

[0067]

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Where Ar is as defined herein above. Typically, suitable phosphoric acids and esters include:

[0069]

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And their pharmaceutically acceptable salts.

As used herein, the term “heterocyclic ester” means a heterocyclic ester of the formula:

[0072]

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Wherein R ₇ is as defined herein above, W is an integer from 1 to 5, preferably W is from 1 to 3; q and q ′ are independently 1 ~ 4,
The q + q 'are preferably equal to 2, 3, 4 or 5, and Y is _{CHR 7, -O-, NH, NR} 7, S, SO, or SO _2.

Typically, suitable heterocyclic esters include the following:

[0075]

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As used herein, the term “alkanoate and alkenoate ester” refers to a straight or branched alkanoate or alkenoate group optionally substituted by a hydroxy or ether moiety, or A mixture of such alkanoates or alkenates is meant.

Preferred alkanoate esters include acetate to decanoate, especially acetate to butanoate. Preferred hydroxy-substituted alkanoate esters include one hydroxy moiety or one C ₁ -C ₆ alkoxy group, especially the formula:

[0078]

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C ₁ -C ₈ alkanoates substituted with

Preferred alkenoate esters are C ₁₀
-C was ₂₀ alkenoates and include C ₁₄ -C ₁₈ alkenoates such as cis-7-hexadecene Seno benzoate.

As used herein, the term “amino acid ester” refers to an α-aminoalkanoyl-oxy group and includes the natural (ie, (L) -α-amino acid ester group (eg, Esters of glycine (ie, OCOCH ₂ NH ₂ ), their di- and polypeptide esters (eg, non-naturally occurring α-amino acid ester groups such as:

[0082]

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)) And -OCOCH (NR ₂₀ R ₂₁ ) R ₂₂
Wherein R ₂₀ and R ₂₁ are independently hydrogen or a (C ₁ -C ₈ ) linear or branched alkyl group, or R ₂₀ and R ₂₀
Together with N form a 4, 5, or 6 membered ring optionally substituted by NR ₂₁ , —O—, or —S—, and R ₂₂ is H, CH ₃ , CH ₂ OH, CH (OH)
CH ₃ , CH ₂ SH,

[0084]

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Or a pharmaceutically acceptable acid addition salt thereof, or optionally a hydroxyl or NR
(C ₁ -C ₈ ) straight-chain and branched-chain alkyl groups substituted by ₂₀ R ₂₁ . Preferred amino acids are natural α-amino acid groups, dipeptides (eg, glycylglycine) and α-aminoalkanoates (where R ₂₀
And R ₂₁ are each CH ₃ ). Most preferred amino acid esters are the natural α-amino acids, L-alanine, L-phenylanine, glycine, L-leucine, L-isoleucine, and L-valine.

The term “acid esters” as used herein means those acid esters represented by the formula:

[0087]

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Wherein R ₇ is as defined herein above, and k is an integer from 1 to 8. Typically, suitable acid esters include oxalic acid, malonic acid,
Includes succinic, glutaric and adipic acids and branched dibasic acids such as:

[0089]

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The compounds of the present invention include Candida , other yeasts, d
It shows broad antifungal activity in various in vitro assays against ematophytes, Aspergillus and opportunistic fungi. In vitro antifungal activity tests were performed on a number of fungi on Sabouraud dextrose agar ("SDB") medium and Eagle's Minimum Essential Medium ("EMEM") by conventional agar diffusion methods. Minimum inhibitory concentration ("MIC") of 2
Measured after 4, 48 and 72 hours of testing. Often, the minimum myocardialicidal concentration ("MFCS") was measured at 48 and 72 hours.

The term "opportunistic fungus" includes Crytococcus, Histoplasma, Blas as indicated by the in vivo activity of the appropriate animal (eg, mouse, rat or rabbit).
tomyces, Coccidioides, Fusarium, Mucor, Paracoccidioid
es, Fonsecaea, Wangiella, Sporothrix, Pneumocystis, Tri
chosporon . The compounds of the present invention include bacteria, protozoa, bacterial gram negative bacteria,
Gram-positive bacteria, anaerobic organisms ( Legionella , Borrelia , My
coplasma , Treponema , Gardneralla , Trichomononas, and Trypanosoma ).

Preferred compounds of formula III wherein R ₁₁ can be converted in vivo to monohydroxy substituted C ₄ and C ₅ alkyl groups are 37 Aspergillus , flavu
s , fumigatus and other species showed the following in vitro antifungal activity in SDB: Geometric mean MIC was ≦
In the range of 0.05 to ≦ 0.81 (mcg / ml) and the geometric mean MF
C ranged from 0.42 to ≧ 3.78 mcg / ml.

More preferred compounds of formula III wherein R
₁₁Is a hydroxy substituted C in vivo_FiveTo alkyl group
Amino ester groups that can be converted)
Compared to fluconazole,C.albicans
(N = 26),C.krusei(N = 16),C.glabrata(N =
9),C.tropicalis(N = 4),C.stellatoidea(N =
1),C.neoformans(N = 3), and skin fungi (de
rmatophytes),T.rubrum,T.mentagrophytes,
ToT.tonsurans(N = 6) (after 48 or 78 hours)
Geometric mean MIC in various in vitro assays
Excellent antifungal activity as measured by and MFC
Gender, and (2) in the following in vivo model:
Excellent antifungal activity: other azoles (eg
Traconazole) compared to lung immune compromised mice
Model (PO-1XDX4D), and other azoles (eg,
Fluconazole) compared to normal and defenseless mice
(PO-1XDX4D)Candida albicans(Four kinds of fungi
Ltd.) in the lineage modelAspergillusflavusandfumig
atus(4 strains). R⁹But

[0094]

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Wherein R ₆ is a group capable of being converted to OH in vivo, preferred compounds of formula IV wherein R ₁₀ is a hydroxy group (eg, Tables Q, R, and S As compared with the compounds listed in the above).

The in vivo oral antifungal activity of the compounds of the present invention can be measured by azole antifungal agents (eg, As
pergillus pulmonary infection model). David Loebenberg et al., Title "Activity of Sch 42427 in vivo and in vitro, Active Enantiomer of the Antifungal Agent Sch 39304", Antimicrobial Agents and Chem
otherapy , (1992), 36 498-501. Aspergil
The lus flavus lung model is also described in European Patent Application No. 0 539,938 Al, issued May 5, 1993.

Preferred compounds of formula III are 37 Aspergi
For llus , in SDB (a) compared to fluconazole (geometric mean MIC ≧ 32), the geometric mean M from ≦ 0.05 to ≦ 0.81
It showed excellent in vitro antifungal activity with a geometric mean MFC of ≦ 0.42 to ≧ 3.78 compared to IC and (b) fluconazole (geometric mean MFC ≧ 32).

Tables 1, 2 and 3 hereinbelow show that
Shows superior in vitro antifungal activity of hydroxy derivatives from three preferred compounds of Formula III as compared to fluconazole. Table 1 shows such antifungal activity as a percentage of various fungal strains having MIC ≦ 1 mcg / ml for the three preferred compounds of formula III compared to fluconazole. Table 2 shows the antifungal activity, MFC ≦ 1 mcg / ml.
As the percentage of identical strains with Table 3 shows in vitro MIC 90 values for hydroxy derivatives from three preferred compounds of formula III for the same organisms listed in Tables 1 and 2.

Most preferred compounds of formula III wherein R ₅
Is:

[0100]

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Shows stable high serum levels in mice, rats, dogs and monkeys after oral administration with a methylcellulose formulation and also OD administration with good tissue distribution as compared to azoles of similar structure. Later it showed a very long serum half-life. The most preferred compounds of formula III listed above are not inducers of various cytochrome P-450 liver drugs that metabolize enzymes after oral administration in an in vivo rat model.

[0102]

[Table 1]

[0103]

[Table 2]

[0104]

[Table 3]

The preferred compounds of the invention of formula III or IV are soluble in aqueous media suitable for IV or oral administration and / or
Or are suspendable and also exhibit excellent in vivo antifungal activity against a wide range of fungi following oral and parenteral (eg, IV administration) administration in mice, rats, dogs and monkeys. Preferred groups convertible in vivo to the corresponding alcohol are at least about 1 mg / ml to 50 mg / ml
(Preferably in an amount greater than or equal to about 10 mg / ml, more preferably about 20 mg / ml).
~ About 50 mg / ml). Preferred esters and ethers of formula IV, wherein R ₉ is:

[0106]

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[0107]

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[0108]

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The mass spectral data, referred to herein as M ⁺ , is the parent ion measured by the fast atom bombardment (FAB) technique and represents [M + H ⁺ ], ie, {molecular ion + 1} peak. .

The more preferred esters mentioned hereinabove are water-soluble (eg> 10 mg / ml) and in vivo correspond to the corresponding alcohol compound of formula V (where R ₁₀
Is easily converted to:

[0111]

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The most preferred esters can be converted in vivo to alcohols and the compounds of formula IV wherein R
₉ is the following formula):

[0113]

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The antifungal compounds of the invention of the formula I
Having the stereochemical absolute configuration of R at the carbon in the tetrahydrofuran ring with di-halophenyl and 1H , 1,2,4-triazol-1-ylmethyl moieties, and CH
_The 2OY moiety has a “cis” stereochemical configuration with respect to the 1H , 1,2,4-triazol-1-ylmethyl moiety. See Formula I below.

[0115]

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Wherein R ₁ is a linear or branched (C ₄ -C ₅ ) alkyl group substituted by a group convertible in vivo to one or two hydroxy moieties, which is preferably Although present as a single stereoisomer, mixtures of stereoisomers are also included within the scope of the invention.

Compounds of formula I are disclosed in Saksena et al., US Pat.
No. 5,039,676, column 9 lines 59-68 and column 5 line 16 to column 52, line 44, Example 68, common as "cis" series, type ii, but not specified Is disclosed.

General Synthetic Preparations C ₄ and C ₅ hydroxy-substituted alkyl compounds useful for preparing compounds of the present invention are described in Schemes I-
It can be prepared by using the continuous process described in VI. Compounds of the present invention can be prepared by using compounds 20F of IV-VI in Schemes II and VII-XIB below. In Scheme I, compound 3 is readily prepared from commercially available compound 1 according to Examples 1a , 1b and 1c . Compound 4 is prepared by heating titanium 4 in an aprotic solvent (eg, methylene chloride) at a temperature of 0 ° C.
L in the presence of tetra- isopropoxide (i-PrO) ₄ Ti
It is prepared by reacting (+)-diethyl tartaric acid ("L-DET") with molecular sieves. For example,
T.Katsuki, KBSharpless, J.Am.Chem.Soc . , 102,5974 (19
80); and 103 , 464 (1981). An oxidizing agent (eg, tert -butyl hydroperoxide (“TBHP”)) is added to the reaction mixture (Step d of Scheme I). Compound 3 is added and produces the compound of formula 4 (when using L (+)-diethyltartaric acid). 0 ° C. in the presence of a strong base (eg, NaH in an aprotic solvent (eg, DMF))
Reaction of compound 4 with 1H -1,2,4-triazole at -80 ° C provides the diol compound of formula 5. The primary hydroxyl group in Compound 5 is a base (for example,
A leaving group (eg, mesylate or tosylate (compound) in the presence of triethylamine (“Et ₃ N”) in an aprotic solvent (eg, methylene chloride) by reaction of 5 with, for example, mesyl chloride (“MsCl”) 6)). Compound 6 is reacted at room temperature with an aprotic solvent (eg,
DMF) in strong bases (eg sodium hydride (NaH))
To give the oxirane compound 7. At 25 ° C to 75 ° C,
Lactone 8 is provided by reaction of 7 with diethyl malonate in an aprotic solvent (eg, DMSO) in the presence of a strong base (eg, sodium hydride). Reduction of 8 with a metal hydride (eg, lithium borohydride (LiBH ₄ )) in an alcohol (eg, ethanol (EtOH)) provides the triol 9. Base (for example,
The reaction of 9 with an excess of tosyl chloride in an aprotic solvent (eg, THF) in the presence of Et ₃ N) converts the two primary alcohols 9 to a leaving group (mesylate or tosylate). Thereby, ditosylate 10 is provided. Compound 10 is contacted with a strong base (eg, NaH) in an aprotic solvent (eg, toluene) at an elevated temperature of 100 ° C. to 120 ° C. to form two tosylates ( cis and tris ).
Lance ) mixture is provided and is separated by chromatography to give cis -tosylate 11. At a temperature of 25 ° C. to 75 ° C., an aprotic solvent (eg,
DMSO) in the presence of a strong base (eg, NaH)
And by reacting the alcohol HOY, C ₄ and -C useful for preparing compounds of Formula I ₅ - hydroxy
-Substituted alkyl compounds are provided.

Scheme II provides another reaction sequence for obtaining the compounds of the present invention. Reaction of compound 11 with commercially available compound 12 in the presence of NaH gives compound 13.
Hydrolysis of the N-acetyl group in 13 is achieved using a strong base (eg, NaOH) in the presence of n-BuOH,
14 are provided. Instead of the N-acetyl group in compound 12, any other base labile group (eg, N-formyl, N-benzoyl, etc.) also provides the corresponding N-formyl and N-benzoyl derivatives of compound 13. It should be clear that it can be used for By reacting 13 with p-chloronitrobenzene in the presence of a hydrochloric acid scavenger (eg, K ₂ CO ₃ ), the nitro compound
15 are provided. Catalytic reduction of 15 gives amine 16 in the presence of a platinum or palladium catalyst. Treatment of 16 with phenyl chloroformate in the presence of pyridine gives urethane intermediate 17. Reaction of 17 with hydrazine yields semicarbazide 18, which cyclizes in the presence of formamidine acetate to provide the key triazolone 19. Example 19 and
Alkylation of 19 according to 20 can be accomplished by reacting a compound of formula I wherein R
Wherein ₁ is as defined herein above), provided a compound of structure 20F comprising C ₄ and C ₅ hydroxy-substituted alkyl compounds useful for preparing

[0120] Scheme III, by applying the enzyme chemical stereospecific cis - providing a reaction to the tosylate 11 - alcohol 26 and cis. For example, by reacting triol 9 with ethyl acetate in the presence of porcine pancreatic lipase, a single type of monoacetate 21 can be obtained. twenty one
The remaining primary hydroxyl groups therein are protected by acid labile groups (eg, tetrahydropyranyl groups) to give compounds such as 22. Hydrolysis of the acetoxy group in 22 is accomplished with a base (eg, KOH) to provide 23. The remaining steps are as follows: (i) Tosylation of compound 23 yields 2
(Ii) cyclization of 24 in the presence of NaH to give 25
(Iii) deprotection of the THP ether in 25 using an acid catalyst (eg, p-toluenesulfonic acid) (26
Is obtained), followed by tosylation of the resulting 26 to provide key intermediate 11.

A detailed description of the preferred preparation of key intermediates can be found in US patent application Ser.
Issue 55,268, which is owned by the same assignee as the present application
And this is incorporated herein by reference.

[0122]

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[0123]

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[0124]

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[0125]

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[0126]

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[0127]

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[0128]

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[0129]

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[0130]

[Table 4]

PEG2000 and P used as starting materials
A range of MS values corresponding to the range of the molecular weight of EG5000 was observed.

[0132]

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[0133]

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[0134]

[Table 5]

[0135]

[Table 6]

[0136]

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[0137]

[Table 7]

[0138]

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[0139]

[Table 8]

[0140]

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[0141]

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[0142]

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Scheme IV provides a further reaction sequence to obtain C ₄ and C ₅ hydroxy substituted compounds useful as intermediates of the compounds of the present invention. Compound 27 is a compound
Prepared from the methyl ether of compound 12 in Scheme II by subjecting the methyl ether of 12 to the step reactions ag of Scheme II. By reacting a compound 27 with aqueous HBr or BBr _3, phenolic compounds 28 are obtained. SEM-protected compound by reacting compound 28 with 1 equivalent of NaH at room temperature and then treating with, for example, 2- (trimethyl) -silylethoxymethyl chloride ("SEM-Cl") and DMF 29 generates. Deprotonation of compound 29 with NaH followed by reaction of the thus formed anion in DMF or DMSO with tosylate 11 at elevated temperature produces compound 30. The 30 nitrogen protecting groups (eg, SEM) are removed, for example, by treatment with 6N HCl in methanol at room temperature for 3 hours, resulting in compound 19. Compound 19
Is treated with NaH and DMSO at 20 ° C. for 3/4 hours and then alkylated with R ₁ X to produce compound I.
In R ₁ X, R ₁ is a C ₃ -C ₈ alkyl group having at least one protected hydroxy moiety (eg, O-SEM), and X ′ is a leaving group (eg, brosylate) It is. Removal of the hydroxy protecting group (eg, O-SEM) from compound 31 is accomplished, for example, by 6N HCl in methanol and is a C ₄ -C ₅ hydroxy substitution useful for preparing compounds of the invention of formula I. This gives an alkyl group compound.

Scheme V provides a preferred route for the preparation of intermediates of the compounds of the present invention shown in Scheme II. (4- [4-
[4-Nitrophenyl) -1-piperazinyl] phenol was prepared by reacting the sodium salt of compound 31 with NaH at 50 ° C. to 70 ° C. for 1 hour at 2,4-diflurophenyl phenyl tosylate 11F ( After flash silica chromatography or crystallization, compound 15 is reacted with compound 11 of Scheme II, where X is F.
F (compound 15, of Scheme II, wherein X is F) is provided. 5% P in ethanol containing 1N HCl
Reduction of 15F by hydrogenation in the presence of d / C gives the amino compound 16F (compound 16 of Scheme II, where X is F
Is provided). Reaction of 16F with phenyl chloroformate in anhydrous pyridine at 0 ° C. to 5 ° C. for 2 hours provided phenyl carbamate 17F (compound 17 of Scheme II, where X is F). 4 at 80 ° C
By reacting 17F with hydrazine hydrate in 1,2-dimethoxyethane for a time, the semicarbazide 18F
(Compound 18, Scheme II, where X is F) was provided. 3H by reacting 18F with formamidine acetate and Et ₃ N in 2-methoxyethanol in a stirred reactor at 80 ° C. under dry argon overnight.
-1,2,4-triazol-3-one 19F (Scheme I
Compound 19 of I, where X is F) was provided.
A useful C for preparing compounds of formula I by reacting compound 19 (f) with R ₁ X according to the procedure of Scheme IV.
₄ -C ₅ hydroxy substituted compounds 20F was formed.

Scheme VI provides an alternative, stereoselective route for the preparation of intermediates of the preferred compounds of the present invention. Contacting compound 35 (eg, S -lactate methyl ester) with excess pyrrolidine in methylene chloride at room temperature for 24 hours provides amide 36. 36 and NaH, for example, D
By reacting with benzyl halide in MF, 37
was gotten. Aldehyde 38 was obtained by selective reduction of amide 37 using a 3.4 M solution of sodium bis (2-methoxyethoxy) aluminum hydride ("RED-Al") at -20 ° C. Aldehyde in methanol
Reaction of 38 with H ₂ NNHCHO gives 39, which is reacted at -10 ° C. to room temperature for 24 hours with a Grignard reagent (eg,
Reaction with ethyl magnesium bromide in dry ether) gave 40 (where the ratio of S, S isomer: S, R isomer was 94: 6). When the Grignard reaction was performed in the presence of 1.2 equivalents of bis (trimethylsilyl) acetamide, the ratio of SS: SR was 99: 1. Compound 40
In toluene with DBU (1,8-diazabicyclo [5.
4.0] Undec-7-ene) in the presence of 80 ° C. for 6 hours,
Reaction with compound 17F of Scheme V. The cyclization was carried out by increasing the temperature from 100 ° C. to 110 ° C., and this temperature was maintained overnight. After purification by TLC, 20F was obtained. In methanol containing formic acid heated to 60 ° C,
Treatment of 20F with hydrogen and palladium black gives a crude product, which is isolated and purified (by TLC) to give compound 20F (ie, a compound of formula V, wherein R ₁₀ is And X is F, Mt is 701 ^*
Got):

[0146]

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The reaction of propanimine 39 with a Grignard reagent produces 40, where
The absolute stereochemistry derived at the new chiral center in 40 is
Substantially the same as the absolute stereochemistry at the chiral carbon in 39 (ie, S). By the term "substantially the same" as used herein, S: S and S:
It is meant that the ratio of R (eg, at 40) is greater than 9: 1, preferably greater than 15: 1, and most preferably at least 99: 1.

The mass spectral data, referred to herein as M ⁺ , was measured by the fast atom bombardment (FAB) technique and was [M + H ⁺ ], ie, {molecular ion +
It is a parent ion representing a 1｝ peak.

We believe that Schemes I-VI describe a preferred process for preparing C ₄ -C ₅ alcohol intermediates of compounds of the present invention. Another process for preparing alcohol intermediates of compounds of the present invention is described in commonly assigned U.S. Ser. No. 08 / 425,129 (April 19, 1995).
No. CD0475 (April 1995)
(Filed on Jan. 19), and these two patent applications are incorporated herein by reference.

Scheme VII provides a general method for the preparation of the polyetheresters of the present invention. The alcoholate of alcohol ether 42 (eg, CH ₃ (OCH ₂ CH ₂ ) ₃ OH) (ie, 42, where R ₇ is H and t is 3) is added to the ice bath temperature In anhydrous ether (eg, THF), 42 and an excess of a strong base (eg, NaH)
Prepared by the reaction with The reaction mixture so formed is stirred for several hours (ie, 2 hours or more) and the sodium salt of acid 43 (eg, chloroacetic acid (43, where LG is a halogen (Hal) (eg, C
l), R ₇ is H and s is 1)), the sodium salt of)) was added thereto. The reaction mixture so formed was stirred at ice bath temperature and stirring was continued as the temperature was allowed to warm to room temperature. Water was carefully added to the reaction mixture and the polyether acid 44 was separated off and purified by conventional techniques.

[0151] 1.3 to 1.5 to a CH ₂ Cl ₂ solution of the 44 equivalents of base 4
(N, N- dimethylamino) pyridine ( "DMAP") and 20F (wherein, R ₁ is the formula) was added:

[0152]

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The temperature of the reaction mixture so formed was lowered by using an ice bath, and 1.3 to 1.5 equivalents of dicyclohexylcarbodiimide ("DCCD") were added thereto. The reaction mixture so formed was continuously stirred as the temperature was allowed to warm to room temperature. The dicyclohexylurea precipitate was removed and the crude product was isolated by conventional techniques. The residue so formed is purified by chromatography on silica gel,
Pure compound ([M + H] ⁺ is 906 by FAB) was provided. Compound 45 listed in the table for Scheme VII was prepared by appropriate substitution of different starting materials 42 and 43. MS values for compounds listed below 45 in the table for Scheme VII were measured by fast atom bombardment ("FAB").

Schemes VIII AC illustrate a generalized method for preparing the phosphate esters of the present invention.
Scheme VIIIA illustrates a phosphoric ester of formula IV wherein R ₆
Is the following formula, and z, m and n are 0):

[0155]

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Compound 20F of Scheme II was treated with 1.5 equivalents of N, N-diisopropyldibenzylphosphoramide and 3 equivalents of a base (eg, tetrazole) in methylene chloride at room temperature for several hours, followed by 1.5 equivalents of excess. Reaction with tert-butyl oxide (3M isooctane solution). The progress of the reaction was followed by TLC on silica gel (5% methanol: EtOAc v: v). The crude product in EtOAc was washed with sodium thiosulfate and purified using standard techniques to provide dibenzyl phosphate 46. The dibenzyl ester group of 46 was removed by treating 46 dissolved in an equal volume of ethanol and glacial acetic acid in the presence of 10% Pd / C under a hydrogen atmosphere at room temperature overnight in a stirred reactor. I got
The reaction was continued until no starting material was found by TLC (or NMR). The catalyst is removed by filtration,
The crude phosphate 47 was then purified by standard techniques. 47 equivalents of 2 equivalents of a base in methanol at room temperature (eg,
Processing with NMG (or Et ₃ N) provided 47.2 NMG. Compound 46 prepared according to Scheme VIIIA
And 47 are listed in the table for Scheme VIIA.

Scheme VIIIB illustrates a phosphoric ester of formula IV wherein R ₆ is of the following formula, z and m are 1,
And n is 0).

[0158]

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Compound 20F dissolved in methylene chloride was treated with 1.3
Equivalents of DMAD, 1.3 equivalents of DCCD and 1.3 equivalents of acid 49
(Eg, HO ₂ C (CH ₂ ) ₄ Br, ie, z is 1, n
Is 4, R ₇ is H, and the leaving group LG is Hal, eg, Br).

[0160]

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The reaction was stirred at room temperature until no starting material was found by TLC purification of the crude product to give bromide 50 as a white solid, where R ₁ is

[0162]

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Bromide 50 in benzene was heated at 80 ° C. overnight with 1.5 equivalents of silver dibenzylphosphate (available from Sigma Chemical Co., St. Louis). The reaction mixture was cooled and washed with an aqueous base (eg, K ₂ CO ₃ ). The crude product was separated and purified by silica gel column chromatography to obtain dibenzyl phosphate 51. Phosphate ester 52 was obtained by treating 51 in ethanol / glacial acetic acid with 10% Pd / C overnight at room temperature under a hydrogen atmosphere. In methanol, 52 is replaced with 2 equivalents of a base (eg, NM
G (or Et ₃ N)) to give 52.2NMG.

Scheme VIIIC is for the preparation of a phosphate ester of formula IV wherein R ₆ is as defined above for Scheme VIIIB, and z is 1 and n is 1. Provide another procedure for: Methanol
The benzyl ether of methyl acetate 53 in water and excess base (eg, K ₂ CO ₃ ) were stirred at room temperature overnight to give benzyl ether 54. 20F and 54 methylene chloride solution
Reaction with 1.3-1.5 equivalents of DCCD and DMAP at room temperature overnight gave ester 55. The 55 benzyl ether groups were removed by treatment with excess 10% Pd / C in ethanol-glacial acetic acid under a hydrogen atmosphere at room temperature overnight. Purification of the crude product yielded 56. Treatment of 56 according to the procedure of Scheme VIIIB with 1.5 equivalents of N, N-diisopropyldibenzylphosphoramide and tetrazole followed by 1.5 equivalents of tert-butyl peroxide gave dibenzyl ester 57. Removal of the dibenzyl group using 10% Pd / C in ethanol-glacial acetic acid under a hydrogen atmosphere provided the phosphoric ester 58 (above, herein). 58 to 2 equivalents of base (eg, NM
58.2NMG was obtained by treating with G).

Further phosphate esters of the invention of the following formula, as listed in the table of Scheme VIIIC, are:

[0166]

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(Where z = m = 1, n = 1 or 2,
Compound 20F (where f = 0 or 1, and W = H) wherein R ₁ is the same as that used in Scheme VIIIA by replacing equivalent amounts of starting materials 54a and 54b with compound 54. , Followed by the procedure shown in Scheme VIIIC).

Scheme IX illustrates the preparation of the heterocyclic esters of the present invention. Compound 20 dissolved in methylene chloride
F (where R ₁ is the following formula) is reacted with a compound 62 (Ha) at a temperature of 0 ° C. to 5 ° C. for 4 hours in the presence of a base (eg, pyridine).
l is Br or Cl, w is 1 to 5, for example, Cl-
CH ₂ -COCl):

[0169]

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The reaction was left in the refrigerator overnight. If necessary, additional compound 62 and base can be added and TL
The reaction was continued until C completely eliminated 20F.
The crude product was purified by column chromatography on silica gel to give pure 59 (w is 1 and Ha
l is Cl). For 1 hour at a temperature of 50 ° C. to 60 ° C., 59 is replaced with an excess of nitrogen heterocyclic compound 60 (eg,
NH, R ₇ is H, and q is 4) to yield 61. Replacing the nitrogen heterocyclic compound 60 with a 5- and 6-membered ring compound (eg, morpholine, N-methylpiperidine) provided the compounds listed in the table below Scheme IX.

Scheme X illustrates the preparation of the amino acid esters of the present invention. Compound 20F is contacted with an excess of N- (butoxycarbonyl α-amino acid or α-aminoalkanoate at 0 ° C. to 25 ° C. in the presence of DCCD and DMAP in an aprotic solvent (eg, CH ₂ Cl ₂ ) The reaction is then subjected to TLC and, if necessary, additional α-amino acids and DCCD are added to completely convert the starting material 20F to the amino acid ester derivative 64. Compound 64 is treated with HCl in dioxane, An α-amino acid ester is obtained as the acid addition salt 65. The crude product is
Purify by standard techniques. When carbobenzooxy is used as a protecting group, hydrogen on palladium black is used and the protecting group is removed in step b. Other protecting groups (eg, "protecting groups in organic synthesis", TWGreen and PGM
Wuts. John Wiley and Sons 1991 NY 97-98 or 389
Protecting groups disclosed on pages 394 to 394) can also be used.

Schemes XIA and XIB illustrate the preparation of the following additional phosphate esters of the present invention:

[0173]

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(Where z = f = m = 1, n = 0 or 1, and W = H).

In Scheme XIA, benzoyl bromide 7
Treat 0 with 2,2,2-trichloroethanol to produce the corresponding trichloroethyl ester. scheme
Benzyl bromide was converted to dibenzyl phosphate by treating trichloroethyl ester with an excess of silver dibenzyl phosphate under conditions similar to those used in VIIIC. The trichloroethyl ester group is replaced with acetic acid-TH
Removal by using zinc in F gave dibenzyl phosphate 72. Treatment of 72 with thionyl chloride afforded the corresponding acid chloride, which was prepared in Step 1 of Scheme VIIIC.
Under the conditions described above, the mixture was brought into contact with a 20 F methylene chloride solution to obtain ester 74. Under a hydrogen atmosphere as described in Scheme VIIIA, the dibenzyl ester group at 74 was removed with 10% Pd / C to give the corresponding phosphate ester, which was treated with two equivalents of a base (eg, NMG) And 76 was obtained. Scheme XIB
In, 2-methylphenylacetic acid 80 was esterified with 2,2,2-trichloroethanol and the ester so formed was converted to the corresponding benzyl bromide by treatment with N-bromosuccinimide. Benzyl bromide is treated with an excess of silver dibenzyl phosphate in Scheme VI
Treatment under IIC conditions gave the corresponding dibenzyl phosphate. The trichloroethyl ester group is replaced with acetic acid-TH
Removal with zinc in F gave dibenzyl phosphate 82. Solutions of 82 and 20F (where R ₁ is the same as in Scheme VIIA) were treated with DCCD and DMAP to give the corresponding phosphate esters. The phosphate ester was treated with 2 equivalents of NMG to give compound 84.

The alkanoate and alkenoate esters of 20F are conveniently prepared by standard synthetic techniques, such as by reacting an anhydride or acid halide of an alkanoic or alkenoic acid in the presence of a base such as pyridine. Prepared to produce the alkanoate or alkenoate of the compound of formula I.

Sulfate esters are described in RMMoriarty et al., Tetrah.
According to the procedure of edron Letters , Vol. 35, No. 44, pages 8103-8106 (1994) in the presence of an excess of pyridine at a temperature of 70 ° C. to 90 ° C. for at least 2 hours with an alcohol compound of formulas I to IV. It can be prepared by reaction with sulfur.

The corresponding alcohol compound of formula I is also
Strong bases (eg, Na in aprotic solvents such as DMSO)
H) can be prepared by reacting compound 11 with an alcohol of formula HOY in the presence.

[0179]

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(R)-"Tosylate" series See Example 15 where X is F or Cl and Y is

[0181]

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And R ₁ is a (C ₄ -C ₅ ) alkyl group substituted by one or two hydroxy moieties.

The compounds of the present invention of the formula I show broad antifungal activity against human and animal pathogens (for example) in conventional antifungal screening tests: As
pergillus, Blastomyces, Candida, Cryptococcus, Coc
cidioides, Epidermophyton, Fonsecaea, Fusarium, Mu
cor, Saccharomyces, Torulopsis, Trichophyton, Tric
hosporon, Sporothrix and Pneumocysitis.

Preferred compounds of formula IV show topical, oral and parenteral antifungal activity in vivo in animals, and such activity is surprisingly evident in existing antifungal agents such as itraconazole and Fluconazole) as well as Saksena et al., US Pat.
39,676 and WO 93/09114, better than the activity of the azole compounds specifically disclosed.

The antifungal compounds and pharmaceutical compositions of Formula I of the present invention have anti-allergic, anti-inflammatory and immunomodulatory activity, broad anti-infective activity (eg, antibacterial, antigenic animals and antiparasites). (Antihelminthic) activity).

The present invention also provides a composition for treating or preventing a fungal infection, comprising a compound represented by formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or a pharmaceutically acceptable carrier therefor. A composition is provided that contains an antifungal effective amount of a diluent.

The pharmaceutical compositions of the present invention also contain a bactericidal effective amount of another antifungal compound (eg, a cell wall active compound). As used herein, the term “cell wall active compound” means any compound that interferes with the fungal cell wall and includes, but is not limited to: papulacandins, echinocandins ( echinocandins and acreacin (aculeacin)
s), as well as nikkomycin
cins) (eg, nikkomycin K and US Pat.
A fungal cell wall inhibitor such as other nikkomycin disclosed in US Pat. No. 6,513, which is incorporated herein by reference.

Pharmaceutically acceptable salts of the compounds of the present invention include pharmaceutically acceptable acid and base addition salts.

A preferred pharmaceutically acceptable acid addition salt is
Compounds of the present invention may be added to a calculated amount of a mineral acid (eg, HC
_{l, HBr, H 2 SO 4} , HNO 3 or H ₃ PO _4), or an organic acid (e.g., methanesulfonic acid, isethionic acid (Isithioni
c), non-toxic acid addition salts formed by the addition of alkyl or aryl sulfonic acids, such as paratoluenesulfonic acid, naphthylsulfonic acid, and the like.

Pharmaceutically acceptable bases which have been found to be suitable for use in the present invention are those of formulas I, II,
Bases that form pharmaceutically acceptable salts of the acidic pharmaceutically acceptable esters of the III or IV antifungal compounds, and include suitable organic and inorganic bases. Suitable organic bases are primary, secondary and tertiary alkyl amines,
Includes alkanolamines, aromatic amines, alkylaromatic amines and cyclic amines. Typical organic amines include pharmaceutically acceptable bases selected from: chloroprocaine, procaine, piperazine, glucamine, N-methylglucamine, N-N-dimethylglucamine ethylenediamine (NN-dimethyl) glucamine e
thylendediamine), diethanolamine, diisopropylamine, diethylamine, N-benzylenediamine, diethanolamine, diisopropylamine, diethylamine, N-benzyl-2-phenylethylamine, Nn'dibenzylethylenediamine, choline, clemizole, triethylamine (“ET ₃ N "), Tris (hydroxymethyl) aminomethane, or D-glucosamine. Preferred organic bases include N-methylglucamine ("NMG"), diethanolamine, and tris (hydroxymethyl) aminomethane ("TRIS"). In the present invention, the use of 2 equivalents of NMG is more preferred. Suitable inorganic bases also include alkali metal hydroxides (eg, sodium hydroxide).

The pharmaceutical compositions of the present invention can be administered in any mode of administration (eg, oral, parenteral (eg, SC, IM, IV and I).
P), for topical or vaginal administration, or for inhalation (oral or intranasal)). Such compositions are formulated by combining a compound of Formula I or an equal volume of a pharmaceutically acceptable salt of Compound I with a suitable, inert, pharmaceutically acceptable carrier or diluent. You.

Examples of suitable compositions are solid or liquid compositions for oral administration (eg, tablets, capsules, pills,
Powders, granules, solutions, suppositories, troches, lozenges,
Suspensions or emulsions). The solid carrier can be one or more substances that can also act as diluents, flavoring agents, solubilizing agents, lubricants, suspending agents, binders or tablet powdering agents; It can also be an encapsulating substance. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

Topical dosage forms may be prepared according to procedures well known in the art and may include various components, excipients and additives. Formulations for topical use include ointments, creams, lotions, powders, aerosols, pessaries and sprays.

For preparing suppositories, low melting waxes, such as a mixture of fatty acid glycerides or cocoa butter.
Is first melted and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions and emulsions. By way of example, aqueous solutions or water-propylene glycol solutions for parenteral injection may be described.
Liquid preparations can also be prepared using the appropriate hydroxypropyl α-β or -γ-cyclodextrin having 2 to 11 hydroxypropyl groups per molecule of cyclodextrin, polyethylene glycol (eg, PEG-200) or propylene glycol. Can be formulated in a solution having a volume, and the solution also includes water. Aqueous solutions suitable for oral use can be prepared by adding the active component to water and adding suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the active ingredient in finely divided form in water. A particularly preferred aqueous pharmaceutical composition is hydroxypropyl- in water.
It can be prepared from compounds of formulas I-IV together with β-cyclodextrin. The use of derivatives of α-, β- and γ-cyclodextrin (eg, hydroxypropyl-β-cyclodextrin) is described in N. Bodor U.S. Pat.
No. 3,586; Pitha U.S. Pat.No. 4,727,064 and Janssen
It is disclosed by Pharmaceutical International Patent Application No. PCT / EP 84/00417.

The pharmaceutical compositions of the present invention comprise a pharmaceutically acceptable carrier (eg, hydroxypropyl-β-cyclodextrin) mixed in water and an antifungal effective amount of an agent of the present invention. Can be prepared by adding The solution so formed can be filtered and, if necessary, the water removed by well-known methods (eg, rotary evaporation or lyophilization). The formation of the solution can take place at a temperature of about 15C to 35C.
The water is usually sterile water and may also include pharmaceutically acceptable salts and buffers (eg, phosphate or citrate) and preservatives. The molar ratio of the antifungal compound of formula I to hydroxypropyl-β-cyclodextrin is about 1: 1 to 1:80, preferably 1:
1-1: 2. Usually, the hydroxypropyl-β-cyclodextrin is present in an excess of moles.

Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Preparations in solid form intended to be converted into a liquid form further comprise the active substance (eg, a compound of the present invention), and optionally, cell wall active compounds, especially fungal cell wall inhibitors (eg, nikkomycin), Fragrances, colorings, stabilizers,
It may include buffers, artificial and natural sweetening agents, dispersing agents, thickening agents, solubilizing agents and the like. The solvent utilized to prepare the liquid form preparation can be water, isotonic water, ethanol, glycerin, polyethylene glycol, propylene glycol, and the like, as well as mixtures thereof.

Parenteral forms, which are injected intravenously, intramuscularly, or subcutaneously, are usually in the form of a sterile solution and may contain salts or glucose to make the solution isotonic.

A compound of Formula I (usually at a concentration in the range of about 0.1% to about 20% by weight, preferably about 0.5% to about 10% by weight) is combined with a non-toxic, pharmaceutically acceptable topical carrier. For antifungal use in the form of a pharmaceutical formulation, including topical administration to humans is applied daily to the affected area of the skin until symptoms are ameliorated.

Generally, for antifungal use in the range of about 1 mg / kg body weight per day to about 30 mg / kg body weight, oral administration to humans, in single or divided doses, will result in 1 kilogram of body weight per day. It is preferred to use from about 1 mg per kilogram to about 20 mg per kilogram of body weight, and most preferably a dose of about 1 mg per kilogram of body weight to about 10 mg per kilogram of body weight per day.

Generally, about 0.25 mg / kg of body weight per day to about 0.25 mg / kg of body weight per day
Parenteral administration to humans for antifungal uses in the 20 mg range preferably employs from about 0.5 mg to about 10 mg per kilogram of body weight per day, in single or divided doses.

The precise amount, frequency and duration of administration of the compounds of this invention for antifungal use will depend on the sex, age and medical condition of the patient and the severity of the infection as determined by the attending physician. Change.

[0203]

EXAMPLES General Experiments The compounds of the present invention are prepared according to the following Examples using Schemes I-IX herein above and commercially available starting materials.

[0204]

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Example 1 Example 1a 2-Acetyloxy-1- (2,4-difluorophenyl) ethano
Of emission 191 g 2-chloro-2 ', 4'-difluoro acetophenone (ALDR
ich Chemical Co.) with 246 g of sodium acetate, 3 g of NaI
And 3 L of DMF to the mixture. Stir the mixture at 20 ° C. for 18 hours, then concentrate it to 1 L. Pour the residue into 6 L of cold dilute aqueous HCl and extract with EtOAc.
The extract was washed with brine, it was dried over anhydrous Na ₂ SO _4, The mixture thus formed was filtered, and a residue was evaporated the filtrate. The residue is chromatographed on silica gel, eluting with CH ₂ Cl-2-hexane to give 198 g of the title compound.

[0206]

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Example 1b 1- [2- (2,4-difluorophenyl)]-2-propenolacetate
The MePh ₃ PBr Tate 131 g, is suspended in 20 ° C. in a mechanically stirred dry THF to the 270 mL. Using just enough ice to cool and maintain the temperature below 23 ° C., 393 mL of 1 M NaN in THF
(Me ₃ Si) ₂ is added slowly, then quickly over 5 minutes. The mixture thus formed is heated to 20 ° C
Stir at 時間 24 ° C. for 1 hour, cool to about −70 ° C., and stir for an additional 1/2 hour. Then in 140 mL of dry THF at a rate slow enough to keep the temperature below -70 ° C.
65.5 g of a solution of the product of Example 1a are added to it. The reaction mixture thus formed is brought to a temperature of 20 ° C.
Continue to stir in the cold bath overnight while rising. 50 mL Et
OAc is added to the suspension thus formed, followed by 3 L of hexane. The mixture thus formed is left for about 15 minutes and filtered with suction to obtain Ph ₃ P
Remove O. Transfer the filter cake to a beaker while it is still wet. The cake is triturated thoroughly with 1/2 L of hexane and suction filtered again to remove residual product. The combined hexane filtrate is washed twice with 1 L of 1: 1 (v / v) MeOH-water and then with brine. Dry the organic layer over MgSO ₄ , filter, and evaporate the filtrate to give a red oil. Add 1.5 L of hexane and suction filter through a pad of celite to give a clear yellow solution. The yellow oil was chromatographed on silica gel, 1/2 L of hexane and then 1 L of 15: 1 (v / v).
v) Elution with hexane-EtOAc. Combine the uniform fractions,
38.6 g of the title compound are obtained as an oil.

[0208]

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Example 1c 2- (2,4-difluorophenyl) -2-propenol. 40 g of the product of Example 1b are dissolved in 400 ml of dioxane. Add 18 g of a 85% KOH solution in 315 mL of water. The mixture thus formed is stirred vigorously for 1 hour,
Then pouring the mixture into of Et ₂ O 1L. Separate the aqueous layer,
Then it is extracted with 250 mL of Et ₂ O. Combine the organic extracts and wash them with water and then brine.
The organic extract was dried with anhydrous K ₂ CO _3, and adding 10g of charcoal (charcoal) to it. Filter and evaporate the filtrate to give 31.3 g of the title compound as a pale yellow oil.

Example 1d (S)-(-)-[2- [2- (2,4-difluorophenyl)] oxirani
[ 3 ] Methanol 33g activated 3na molecular sieve powder 2.3L C
13 g of L-(+)-diethyl tartrate solution in H ₂ Cl ₂ are added and the mixture thus formed is cooled to −5 ° C. 100mL of CH ₂ Cl in ₂ titanium tetra 15.4 mL - isopropoxide solution was added over 2-3 minutes, then the mixture thus formed is cooled to -22 ° C.. 5.5M of 109.5 ml of tert-butyl hydroperoxide
The 2,2,4-trimethylpentane solution is added over 4-6 minutes and the mixture thus formed is cooled to -25 ° C. The mixture is stirred at -25 ° C for 25 minutes, then 40 g
Of Example 1c of 2- (2,4-difluorophenyl) -3-propenol in CH ₂ Cl ₂ (100 ml) is added over 3-4 minutes.
The mixture thus formed is stirred at -27 ° C for 4.5 hours. 102 mL of a 30% aqueous sodium hydroxide solution saturated with NaCl are added and the mixture thus formed is stirred while warming to + 10 ° C. over 1/2 hour.
Thereto 100 g of anhydrous MgSO ₄ and 33 g of celite were added,
Stir for 1/2 hour at + 10 ° C. The mixture is suction filtered, the filter cake thus formed is washed with 1.2 L of diethyl ether (Et ₂ O), then with 1.5 L of toluene, and the combined organic layers are dried over anhydrous MgSO ₄ . The organic layer is filtered, and the filtrate is evaporated under reduced pressure to form a residue. The residue is dissolved in 1 L of Et ₂ O and the mixture is suction filtered to remove insolubles. The filtrate is suction filtered through 100 g of silica gel and 200 mL of fresh E
Wash pad with t ₂ O. Evaporate the filtrate under reduced pressure to give 41 g (94%) of the crude title compound as a yellowish oil:

[0211]

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Example 2 (R)-(+)-[2- [2- (2,4-difluorophenyl)] oxirani
Example 1d, except replacing the equivalent amount of D-(-) diethyl tartrate in place of l- methanol L-(+) diethyl tartrate
To obtain the title crude compound:

[0213]

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A portion of the crude compound is purified by silica gel chromatography to obtain a homogeneous sample by TLC:

[0215]

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Example 3 (R)-(-)-2- (2,4-difluorophenyl) -3- (1,2,4-tria
1-yl) -1,2-a 1 H-1,2,4-triazole-propanediol 8.91g were dissolved in anhydrous DMF 150 mL, and The mixture thus formed 0 to 5 ° C.
Cool down to 2.81 g of sodium hydride (60% oil dispersion) are added and the mixture thus formed is stirred for 30 minutes at room temperature. 10.9 g of the product of Example 1d are added thereto. The reaction mixture thus formed is stirred for 2 hours at 60-70 ° C. Cool the mixture to room temperature, add 10 mL of H ₂ O thereto and evaporate it under reduced pressure to obtain a residue. The residue was made up to 100 mL H ₂ O and
Dissolve in 900 ml of ethyl acetate (EtOAc). An additional 250m
Extract the H ₂ O layer with L EtOAc. 10 combined EtOAc extracts
Wash with 0 mL of brine. The EtOAc extract was dried with anhydrous MgSO _4, and evaporated. Thus the oily residue formed was triturated with of CH ₂ Cl ₂ 10 mL, and
Adding of Et ₂ O 100 mL. The CH ₂ Cl ₂ -Et ₂ O mixture is stirred at room temperature for 1 hour. Filter to give 11.2 g (75%) of the title compound:

[0219]

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Recrystallize 1.0 g of the product filtered from 5 mL of CH ₃ CN to obtain 0.83 g of the title compound:

[0219]

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Example 4 (S)-(+)-2- (2,4-difluorophenyl) -3- (1,2,4-tria
(Zol-1-yl) -1,2-propanediol Following the procedure of Example 3 except that the product of Example 1 is replaced by the equivalent of the product of Example 2, the title compound is obtained:

[0221]

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The PMR and mass spectrum were consistent with the structure of the title compound.

Example 5 (R) -2- (2,4-difluorophenyl) -3- (1,2,4-triazo
1-yl) -1,2-propanediol-1-methanesulfone
Suspending the powdered product of Example 3 bets 10.9g in of CH ₂ Cl ₂ 150 mL. There 8.89mL of triethylamine was added,
The mixture thus formed is cooled to 0-5 ° C. Methanesulfonyl chloride 3.64mL of CH ₂ Cl ₂ 20ml is added over 10 minutes. The mixture thus formed is stirred for 1 hour at room temperature. Cool it to 0-5 ° C. and add 100 mL cold (0-5 ° C.) 5% KH ₂ PO ₄ followed by 100 mL
Cold (0~5 ℃) H ₂ O, followed by extraction with brine 50 ml. The separated organic layer is dried over anhydrous MgSO ₄ and evaporated to give 13.7 g (96%) of the title compound: [M + H
+] ⁺ ; PMR (CDCl ₃ ) δ7.95 (s, 1), 7.82 (s, 1), 7.53 (m,
1), 6.81 (m, 2), 4.84 (d, 1), 4.65 (d, 1), 4.46 (m, 2), 3.
05 (s, 3).

Example 6 (S) -2- (2,4-difluorophenyl) -3- (1,2,4-triazo
1-yl) -1,2-propanediol-1-methanesulfone
The title compound is obtained according to the procedure of Example 5, except that the product of Example 3 is replaced by an equivalent amount of the product of Example 4. PMR is consistent with the structure of the title compound.

Example 7 (R) -1- [2- [2- [2,4-difluorophenyl] oxiranylme
Chill] -1,2,4-triazole 13.7g product of Example 5 was dissolved in anhydrous DMF 200 mL, and this solution thus formed in the is cooled to 10 to 15 ° C.. 1.71 g of sodium hydride (60% oil dispersion) are added thereto and the reaction mixture thus formed is stirred at room temperature for 90 minutes. Concentrate to 50 mL under reduced pressure. Was added thereto cold H ₂ O (0~5 ℃) of 200 ml, and extracted with three portions of EtOAc 200 mL. Et together
Wash the OAc extract with 100 mL of brine. The EtOAc extract was dried over anhydrous MgSO ₄ and it was evaporated to 1
0.8 g of residue is obtained. The residue in CH ₂ Cl _2, by slurrying packed in CH ₂ Cl ₂ containing Et ₃ N in 1mL per liter, applied to a column of MPLC grade silica gel 400g was previously prepared. 25 liters each
%, 50%, and 75% _{EtOAc; CH 2 Cl 2 (v} / v), followed by 2
Elute with 1 liter of EtOAc. Combine these fractions to give 6.92 g (68%) of the title compound. Mass petrol
(FAB): 238 [M + H] ⁺ ; PMR (CDCl ₃ ) δ 7.97 (s, 1), 7.77 (s.
1), 7.07 (m, 1), 6.73 (m, 2); 4.73 (d, 1), 4.41 (d, 1), 2.
84 (d, 1), 2.78 (d, 1).

Example 8 (S) -1- [2- [2- (2,4-difluorophenyl) oxiranylmethane
[Tyl] -1,2,4-triazole Following the procedure of Example 7, but replacing the product of Example 5 with an equal amount of the product of Example 6, the title compound is obtained. [PMR is consistent with the structure of the title compound] (Example 9) Ethyl (5R-cis)-and (5R-trans) -5- (2,4-diph
Fluorophenyl) -2-oxo-5-[(1H-1,2,4-triazole
-1-yl) methyl] tetrahydro-3-furancarboxylate
Diethylmalonate bets 9.35mL dissolved in anhydrous 70 mL DMSO. 2.24 g of sodium hydride (60% oil dispersion) are added in two portions and the reaction mixture thus formed is stirred at room temperature for 1 hour. Example 7 of 6.65 g
And stirred at 50-55 ° C. for 18 hours.
Cool to room temperature and stir the reaction mixture well
0 mL KH ₂ PO ₄ , 500 mL brine, and 1 liter Et
Pour into the mixture of OAc. Separating of H ₂ O layer, and another 300m
Extracted with L of EtOAc. Wash the combined EtOAc extracts with 500 mL of brine, dry the EtOAc extracts with anhydrous MgSO ₄ and evaporate to give an oil. The oil with CH ₂ Cl _{2 is applied} to a column of 400 g MPLC grade silica gel prepared with hexane. 500 mL of hexane, followed by 2 L of 5
0% EtOAc: hexane (v / v), followed by 2 liters of EtOAc
Elute at The fractions are combined to give 8.66 g (80%) of the title compound. Mass spectrum (FAB): 352 [M + H] ⁺ , PMR (CD
Cl ₃ ) d 8.08 (s, 2), 7.91 (s, 1), 7.71 (s, 1), 7.42 (m,
1), 7.13 (m, 1), 7.85 (m, 2), 4.60 (m, 4), 4.10 (m, 4), 3.
49 (t, 1), 3.14 (t, 1), 3.89 (m, 4), 1.18 (m, 6).

Example 10 Ethyl (5S-cis) and (5S-trans) -5- (2,4-difur
(Orophenyl) -2-oxo-5- (1H-1,2,4-triazole-1-
Yl) methyl] tetrahydro-3-furancarboxylate Following the procedure of Example 9 but replacing the product of Example 7 with an equal amount of the product of Example 8, the title compound is obtained. [PMR and mass spectra are consistent with the structure of the title compound. (Example 11) (R)-(-)-4- (2,4-difluorophenyl) -2-hydroxyme
Tyl-5- [1H- (1,2,4-triazol-1-yl)]-1,4-penta
The product of Example 9 of Njioru 8.5g was dissolved in EtOH in 125 mL, and add LiCl of 2.15 g. The stirred mixture is cooled to 0 ° C. and 1.92 g of NaBH ₄ are added in several portions. The mixture is stirred at 0 ° C. for 18 hours without further cooling. H ₂ O was added 125mL of MeOH and 10mL mixture,
Then, stir for 4 hours. The mixture is evaporated to dryness and the precipitate is extracted with warm EtOH. Evaporate the extract to dryness, add 200 mL of THF to the residue and sonicate the stirred mixture for 15 minutes. The mixture is filtered and the filtrate is evaporated.
The residue is chromatographed on silica gel with CH ₂ Cl _{2
-MeOH-NH 4 OH (95:} 5: 1) eluting with (v / v / v), to give the title compound in 3.9 g. Mass spectrum (FAB): 314 (M + H +); PMR
(DMSO) δ8.25 (s, 1), 7.69 (s, 1), 7.35 (m, 1), 7.13 (m,
1), 6.94 (m, 1), 6.27 (s, 1), 5.16 (t, 1), 4.44 (m, 4), 3.
39 (m, 1), 3.20 (m, 1), 3.05 (t, 2), 2.11 (m, 1), 1.52 (m,
1).

Example 12 (S)-(+)-4- (2,4-difluorophenyl) -2-hydroxymeth
Cyl-5- [1H- (1,2,4-triazolyl)]-1,4-pentanedio
The title compound is obtained according to the procedure of Example 11 except that the product of Example 9 is replaced by an equivalent amount of the product of Example 10. A portion of the crude product was chromatographed on silica gel eluting with CH ₂ Cl ₂ -MeOH-NH ₄ OH to afford TLC
To obtain a more uniform product. This material was dissolved in H ₂ O, and filtered and the filtrate lyophilized to give the title compound.

[0229]

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Example 13 (R)-(-)-4- (2,4-difluorophenyl) -2-[[(4-methylphenyl
Enyl) -sulfonyloxy] methyl] -5- [1H- (1,2,4-tri
Azolyl)]-1,4-pentanediol-1- (4-methylbenze
Emissions) product 50mL of CH ₂ Cl ₂ -THF in Example 11 sulfonate 4.4g (1: 1, v / v)
Dissolve in. 4.7 mL of Et ₃ N and 180 mg of N, N-dimethylaminopyridine are added and the solution is cooled to 0 ° C. Thereto 5.9 g of p -toluenesulfonyl chloride are added in several portions and the reaction mixture thus formed is stirred at 0 ° C. for 1/2 hour and then at room temperature for 5 hours.
Stir it for hours. 100 mL of EtOAc are added and the mixture is suction filtered. Concentrate the filtrate and add 150 mL of EtO
Ac is added and washed with 5% aqueous KH ₂ PO ₄ . Wash the organic layer with 5% cold aqueous NaHCO ₃ solution, then with saturated brine, then dry it over anhydrous MgSO ₄ . The mixture is filtered and the filtrate is evaporated. The residue is chromatographed on silica gel, eluting with EtOAC-hexane, to give 6.4 g (73%) of the title compound: PMR (CDCl ₃ )
δ7.95 (s, 1), 7.67 (m, 5), 7.30 (m, 6), 6.70 (t, 2), 4.74
(d, 1), 4.53 (d, 1), 4.13 (m, 1), 3.97 (m, 1), 3.8 (m, 2),
2.43 (s, 6), 1.95 (m, 2), 1.77 (m, 1). Mass spectrum (FA
B): 622 [M + H] ⁺ .

Example 14 (S)-(+)-4- (2,4-difluorophenyl) -2-[[(4-methylf
Enyl) -sulfonyloxy] methyl] -5- [1H- (1,2,4-tri
Azolyl)]-1,4-pentanediol-1 (4-methylbenze
G) Sulfonate Following the procedure of Example 13 but replacing the product of Example 11 with an equal amount of the product of Example 12, the title compound is obtained:

[0232]

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Example 15 (-)-(5R-cis) -5- (2,4-difluorophenyl) -5-[(1H-1,
2,4-triazol-1-yl) methyl] -tetrahydro-3-fu
Dissolve 6.3 g of the product of Example 13 in lanthanum methanol, 4-toluenesulfonate in 150 mL of toluene and heat the solution thus formed to 100 ° C. 2.4 g of 60% NaH in oil are added in portions, and the reaction mixture thus formed is heated under reflux until cyclization is complete (about 3-4 hours).
The mixture is cooled and the solution is decanted from excess NaH. The solution is washed with 5% cold aqueous KH ₂ PO _4. The organic layer was evaporated to form a residue, and the residue was chromatographed on silica gel, acetone
Elution with -hexane gives 1.6 g (35%) of the title compound as two less polar products:

[0234]

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Example 16 (+)-(5S-cis) -5- (2,4-difluorophenyl) -5-[(1H-1,
2,4-triazol-1-yl) methyl] -tetrahydro-3-fu
Lanmethanol, 4-toluenesulfonate Following the procedure of Example 15 but replacing the product of Example 13 with an equal amount of the product of Example 14, the title compound is obtained:

[0236]

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Example 17 (-)-[(2R) -cis] -4- [4- [4- [4-[[5- (2,4-difluorophenyl
Nil) -tetrahydro-5- (1H-1,2,4-triazol-ylmeth
Tyl) furan-3-yl] methoxy] phenyl-1-piperazini
[Phenyl] -2,4-dihydro-3H-1,2,4-triazole-3-
The title compound was prepared using the tosylate of Example 15 and 4- [4- (4-nitrophenyl) -1-piperazinyl] phenol (U.S. Pat.
Starting from Example 3a) of 791,111 and Heeres
Prepared using the synthetic scheme outlined in Schemes V and J of J. Med . Chem 1984, Vol. 27, pages 894-900 (at pages 898 and 900).

Example 18 (-)-[(2R) -cis] -4- [4- [4- [4-[[5- (2,4-difluorophenyl
Nyl) -tetrahydro-5- (1H-1,2,4-triazol-1-yl
Methyl) -3-furanyl] methoxy] phenyl] -1-piperazini
[Phenyl] -2,4-dihydro-2- [1 (S) -methyl-2 (R) -hydr
Roxypropyl] -3H-1,2,4-triazol-3-one.

A. 2-O-SEM of (2R, 3R) -2,3-butanediol
To a stirred solution of 4.95 g of (2R, 3R) -2,3-butanediol, (55 mmol) and 9.3 g of SEM-CI (55.7 mmol) in 55 ml of anhydrous DMF at 0 ° C. was added 2.34 g of 60 % Oil dispersion type NaH (58.5%
Mmol) was added in four portions over 10 minutes. The resulting mixture was stirred at 0 ° C. for 4 hours and at room temperature overnight. The cloudy reaction mixture was poured onto 0.5 L of a 5% KH ₂ PO ₄ solution and extracted twice with 300 ml of ether, and the combined ethereal solution was extracted with distilled water, saturated brine for 1 hour.
Washed twice, dried over MgSO ₄ and evaporated,
A colorless liquid was obtained. 1L 7% EtOAC / hexane, 2L
Of 10% ETOAC / hexane and 1 L of 15% EtOAc / hexane was flash chromatographed on 350 g of silica gel to give 1.74 g of the title compound (yield 1
4.4%). MS: (M + H) ⁺ = 221.

B. Brosylation A mixture of 0.7 g of the 2-0-SEM ether of Example 18 (a) (3.18 mmol) and 0.97 g of 4-bromobenzenesulfonyl chloride in 5 ml of anhydrous pyridine was prepared. The mixture was stirred at room temperature under N ₂ atmosphere for 6 hours. The reddish slurry reaction mixture
Dilute with 50 ml of ice-cold water and extract twice with 25 ml of ether. The combined ether solution was washed twice with 25 ml of 1% CuSO ₄ solution, distilled water, saturated brine, dried over MgSO ₄ and evaporated to give a reddish oily residue. Flash chromatography on 50 g of silica gel using 1 L of 10% ETOAC / hexane provided 1.02 g of brosylate as a colorless liquid (yield 7).
2.9%):

[0241]

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C. Alkylation reaction 0.98 g of the brosylate of Example 18 (b) in 20 ml of anhydrous DMF
(2.23 mmol), 0.69 g of 3H-1,2,4-triazol-3-one of Example 17 (1.12 mmol) and 0.37 g of cesium carbonate
(1.12 mmol) was stirred under N ₂ at 80 ° C. overnight (about 20 hours). The reaction mixture was diluted with 100 ml of ice-cold water and extracted twice with 50 ml of ethyl acetate. The combined organic solution of distilled water, once with saturated brine, washed, dried over MgSO _4, and evaporated to give a brown solid residue. 80% of 1.2L
Flash chromatography of the residue on 125 g of silica gel with ETOAC / hexane provided 0.327 g of the product as a tan solid (35.7% yield). MS = (M + H) ⁺ = 8
1.7.

D. Acidic hydrolysis of 18 (C) to the title product
A mixture of 6N HCl solution SEM- ether and 6ml embodiment of 0.32g of methanol solution 6ml 18 (c) was stirred at room temperature for 4 hours, and evaporated under reduced pressure. 5 residues
Dilute with ml of ice water and add 10% until pH = 8-9 is obtained
Carefully basified with Na ₂ CO ₃ solution. The reaction mixture thus formed was extracted twice with 25 ml of CH ₂ Cl ₂ , followed by washing with saturated brine, drying over MgSO ₄ and evaporation to give a tan solid. The tan solid is filtered through a 50 g silica gel column and 0.75 L of 4%
Elution with MeOH / CH ₂ Cl ₂ afforded 0.26 g of the title product as a tan solid (96.6% yield). MS = (M + H) ⁺ = 687:

[0244]

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Example 19 (-)-[(2R) -cis] -4- [4- [4- [4-[[5- (2,4-difluorophenyl
Nyl) -tetrahydro-5- (1H-1,2,4-triazol-1-yl
Methyl) -3-furanyl] methoxy] phenyl] -1-piperazini
[Phenyl] -2,4-dihydro-2-1 [1 (R) -methyl-2 (R)-
Droxypropyl] -3H-1,2,4-triazol-3-one.

A. Mitsunobu reaction 0.72 g of 2-O-SEM of Example 18 (a) in 30 ml of dry benzene
To a stirred solution of ether (3.27 mmol), 2.1 g of triphenylphosphine (8.06 g), and 1.2 g of p-nitrobenzoic acid (7.17 mmol) was added 1.25 ml (8.06 mmol) of diethyl azodicarboxylate (`` DEAD )) Was added dropwise at 0 ° C. The clear yellow solution thus formed was cloudy. The mixture was then stirred at room temperature for 2 hours, and the mixture was packed in a 100 g silica gel column. 15% ETOAC /
Elution of the column with hexane provided 1.5 g of 3-β-nitrobenzoate having the S absolute configuration (95 yield).
%). MS: 219 (M ⁺ -150), 252 (M ⁺ -117).

B. Basic Hydrolysis of p-Nitrobenzoate
Solution 1.12 g of a solution of p-nitrobenzoate of Example 19 (a) (3
Mmol) and 3.5 ml of 1N NaOH in 20 ml of methanol
The solution was stirred at room temperature for 3 hours. Evaporate the solvent,
The residue was diluted with 10 ml of distilled water and extracted twice with 20 ml of ether. The combined ether solution was washed once with saturated brine, dried over MgSO ₄ and evaporated to give 0.67 g of the corresponding alcohol as a colorless liquid (about 100%). This was used directly in the next reaction without further purification.

C. Brosylation, alkylation and acidification
Hydrolysis According to the procedure of Examples 18 (c) and (d), the title compound was prepared in three steps from the products of Example 19 (b) and Example 17 in 32% overall yield.

[0249]

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Example 20 (-)-[(2R) -cis] -4- [4- [4- [4-[[(5- (2,4-difluorophenyl)
Enyl) -tetrahydro-5- (1H-1,2,4-triazol-1-i
Methyl) -3-furanyl] methoxy] phenyl] -1-piperazi
Nyl] phenyl] -2,4-dihydro-2-[(S) -1-methyl-3-hydrido
Roxypropyl] -3H-1,2,4-triazol-3-one a. Formation of TBDPS ether 0.9 g of (R)-(-)-1,3-butanediol in 10 ml of anhydrous DMF
(10 mmol), 1.5 g of imidazole (22 mmol) were added to 3 ml of t-butylchlorodiphenylsilane ("TBDP
S ") (11 mmol) at 0 ° C. over 3 minutes. The reaction mixture was stirred at 0 ° C. for 4 hours, diluted with 50 ml of ice-cold water,
Then it was extracted twice with 30 ml of ether. The aqueous phase was back-extracted with ether 50 ml, and the combined ether solution was washed once with saturated brine, dried over MgSO _4, and evaporated to give a colorless residue. Flash chromatography on 150 g silica gel using 1.5 L of 5% EtOAC / hexane and 1 L of 10% EtOAC / hexane gave 2.
87 g of TBDPS ether were obtained (87.5%):

[0251]

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B. Brosylation 0.984 g of TBDPS of Example 20 (a) in 7 ml of anhydrous pyridine
To the solution of (3 mmol) was added 0.845 g of 4-bromobenzenesulfonyl chloride (3.3 mmol). The reaction was carried out according to the procedure of Example 18 (b) and proceeded slowly and purified and gave 1.02 g of brosylate in 61.1% yield:

[0253]

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C. Alkylation 0.95 g of the brosylate of Example 20 (b) (1.74 mmol) was
Reacted with the compound of Example 17 according to the procedure of Example 18 (c) to give 0.49 g of the corresponding alkylated product (yield 6
0.3%):

[0255]

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D. Acidic hydrolysis 0.32 g of the compound of Example 20 (c) (0.35 mmol)
Hydrolyze with 6N HCl solution to give 0.2
2 g of the title compound were obtained (92.4% yield):

[0257]

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Alternatively, 0.19 g of Example 20 in 5 ml of THF
A solution of the compound of (c) and 60 mg of tetrabutylammonium fluoride (0.23 mmol) was stirred at room temperature for 24 hours. The brown solution was concentrated to a syrup. 0.5L
The syrup was flash chromatographed on 50 g of silica gel using 2% and 4% MeOH / CH ₂ Cl ₂ respectively to give 0.11 g of the title compound (88.7% yield).

Example 21 (-)-[(2R) -cis] -4- [4- [4- [4-[[5- (2,4-difluorophenyl
Nyl) -tetrahydro-5- (1H-1,2,4-triazol-1-yl
Methyl) -3-furanyl] methoxy] phenyl] -1-piperazini
[Phenyl] -2,4-dihydro-2-[(R) -1-methyl-3-hydro
[Xypropyl] -3H-1,2,4-triazol-3-one The procedure of Example 20 was followed except that an equivalent amount of S-(+)-1,3-butanediol was replaced with the corresponding R enantiomer. Was. The title compound was obtained in 4 steps with an overall yield of 31.8%; MS = [M + H] ⁺ = 687.

Example 22 (-)-[(2R) -cis] -4- [4- [4- [4-[[5- (2,4-difluorophenyl
Nyl) -tetrahydro-5- (1H-1,2,4-triazol-1-yl
Methyl) -3-furanyl] methoxy] phenyl] -1-piperazini
[Phenyl] -2,4-dihydro-2- [1 (S) -methyl-2-hydro
Kishipuropiru] 10 g of-3H-1,2,4-triazol-3-one a. In cyclohexane anhydrous CH ₂ Cl ₂ and 80ml of benzylated 40ml
Of a solution of (2R, 3R)-(-)-2,3-butanediol (111 mmol) in 1 ml of trifluoromethanesulfonic acid (TfOH)
C. followed by dropwise addition of 21 ml of benzyltrichloroacetimidate (113 mmol). The resulting slurry was stirred at room temperature overnight, diluted with 125 ml of hexane and filtered. The combined filtrate was concentrated to a yellow syrup. 1.5L 7% ETOAC / hexane, 2L 15% E
TOAC / hexane and 2 L of 25% ETOAC / hexane, 1.5
Applying a yellow syrup flash chromatographed 250g of silica gel using 10% MeOH / CH ₂ Cl ₂ for L, 1
1.88 g of starting material 2-monobenzyl ether (yield 74.5
%) And 2.03 g of unreacted starting material; MS: [M +
H] ⁺ : 181.

B. Mitsunobu Reaction 5.4 g of the 2-monobenzyl ether of Example 22 (a) was converted to 6.6 g of 3-Mitsunobu reaction by the Mitsunobu reaction according to the procedure of Example 19 (a).
Converted to benzoate ester (66.9% yield); MS: [M
+ H] ⁺ = 330.

C. Alkaline Hydrolysis 5.3 g of the product of Example 22 (b) was subjected to alkaline hydrolysis according to the procedure of Example 19 (b) to give 2.33 g of (2R, 3S) -2,3 -
The 2-monobenzyl ether of butanediol was obtained (yield 8
0.3%): (M + H) ⁺ = 181

[0263]

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D. Formation of SEM ether 3.14 g of the product of Example 22 (c) in 30 ml of anhydrous CH ₂ Cl ₂ (17.
44 mmol) and 3.8 ml of di-isopropylethylamine (2.82 g, 21.8 mmol) in 3.8 ml of SEM-Cl
(3.64 g, 21.8 mmol) was added in one portion at room temperature. A fume was generated and the resulting yellow solution was stirred for 20 hours. The orange reaction mixture was evaporated under reduced pressure and the solid residue was partitioned between ether and water. The ether solution was washed once with distilled water, saturated brine, dried at mg 504 and concentrated to give the crude product. 2L 3% ETO
The crude product was flash chromatographed on 200 g of silica gel with AC / hexane to give 5.3 g of Example 22.
3-O-SEM ether of the product of (c) was obtained as a colorless liquid
(98% yield); MS: [M + H] ⁺ = 311.

E. Hydrocracking 5.25 g of the product of Example 22 (d) in 150 ml of methanol (1
6.94 mmol) and 0.5 g of a 10% Pd / C mixture were hydrocracked at atmospheric pressure for 6 hours. The catalyst was filtered and washed with more methanol. The combined filtrate was concentrated to give a colorless liquid. The liquid was flash chromatographed on 100 g of silica gel using 2 L of 10% ETOAC / hexane to give 3.53 g of free alcohol.
lchool) as a colorless liquid (95% yield); MS: 174;
103.

F. Brosylation 1 g of the product of Example 22 (e) was prepared according to the procedure of 18 (b).
Converted to 1.52 g of the corresponding brosylate in 76.2% yield;

[0267]

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G. Alkylation reaction 1.48 g of the brosylate of Example 22 (f) were reacted with the product of Example 17 to give 0.75 g of 2-alkylated triazol-3-one (yield 54.3). %);

[0269]

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H. Acidic hydrolysis 0.7 g of the product of Example 22 (g) was hydrolyzed according to the procedure of Example 18 (d) to give 0.51 g of the title compound as a creamy solid. (86.7% yield);

[0271]

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Example 23 (-)-[(2R) -cis] -4- [4- [4- [4-[[5- (2,4-difluorophenyl
Nyl) -tetrahydro-5- (1H-1,2,4-triazol-1-yl
Methyl) -3-furanyl] methoxy] phenyl] -1-piperazini
[Phenyl] -2,4-dihydro-2- [1 (R) -methyl-2 (S) -hydr
Rokishipuropiru]-3H-1,2,4-triazol-3-one a. Mitsunobu product of step e of Reaction Example 22 (1.99 g, 9.05 mmol), following the procedure of Example 19 (a), p Reacted with -nitrobenzoic acid to give 3.3 g of product (98.8% yield); MS = [M + H] ⁺ = 22
1.

B. Alkaline hydrolysis The product of step (a) of this example (2.36 g, 6.4 mmol) was
Hydrolysis with 7 ml of 1N NaOAc gave 1.18 g of (2S, 3S)-
3-O-SEM ether of 2,3-butanediol was obtained (yield 83.7
%). MS: [M + H] ⁺ = 221

[0274]

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[0275] c. Brosylate formed product of steps of this embodiment (b) a (1.15 g), according to the procedure of Example 18 (b), to give the brosylate of 3.47g was converted to the brosylate (yield 97.7 %).

D. Alkylation and Acid Hydrolysis The procedure of Examples 18 (c) and (d) was repeated, except that the product of Example 23 (c) was replaced with the product of 18 (b). Was obtained.

Example 24 (2R-cis) -4- [4- [4- [4-[[-5- (2,4-difluorophenyl)
-Tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl
Le) furan-3-yl] methoxy] phenyl] -1-piperazini
[Phenyl] 2-4-dihydro-2-[(S) -1-ethyl-2 (S) -hydr
Roxypropyl] -3H-1,2,4-triazol-3-one a. WC Still et al., Tetrahedron Letters, 21 , 1035-10
According to the procedure of 38 (1980), the methyl ester of (S) -lactic acid was converted to the corresponding benzyloxymethyl ether.

B. Reduction to Aldehyde 37.7 mL of a 1 M DIBAL-H solution was added to a stirred solution of 7.67 g of the ester of step (a) of this example in toluene under a nitrogen atmosphere.
It was added dropwise at 78 ° C (dry ice / acetone bath). After 6 minutes, methanol (10 mL) was added, followed by an aqueous solution of Rochelle's salt. After warming to room temperature, the water was partitioned between ETOAc and water. The organic phase is separated, washed with water, dried (MgS
O ₄ ), and concentrated to yield the crude aldehyde used in the next step without purification.

B. Grignard step A solution of 80 ml of a 1 molar solution of ethylmagnesium bromide Grignard reagent in THF was added to a stirred THF solution of the crude aldehyde obtained from step (b) of this example under nitrogen atmosphere at -78 ° C (dry ice/
(Acetone bath). After the addition was complete, the resulting mixture was slowly warmed to room temperature overnight and stirred for another 48 hours. An aqueous solution of Rochelle's salt was added, and the resulting mixture was partitioned between acetone and water. The organic phase was separated, washed with water, dried (MgSO _4), and concentrated. The residue was purified by column chromatography on silica gel using ETOAC / hexane (1:10) as eluent: (i) Non-polar alcohol (2S, 3S) as a colorless oil 2.31
g; 31% (ii) a mixture of amphoteric alcohols, 1.23 g; 41% and (iii) 1.23 polar alcohols (2S, 3R) as a colorless oil
g; 16% was obtained.

C. Brosylation of Polar Alcohol The 4-bromobenzenesulfonyl chloride (1.035 g, 4.1 mmol) was added to the polar (2S, 3) compound of step (b) of this example in CH ₂ Cl _2.
R) To a stirred solution of alcohol (0.605 g, 2.7 mmol) and 2.20 g (5.9 mmol) of DMAP was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 12 hours, then partitioned between ETOAC and water. The organic phase was separated, washed with water, dried and concentrated. The residue was washed with ETOAC / hexane (1:10)
Was purified by column chromatography on silica gel using as eluent to give the desired brosylate (85%) as a colorless oil.

D. Alkylation and Acidic Hydrolysis The (2S, 3R) brosylate of step (c) of this example was prepared in Example 18
The procedure of Example 18 (c) and (d) was followed except that the brosylate used in (c) was replaced. The title compound was formed as a white solid by acidic hydrolysis (mp 170-
172 ° C).

Example 25 (2R-cis) -4- [4- [4- [4-[[-5- (2,4-difluorophenyl)
-Tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl
Le) furan-3-yl] methoxy] phenyl] -1-piperazini
[Phenyl] -2,4-dihydro-2-[(R) -1-ethyl-2 (S)-
[Droxypropyl] -3H-1,2,4-triazol-3-one The non-polar (2S, 3S) alcohol from step (b) of Example 24 is
Example 24 except that it was converted to (S, 3S) -3-brosylate.
Procedure was followed. Alkylation of the brosylate was followed by acidic hydrolysis of the SEM protecting group according to the procedure of Example 24 (d) to give the title compound.

Example 26 (2R-cis) -4- [4- [4- [4-[[-5- (2,4-difluorophenyl)
-Tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl
Le) furan-3-yl] methoxy] phenyl] 1-piperazinyl]
2-4-dihydro-2-[(R) -1-ethyl-2 (R) -hydroxypropyl
[3] -3H-1,2,4-triazol-3-one (R) methyl ester of lactate was converted to the step (a) of Example 24.
The procedure of Example 24 was followed, except that the methyl ester of (S) -lactic acid in Example 2 was replaced. The (2R, 3S) alcohol was used in steps (c) and (d) to give the title compound.

Example 27 (2R-cis) -4- [4- [4- [4-[[-5- (2,4-difluorophenyl)
-Tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl
Le) furan-3-yl] methoxy] phenyl] 1-piperazinyl]
Phenyl] 2-4-dihydro-2-[(S) -1-ethyl-2 (R) -hydro
The title compound was obtained according to the procedure of Example 26 except that [ xypropyl] -3H-1,2,4-triazol-3-one (2R, 3R) alcohol was used in steps (c) and (d). .

Example 28 (2R-cis) -4- [4- [4- [4-[[-5- (2,4-difluorophenyl)
-Tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl
Le) furan-3-yl] methoxy] phenyl] 1-piperazinyl]
Phenyl] 2-4-dihydro-2-[(R) -1-ethyl-3-hydroxy
Propyl] -3H-1,2,4-triazol-3-one a. Reduction In methyl (3R) -hydroxyvalerate (5.289, 40.0 mmol) dissolved in 100 ml of anhydrous THF, 60 ml of LiAlH ₄ (60 mmol) Was added dropwise at 0-5 ° C. The solution is allowed to warm to room temperature and then the mixture thus formed
2.5 mL of water was added and 2.5 mL of 15% NaOH and 7.5 mL of water were added dropwise. The reaction mixture thus formed was stirred at room temperature for 4 hours. Removing inorganic solids by filtration;
The filtrate was evaporated to give 4.31 g of (3R) -1,3-pentanediol.

B. 1-O-SEM Example 18 (Example 2) except that an equivalent amount of the product of step (a) of this example was replaced by (2R, 3R) -2,3-butanediol. According to the procedure of a), the title compound was obtained.

C. Mitsunobu reaction Except that an equivalent amount of the product of step (b) of this example was replaced by the 2-SEM ether of (2R, 3R) -2,3-butanediol.
Following the procedure of Example 19 (a), 3.34 g of the corresponding p-nitrobenzezoate was obtained.

D. Basic hydrolysis 1.88 g of (3S)-according to the procedure of Example 19 (b), except that an equivalent amount of the p-nitrobenzoate ester of step (c) of this example was used. 1-O-SEM ether of 1,3-pentanediol was obtained.

E. Brosylation, alkylation, and acidity
A hydrolysis equivalent of the product of step (d) of this example was replaced with the corresponding 1-0-SEM ether of (2R, 3R) 2,3-butanediol used in Example 19 (b). Other than Example 18 (b), (c) and
Following the procedure of (d), 1.04 g of the title compound of this example was produced:

[0290]

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Example 29 (2R-cis) -4- [4- [4- [4-[[-5- (2,4-difluorophenyl)
-Tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl
Le) furan-3-yl] methoxy] phenyl] 1-piperazinyl]
Phenyl 2-4-dihydro-2-[(S) -1-ethyl-3-hydroxy
Propyl] -3H-1,2,4-triazol-3-one 1-O-SEM- (3R) -1,3 according to procedures (a) and (b) of Example 28
-Pentanediol, which was prepared in Example 18 (b)
Was directly converted to 3R brosylate. The product of Example 17 was alkylated using 3R brosylate according to the procedure of Example 18 (c). The product thus formed was acid-hydrolyzed according to the procedure of Example 18 (d) to give 368 mg of the title compound (90% yield):

[0292]

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Example 30 (2R-cis) -4- [4- [4- [4-[[-5- (2,4-difluorophenyl)
-Tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl
Ru) -3-furanyl] methoxy] phenyl] 1-piperazinyl] 2-
4-dihydro-2- [1-hydroxy- (2R) -butyl] -3H-1,2,4-
Triazol-3-one a.Preparation of (2S) -1,2-butanediol A 40 mL ethanol solution of (2S) -3-buten-1,2-diol (3 g, 0.034 mmol) purchased from Eastman Kodak was prepared . 300
Hydrogenated overnight in the presence of mg of 10% Pd / C. The reaction mixture thus formed was filtered through celite. The filter cake thus formed is washed with ethanol and the combined filtrate is evaparated to 2.08
g of the title compound were obtained (68% yield).

B. 1-O-SEM ether formation, brosylation,
The alkylation and acidic hydrolysis equivalent amounts of the product of step (a) of this example were converted to (2R, 3R) of Example 18.
Example 18 except for the replacement with 2,3-butanediol
Following the procedure of (a)-(d), the title compound was obtained:

[0295]

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Example 31 (2R-cis) -4- [4- [4- [4-[[-5- (2,4-difluorophenyl)
-Tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl
) -3-furanyl] methoxy] phenyl] 1-piperazinyl] f
[Enyl] 2-4-dihydro-2- [1-hydroxy- (2S) -butyl] -3
H-1,2,4-triazol-3-one In step (a) of Example 30, an equivalent amount of (2R) -3-buten-1,2
The procedure of Example 30 was followed except that -diol (available from Eastmand Kodak) was replaced with (2S) -3-butene-1,2-diol. After following the procedure of Example 30 (b), the title compound was produced:

[0297]

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Example 32 (-) (2R-cis) -4- [4- [4 [-5- (2,4-difluorophenyl) te
Trahydro-5- (1H-1,2,4-triazol-1-ylmethyl)
Furan-3-yl) methoxy] phenyl] -1-piperazinyl] f
Enyl-2,4-dihydro-2-[(S) -1-ethyl-2 (S) -hydroxy
Cypropyl] -3H-1,2,4-triazol-3-one a. Selective conversion of (S)-(O-benzyl) lactic pyrrolidineamide
(S) -2- (benzyloxy) propionaldehyde
De: a 20ml cooling in an ice methanol bath was dissolved in toluene, Tetrahedron, 1989, Vol. 45, prepared S- (O-benzyl) according to the procedure of pages 57-67 lactic pyrrolidene amide
(5 g, 0.0214 mol) in Aldrich Chemical Catalo
4.25 ml RED in toluene available from gue # 19,619-3
-AL (3.4 M solution of sodium bis (2-methoxyethoxy) aluminum hydride) was added slowly with stirring. The solution was stirred for 5 hours and 2.5 ml acetone,
And then quenched with 35 ml of 2N HCl. The mixture thus formed was extracted with EtoAc. The organic extract was washed with water, NaHCO ₃ and brine, dried over Na ₂ SO ₄ and evaporated to give the title product.

B. (S) -2- (benzyloxy) -N- (formyl
Amino) propaneimine. Hydrazine formate dissolved in 5 ml of methanol (0.73 g,
To the solution (12.18 mmol) was added dropwise the propionaldehyde of step (a) (1 g, 16.09 mml). The reaction mixture thus formed was stirred overnight. The solvent was removed by evaporation and the residue thus formed was stirred with ethyl ether. The undissolved excess hydrazine formate was removed by filtration and the ether was removed to give a residue, which was combined with 20% EtoAc: hexane
Chromatography on silica gel using (v: v) gave 805 mg of the title product as a pale yellow waxy solid with strong UV activity; ms [M + H] ⁺ = 207.

C. 2- [3- (2S, 3S) -2- (benzyloxy) pen
[Tyl] formic acid hydrazide ethylmagnesium bromide (1.3 ml in ethyl ether, 3.9
Mmol, 3.0 M) in 200 ml of 10 ml of ethyl ether.
g, 0.97 mmol, was added at 0 ° C. to a stirred solution of propaneimine from step (b). The reaction mixture thus formed was stirred overnight at room temperature and quenched with water. The organic layer was separated and the solvent was removed to give a residue, which was chromatographed on silica gel with 30-50% EtoAc: hexane (v: v) to give 113 mg of the title compound as an oil ( Yield 50%). The ratio of S, S isomer: S, R isomer in the product was 94: 6. 1.2 equivalent screw
When the reaction was repeated in the presence of (trimethylsilyl) acetamide, the ratio of S, S: S, R was improved to 99: 1: MS:
[M + H] ⁺ = 237.

D. Cyclization reaction 156.3 mg, 0.66 mmol of the product of step (c) and 400 m
g, 0.60 mmol of 17F of Scheme V, and 1 mole of DBU (1,8-diazabicyclo [5.4.0] undec-7-ene (e
The solution of re)) is stirred at 80 ° C. for 6 hours;
And continued stirring at this temperature overnight. The reaction mixture was cooled to room temperature and stirring continued over the weekend. The solvent was removed by evaporation and the crude product was purified by preparative TLC (80% EtoAc: hexane, v: v) to give 200 mg of the benzyl ether of the title product of this example as a foamy solid MS; [M + H] ⁺ = 792.
This cyclization reaction is described in U.S. Patent Application (Attorney Docket No.
No.) (this application is owned by the same assignee)
ergelsberg, Gala et al.

E. Hydrocracking To a solution of the benzyl ether of step (d) (190 mg, 0.24 mmol) dissolved in 10 ml of methanol was added 40 mg of Pd on carbon black and 4 ml of formic acid. Transfer the reaction flask to baron (b
allon) and heated at 60 ° C. for 4 hours. The catalyst was removed by filtration through a celite cake, and the filtrate was poured into cold water. PH of the solution thus formed
Was adjusted to a value of 4-5 with amonia. The mixture thus formed was extracted with EtoAc. The organic layer was separated and dried over Na ₂ SO _4. Removal of the solvent gave the crude product, which was separated by preparative TLC (5% methanol:
Purification by CH ₂ CL ₂ , v: v) gave 95 mg of the title compound of this example as a tan solid (57% yield). MS: [M + H] ⁺
= 701. [α] =-28.4 (c, = 1.0, CHCl ₃ ).

(Example 33) (-)-[(2R) -cis] -4- [4- [4- [4-[[5- (2,4-difluorophene)
Nyl) -tetrahydro-5- (1H-1,2,4-triazol-1-yl
Methyl) -3-furanyl] methoxy] phenyl] -1-piperazini
[Phenyl] -2,4-dihydro-2- [1 (S) -ethyl-2 (S) -hydr
Roxypropyl] -3H-1,2,4-triazol-3-one, hydrochloric acid
Esters with glycine as salt.

A. N-Cbz-glycine (315 mg), N, N-dimethylaminopyridine (DMAP, 200 mg), and Example 24
To a solution of the above compound (900 mg) in CH ₂ Cl ₂ (50 mL) at 0 ° C. is added dicyclohexylcarbodiimide (DCCD, 290 mg). The solution is stirred at 0 ° C. for 30 minutes and then at room temperature for 1 hour. Further N-Cbz-glycine (700 mg) was added and then
DCCD is increased at 20 minute intervals until the reaction is completed by TLC. Pour the reaction mixture into 5% aqueous KH ₂ PO ₄ and add Et
Extract with OAc. EtOAc extracts three times, with 5% KH ₂ PO ₄ solution, then with brine, and extract the anhydrous MgSO
₄ Dry on. Filter, evaporate the filtrate and chromatograph the residue to give the N-Cbz-glycinyl ester (1.3 g). [Mass spectrum actual measurement value:
(FAB) 892 (M + H ⁺ )] B. 100 mL MeOH-96% in a sealed flask with a safety valve
Stir the N-Cbz-glycinyl ester solution from step A above in HCOOH. Until the reaction is completed by TLC (6-1
4 hours), add 30 mg of palladium black every 30 minutes. The mixture is filtered with suction, 12N HCl (0.5 mL) is added to the filtrate and the mixture thus formed is evaporated to dryness. Water (100 mL) and activated carbon (0.8 g) are added to the residue, and suction-filtered on a 0.45 μ nylon membrane. The filtrate is lyophilized to give 356 mg of the title compound. [Mass spectrum found: (FAB) 795 (M + H ⁺ )].

Example 34 Following the procedure of Example 33 except that an equivalent amount of any other N-carboxybenzooxy or N-tert-butoxycarbonyl protected natural amino acid was substituted, the natural corresponding to the compound of Example 32 An α-amino acid ester hydrochloride is obtained.

Example 35 (-)-[(2R) -cis] -4- [4- [4- [4-[[5- (2,4-difluorophenyl
Nyl) -tetrahydro-5- (1H-1,2,4-triazol-1-yl
Methyl) -3-furanyl] methoxy] phenyl] -1-piperazini
[Phenyl] -2,4-dihydro-2- [1 (S) -ethyl-2 (S) -hydr
Roxypropyl] -3H-1,2,4-triazol-3-one, disalt
Esters with 2,4-diaminobutyric acid as acid salts.

The title compound is obtained according to the procedure of Example 33 except that N-Cbz-glycine is replaced by an equivalent amount of N, N'-dicarbobenzooxy 2,4-diaminobutyric acid.

Example 36 (-)-[(2R) -cis] -4- [4- [4- [4-[[5- (2,4-difluorophenyl
Nyl) -tetrahydro-5- (1H-1,2,4-triazol-1-yl
Methyl) -3-furanyl] methoxy] phenyl] -1-piperazini
[Phenyl] -2,4-dihydro-2- [1 (S) -ethyl-2 (S) -hydr
Roxypropyl] -3H-1,2,4-triazol-3-one, hydrochloric acid
Esters with L-alanine as salt.

The title compound is obtained according to the procedure of Example 33 except that N-Cbz-glycine is replaced by an equivalent amount of N-carbobenzooxy-L-alanine.

Example 37 Compounds of formula 20F prepared according to the procedures of Examples 1-32 and Schemes I-VI are listed below:

[0311]

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Here, R ₁ is

[0313]

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Compounds 2 listed above wherein R ₁ is
0F is

[0315]

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With an equal amount of (2R, 3R) -2,3-butanediol, the (2R, 3R) -butanediol used in step d of Example 22
Prepared by substituting 2-monobenzyl ether. The product so formed was processed according to the procedure of Example 22, steps f, g and h. Compounds 20F listed above wherein R ₁ is:

[0317]

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Prepared by replacing the starting material used in step d of Example 22 with an equal amount of 2-O-SEM ester of 2R, 3R-butanediol. The product thus formed was processed according to the procedure of steps c, f, g and h of Example 22.

 ────────────────────────────────────────────────── ─── Continuation of Front Page (71) Applicant 596129215 2000 Galloping Hill Road, Kenilworth, New Jersey 07033-0530, US A (72) Inventor Bjorl M. Gili Jarababban USA New Jersey 07054, Parsippany, Maple Wood Drive 10 (72) Inventor Raymond G. Rabbie USA New Jersey 07006, West Caldwell, Woodside Avenue 65 (72) Inventor Russell E. Pike USA New Jersey 07874, Stanhope, Florence Street 31, Earl. Dee. Number 1 (72) Inventor Hyan Wan United States of America New Jersey 08810, Dayton, Liberty Drive 74 (72) Inventor Eitung Liu United States of America New Jersey 07960, Morris Township, Alexandria Road 34 (72) Inventor Ashit Kay. Gangley USA New Jersey 07043, Upper Montclair, Cooper Avenue 96 (72) Inventor Frank Bennett USA New Jersey 08854, Piscataway, Draco Road 419

Claims (20)

[Claims] 1. A compound represented by the following formula I, or a pharmaceutically acceptable salt thereof: Here, X is independently either both with F or both is Cl, or one X is independently an F, and the other is independently a Cl; R ₁ is, in vivo A straight or branched (C ₄₎ substituted by one or two groups that can be converted to one or two hydroxy moieties
-C ₅₎ alkyl group. 2. R ₁ is a straight or branched (C ₄ -C ₅ ) alkyl group substituted by one or two amino acid ester groups which can be converted in vivo to the respective hydroxy moieties. A compound according to claim 1. 3. A compound represented by the following formula II, or a pharmaceutically acceptable salt thereof: Wherein X is independently, both F or both Cl, or one X is independently, F, and the other is independently Cl; R ₂ is substituted by an amino acid ester group may be converted to hydroxy moiety (C ₄ ~C ₅₎ alkyl group. 4. The compound of claim 3, wherein R ₅ is a C ₅ alkyl group substituted by an amino acid ester group that can be converted in vivo to a hydroxy moiety, and each X is F. 5. The compound according to claim 1, wherein R ₁ is a hydroxy-substituted C ₄ -or C ₅ -alkyl group selected from: or a pharmaceutically acceptable salt thereof. Where R ₄ is an amino acid ester group that can be converted to OH in vivo, and the carbon with a star ( ^* ) has the R or S absolute configuration. 6. A compound represented by the following formula III, or a pharmaceutically acceptable salt thereof: Where R ₅ is Where R ₁₁ is an amino acid ester group that can be converted in vivo to a hydroxy group. 7. A compound represented by the following formula IV, or a pharmaceutically acceptable salt thereof: Where R ₉ is Where R ₆ is an amino acid ester group that can be converted to OH in vivo and the carbon with a star ( ^* ) is
Or have the S absolute configuration. 8. The compound according to claim 7, wherein R ₆ is a dipeptide ester group. 9. The method wherein the dipeptide ester group is an ester of glycylglycine (ie, —OCOCH ₂ NHCO
Is CH ₂ NH _2), compound according to claim 7. 10. The amino acid ester group is an ester of glycine (ie, —OCOCH ₂ NH ₂ ).
A compound according to claim 7. 11. The method of claim 11, wherein the amino acid ester group is an ester of 2,4-diaminobutyric acid (ie, —OCOCH (NH ₂ )
(CH ₂ CH ₂₎ a NH _2), compound according to claim 7. 12. The method of claim 12, wherein the amino acid ester group is an ester of leucine (ie, —OCOCH (NH ₂ ) CH ₂ CH).
The compound according to claim 7, which is (CH ₃ ) ₂ ). 13. The amino acid ester group may be an isoleucine ester (ie, —OCOCH (NH ₂ ) CH).
(CH ₃₎ a CH ₂ CH _3), A compound according to claim 7. 14. The amino acid ester group may be an ester of valine (ie, —OCOCH (NH ₂ ) CH (CH ₃ )
The compound according to claim 7, which is ₂ ). 15. When R ₉ is The compound of claim 7, which is 16. When R ₉ is The compound according to claim 7, wherein 17. The method according to claim 17, wherein the amino acid ester group is The compound of claim 7, which is 18. A pharmaceutical composition for treating or preventing a fungal infection, comprising a compound according to any one of claims 1 to 17 together with a pharmaceutically acceptable carrier thereof. A pharmaceutical composition comprising an amount. 19. A method according to any one of claims 1 to 18, for treating and / or preventing a fungal infection in a mammal suffering from a fungal infection, wherein said compound is sufficient for such treatment or prevention. Administering an antifungal effective amount of the above. 20. The pharmaceutical composition according to claim 18, wherein said mode of administration is oral or parenteral.