JPH01249755A - Novel 2-azolyl-1-cyclopropylethanol derivatives and salts thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (A is CH or N, R<1> is aryl; R<2> is hydroxyl or amino) and a salt thereof. EXAMPLE:1-[Carbamoyl)cyclopropane-1-yl]-1-(4-chlorophenyl)-2-(l,2,4-tr iazol-1-yl) ethanol. USE:An antifungal agent having excellent antifungal action, excellent absorption and internal kinetics and high safety. PREPARATION:A compound shown by formula II is reacted with a compound shown by formula III or a salt thereof in the absence or presence of a solvent (e.g., N,N-dimethylformamide) at 0-200 deg.C to give a compound shown by formula I. The amount of the compound shown by formula III is 1-10mols based on lmol compound shown by formula II.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a compound of the general formula [I] H [wherein Al, t C)-1 or N, and R1 is group; R2 represents a hydroxyl group or an optionally substituted amino group; The present invention relates to a novel 2-azolyl-1-cyclopropylethanol derivative represented by the formula "2-azolyl-1-cyclopropylethanol derivative" and a salt thereof.

Therefore, the object of the present invention is to provide novel 2-azolyl-1-cyclopropylethanol derivatives and salts thereof, which have excellent antifungal activity and exhibit excellent therapeutic effects on human and animal diseases. It is about providing.

[Prior art] Amphotericin B is currently used as a treatment for deep mycoses.
(U.S. Pat. No. 2,908,611) and flucytosine (
U.S. Patent No. 2802005) is mainly used □
Recently, cis-acetyl-4-[4-[2-(2,4-dichlorophenyl)-2-(1H)-imidazol-1-ylmethyl)-1] , 3-dioxolan-4-ylmethoxy]phenyl]piperazine (-Ship name: Ritoconazole, US Pat. No. 4,358,449) has been used and is reported to be useful as a therapeutic agent for fungal diseases.

[Problems to be Solved by the Invention] However, the effects of the above-mentioned therapeutic agents cannot be said to be sufficient in terms of pharmacokinetics, toxicity, etc., and there has been a desire for the development of even better compounds.

[Means for Solving the Problems] Under such circumstances, the present inventors conducted intensive research and found that a novel 2-azolyl-
1-cyclopropylethanol derivatives and salts thereof,
The present inventors have discovered that it has excellent antifungal activity, excellent absorption, and exhibits excellent pharmacokinetics, leading to the completion of the present invention.

The compounds of the present invention will be described in detail below.

Unless otherwise specified in this specification, a halogen atom means, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom; an alkyl group means, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl. , isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl; alkoxy group and 1 to 10 are, for example, methoxy, ethoxy, n-propoxy,
Isopropoxy, 0-butoxy, isobutoxy, 5eC
-butoxy, tert-butoxy, pentyloxy,
C alkoxy groups such as hexyloxy, heptyloxy, octyloxy: Alkylthio groups 1 to 10 are, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, 5ec-butylthio, tert- C1-1o alkyldio groups such as butylthio, pendelthio, hexylthio, hebdylthio, octylthio; aryl groups include, for example, phenyl, naphthyl; dichloroalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopenpur, cycloheptyl C cycloalkyl group such as: aralkyl group is, for example, benzyl,
Groups such as phenethyl and naphthylmethyl; alknyl groups include, for example, C2-6 alkenyl groups such as vinyl, propenyl, and butenyl; examples of halo-lower alkyl groups include fluoromethyl, chloromethyl, trifluoromethyl, and trichloro; A C alkyl group substituted with a fluorine atom or a chlorine atom such as methyl, 2,2,2-trifluoroethyl; an acyl group is, for example, 1
~4 C alkanoyl groups such as formyl, acetyl, propionyl, aro-1-5 yl groups such as benzoyl, and pyridylcarbonyl, furylcarbonyl,
Heterocyclic groups include, for example, heterocyclic groups such as pyridyl, thienyl, furyl; alkylamino, dialkylamino, arylamine, acylamino, alkyloxycarbonyl, ``alkyl'', etc. "゛°", "aryl", and "acyl" each represent the same groups as mentioned above; and "lower" represents a C group, respectively.

1-4 The aryl group in R1 is, for example, ASS syncope,
It may be substituted with one or more substituents selected from lower alkyl, lower alkoxy, lower alkylthio, and halo-lower alkyl groups.

The optionally substituted amino group of R2 is such that R3 and R4 are the same or different, for example, a hydrogen atom,
Alkyl, cycloalkyl, aralkyl, aryl,
Examples include alkylamino, dialkylamino, arylamino, and acylamino groups, and the above groups include hydroxyl, carbamoyl, acylamino, lower alkyl, lower alkoxy, lower alkylthio, halo-lower alkyl, and heterocyclic groups, as well as halogen atoms. It may be substituted with one or more selected substituents. Furthermore, R and R4 may be combined with the nitrogen atom to which they are bonded to form a 3- to 6-membered nitrogen-containing heterocyclic group such as aziridinyl, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, etc. may be substituted with one or more substituents such as lower alkyl, oxo, lower alkyloxycarbonyl groups.

Examples of the salts of the compound of general formula [I] include salts that are used in medicine, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
Salts with mineral acids such as nitric acid; acetic acid, fumaric acid, maleic acid,
Salts with organic carboxylic acids such as malic acid, tartaric acid, citric acid and aspartic acid; salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid;
Examples include salts with alkali metals such as sodium and potassium.

In addition, in the compound of the present invention represented by the general formula [I], those in which R2 is an optionally substituted amino group are preferred. Further, particularly preferred are an alkyl group which may be substituted with a hydroxyl group or an amino group which may be substituted with a cycloalkyl group.

The compound of the present invention can be used in roughly all isomers (geometric isomers,
optical isomers), hydrates, and optical isomers.

[Manufacturing method] The 2-azolyl-1-cyclopropylethanol derivative of general formula [i] and its salts are generally produced by combining methods known per se, but for example, they can be manufactured by the method shown below. .

Production method 1 "In the formula, A, R and R2 have the same meanings as described above." Examples of the salt of the compound of general formula [I[I] include salts with alkali metals such as potassium or storum; Triethylamine, triethylamine, pyridine or 1,8-diazabicyclo[5,4°O] Launk-7
Salts with n bases such as -ene (DBLJ) are removed. Moreover, these salts can also be made within the reaction system.

This reaction can be carried out in the presence or absence of an inert solvent.

The solvent used is not particularly limited as long as it does not adversely affect the reaction, but examples include amides such as N,N-dimethylborumamide and N,N-dimethylacetamide; sulfoxides such as dimethylsulfoxide. ; Sulborane; Nitriles such as acetonitrile;
Examples include ethers such as dioxane and tetrahydrofuran; alcohols such as methanol, ethanol, n-propanol, and n-butanol; aromatic hydrocarbons such as benzene, or water; two or more of these solvents may be mixed together. May be used.

In this reaction, the compound of general formula [I[1] or a salt thereof can be used in an amount of 1 to 10 times the molar amount of the compound of general formula [n].

This reaction is usually carried out at 0 to 200°C, preferably at 20 to 80°C.
'C for 1 to 24 hours.

In addition, the compound of the general formula [1] in which C0R2 is a carboxyl group is the compound of the general formula [I] in which C0R2 is a carboxyl group.
It is also possible to protect the compound of [I] in advance with a conventional carboxyl protecting group, and then carboxylize it by a conventional method after the reaction.

[In the formula, A, R, R and R4 have the same meanings as described above. ” Examples of the reaction Pfii form of general formula [1v] include acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, and derivatives reactive with Vilsmeier's reagent.

(il - After deriving the compound of the formula [Ia] into a reactive derivative of the general formula [IV] by a conventional method, - the compound of the formula [VI]
By reacting amines, a compound of the formula [Ib] can be derived.

This reaction can be carried out in a solvent, and the solvent is
There are no particular limitations as long as it does not adversely affect the reaction = b, but examples include halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; tetrahydrofuran, dioxane, etc. Needles such as r! #M ethyl,
Examples include esters such as butyl acetate; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; ketones such as acetone and methyl ethyl ketone; and nitriles such as acetonitrile. You may use a mixture of more than one species.

(ii) Alternatively, after deriving the reactive derivative of the formula [IV] into a β-lactone of the general formula [VI], by reacting it with the amines of the formula [VI], [Ib] can also be derived. −
The β-lactone form of formula [VI] is prepared by adding a compound of formula [IV] to an organic base such as trimedelamine or trinibulamine at 0 to 70°C in the same solvent as described in (i) above.
It can be obtained by reacting for 5 minutes to 24 hours.

This reaction ([IV] → [Ib] and [V] → [Ib]
), the amount of the compound of formula [v1] to be used is 1 to 2 for the compound of formula [IV] or general formula [VI].
0 (atl), and a deoxidizing agent can also be used,
As the deoxidizing agent, for example, an organic base such as triniblamine, pyridine, or N-methylmorpholine is used.

This reaction may be normally carried out at -60 to 200°C for 0.5 to 24 hours.

As is clear from the above explanation, the compound of the general formula [I] in which R2 is a hydroxyl group (i.e., the compound of the formula [Ia
] Compounds) are also useful as intermediates.

Next, a method for producing the compound of general formula [IIa], which is a raw material for producing the compound of the present invention, will be explained. −
The compound of formula [IIa] can be produced, for example, according to the production method shown below.

"In the formula, R, R, R and R4 have the same meanings as above, and R2a is a carboxyl protecting group and the above R
and R5 represents a carboxyl protecting group. The carboxyl protecting group for R2a and R5 is a usual carboxyl group protecting group, and specific examples include an alkyl group.

Further, the compound of formula [V[] and general formula (2)] can be produced by a known method or a method analogous thereto.

Next, each process will be explained.

(1) - Preparation of compound of formula [IX] - Compound of formula [IX] by reacting the compound of formula [VI] with 1,2-dibromoethane in the presence of a base in a suitable solvent can be obtained.

The solvent used is not particularly limited as long as it does not adversely affect the reaction, but examples include water; alcohols such as methanol, ethanol, and 2-propanol; ethers such as diethyl ether, tetrahydrofuran, and dioxane; : Aromatic hydrocarbons such as benzene, toluene, and xylene; Amides such as N,N-dimethylformamide and N,N-dimethylacetamide; Sulfoxides such as dimethyl sulfoxide, etc. Two or more of these solvents may be used. May be used in combination.

In addition, the length of 1 m used includes, for example, alkali hydroxide, alkali hydrogen carbonate, carbonated alkali, etc.; Examples of metal alcohols include metal alcohols such as lium medillerate and others.

The amount of 1,2-dibromoethane and the base to be used is equal to or more, preferably 1 to 5 times the mole of the compound represented by formula [V[].

This reaction may be carried out from 0°C to the boiling point of the solvent used, preferably at 20-ioo°C, for usually 0.5-50 hours, preferably 3-20 hours.

Moreover, the compound of the formula [IX] can be obtained by reacting the compound of the formula [■] with 1,2-dibromoethane in the same manner as described above. (fly) to a compound of general formula [X] by a method of eliminating, for example, hydrolysis, and then - after leading the carboxylic acid of formula [X] to its reactive derivative, - a compound of formula [VI] It can also be obtained by reacting compounds. Incidentally, the reaction between the compound represented by formula [X] and the compound represented by general formula [VI] can be carried out according to Production Method 2 described above.

(2) - ¥ of the compound of formula [IIa]! General formula [IX
] by reacting the compound of the general formula [IIa] with dimethyloxosulfonium methylide in a suitable solvent.
can be obtained. Dimethyloxosulfonium methylide is usually produced by reacting small trimedersulium iodide with a strong base such as sodium hydride in dimethyl sulfoxide.

This reaction is usually carried out at 0 to 80°C, preferably at 10 to 30°C.
It may be carried out for 0.5 to 24 hours.

This reaction is a method known per se for producing epoxy derivatives from ketones [Reference: JAC3 (Journal
Of American Chemical Society 1 Noiety> 87
．． 1353 (1965)].

When the compound of the present invention is used as a medicine, pharmaceutically acceptable excipients, carriers, diluents, and other additives may be mixed as appropriate. It can be administered orally or parenterally in the form of a tablet, powder, or injection. In the case of oral administration, the dosage is usually about 0.05 to 2 kg per 1 kg of adult body weight.
The dose is approximately 0.00 m'J/day, which is administered once or divided into several doses, and is appropriately selected depending on age, body weight, and symptoms.

[Effects of the Invention] Next, the pharmacological effects of representative compounds of the present invention will be described.

In addition, the test compound Nα used in the following pharmacological test refers to the example number.

1. Infection Treatment Experiment Mice experimentally infected with Candida albicans 0N-28 were used to measure the therapeutic effects of the compounds of the present invention administered orally.

10 ICR male mice per group (body weight, 17-21g)
) to Candida albicans 0N-283, 2x106
Cells/mouse were administered through the tail vein of mice to induce infection. Two hours after infection, 0.1 m3 of the compound of the present invention was orally administered once per mouse, and the mice were carefully monitored for survival and death for 10 days, and the therapeutic index was determined from the average survival days. Ketoconazole was used as a control compound. The results are shown in Table-1. Furthermore, Table 1
, the relative therapeutic index of the compound of the present invention is expressed when ketoconazole is set as 100.

(Margin below) Table 1 2. Acute Toxicity The test compound was intravenously administered to 1 group of 3 male ICR mice (body weight: 20±13) to examine acute toxicity.

Note that the test compound was prepared by dissolving it in propylene glycol.

As a result, test compound NQI and Nα16 were 200
No deaths were observed with my/Ky administration.

, On the other hand, Ke1~conazole is 200 rrvt/
The patient died due to Kg administration.

As is clear from the above, the compound of the present invention exhibits excellent pharmacological effects and is a highly safe compound.

(The following is a blank space) [Examples] Reference examples and examples are given to explain the present invention in more detail, but the present invention is not limited thereto.

The carrier used in column chromatography is silica gel [Kieselgel 60° Art, 7] manufactured by Merck & Co.
734 (Kieselgel 60. Art, 7734
I used the moon.

Further, the mixing ratio in the eluent depends on the volume ratio. moreover,
In the text, the following abbreviations have the following meanings:

To IPE Rainbow Isopropyl Ether IP: Isopropyl Alcohol Reference Example 1 To 198 ml of N,N-dimethylformamide was added 4.09 mL of sodium hydride (purity 60%), and at 5 to 10°C, 19.8 g of 4-chlorobenzoylacetamide was added. After adding in portions, the reaction is stopped at 20-40'C until hydrogen generation stops. Then, 18. 1,2-dibromoethane was added at the same temperature.
89 and react at 50-60'C for 2 hours.

The reaction solution is cooled, and after adding 2.17 g of sodium hydride (purity 60%) at 5 to 10°C, the reaction is allowed to react at 20 to 40°C until hydrogen generation stops. Then, 9.4 g of 1,2-dibromoethane is added at the same temperature, and the mixture is reacted at 50 to 60°C for 2 hours. After the reaction, the solvent was distilled off under reduced pressure and 20% of water was added.
Add 0 ml and 200 ml of ethyl acetate, and adjust to pl+6.0 with 2N hydrochloric acid. The organic layer is separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (elution solvent: chloroform)
When purified, 13.0 g (yield 58.2%) of 1-carbamoyl-cyclopropane is obtained.

Melting point: 161-162°C (recrystallization solvent: benzene) IR
(KBr) to 1B-': 3390, 3140. 1680. 1645, 1
620. 1575 Month MR (CI) CI3) δ value: 1, 10 ~ 1.85 (41L m), 5.20 ~ 6
．． 25 (211bS).

7, 42 (2H, d, J duck Hz), 7. 90(2)
11, d, J=911z) Compounds shown in Table 2 were obtained in the same manner.

Reference Example 2 3.53 ff of sodium hydride (purity 60%) was added to 100 Inl of N,N-dimethylformamide, and 5 to 1
4-chlorobenzoylacetic acid ethyl ester at 0 °C
．． After dropping 07, the mixture is allowed to react at 15 to 20°C until hydrogen generation stops. Then, 16.6 g of 1,2-dibromoethane was added at the same temperature, and the mixture was reacted at 50 to 60°C for 3 hours. After cooling the reaction solution and adding 3.53 g of sodium hydride (purity 60%) at 5-10'C,
Let the reaction take place at ℃ until hydrogen evolution stops. Then, at the same temperature, 16.69% of 1,2-dibromoethane was added, and 50 to 6
React at 0'C for 4 hours. Cool the reaction solution and incubate for 5 to 10
' Liium hydrogenated with C (purity 60%) 2.479
After adding, the reaction is carried out at 15 to 20°C until hydrogen generation stops. Then, at the same temperature, 1,2-dibromoethane 11
．． 69 and react at 50-60'C for 4 hours. After the reaction is complete, add 400 parts of water and 400 parts of ethyl acetate, and adjust to pt+8.0 with 2N hydrochloric acid. The yi layer is separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. If the iq residue is purified by column chromatography (elution solvent: toluene), 1-(4-chlorobenzoyl)
-1-ethoxycarbonylcyclopropane 14.69
(yield 65.5%).

oily substance IR) cm-1: 2960, 1725.1675.158ONHR (CD
Cl2>δ value; 1.00 (31L t, J=711Z), 1.40-1
．． 65 (411, m).

4.06 (2H, Q, J=7H2), 7.10-8.0
0(41,m) Similarly, the next compound is 19.

1-ethoxycarbonyl-1-(2,4-difluorobenzoyl)cyclopropane oil private property IR>cm-1: 1710, 1655.1590.1405.1125N
)IR (CDCl2>δ value: 1,05 (3N, t, J=711z), 1.6
3(411,s>.

4.09 (2H, Q, J=7H2), 6.45-8.2
0(3H,m) Reference Example 3 1-(4-chlorobenzoyl)- in 1υOd of ethanol
Add 10.09 g of 1-ethoxycarbonylcyclopropane and add 1N* sodium oxide aqueous solution io at 15-20'C.
After adding o y dropwise, the mixture is allowed to react at the same temperature for 5 hours. After the reaction is complete, add 200 ml of water and adjust the pH to 1.0 using a 6N salt solution.
Adjust to. If the precipitated crystals are removed and washed with water, 1-
7.89 g of carboxy-1-(4-chlorobenzoyl)cyclopropane (yield 87.6%) is obtained.

Melting point 152-163°C IR (KBr) cm-1; 1670, 158O NMR (d6-f)) fsO) δ value; 1.10-1.
65 (41Lm), 7.59 (2N, d, J=9NZ)
.

7, 91 (2H, d, J=911z), 11.5
0 to 13.50 (1N, bs) Reference Example 4 1-(4-chlorobenzoyl)- to 20% of chloroform
Add 2.09 g of 1-hydroxycarbonylcyclopropane and 0.05 g of N,N-dimethylformamide,
After dropping 2.33 ml of oxalyl chloride at ~10°C,
React for 3 hours at 5-15°C. Then, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 10 ml of chloroform, and then dissolved at 5 to 10°C with 2.43 ml of 2.2-trifluoroethylamine Wm salt and 5 ml of triethylamine.
Add dropwise to 20d of chloroform solution containing 15<2
React at 0°C for 1 hour.

After the reaction was completed, the reaction solution was sequentially washed with water, 1N hydrochloric acid, water and saturated saline, and then dried over anhydrous magnesium sulfate.
The solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (elution elution tS: toluene: ethyl acetate =
20:1), 1-(4-chlorobenzoyl)-1-[N-(2,2°2-trifluoroethyl)
Carbamoylcocyclopropane 1.37 (yield 47.
8%) to 1q.

Melting point 115.5-116.5°C (Recrystallization solvent: benzene-〇-hexane) IR (KBr
') cm-': 3330, 1680.1650.1580.154ON
)l old CDCl3) δ value; 1.10-1.90 (4H, m).

3,85 (211,dQ, J=611z, J=9
11z).

6.00~6.70(Ill,...), '/, 42(
2H, d, J=9H7).

7, 80 (2H, d, J=911z) Similarly, compound 17 in Table 3 was obtained.

(Leaving space below) Reference Example 5 4.2 g of sodium hydride (purity 60%) was added to 180 d of dry dimethyl sulfoxide, and 26.49 g of trimethylsulfonium iodide was added in portions at 20° C. while stirring.
The reaction is allowed to proceed at 0-25°C until hydrogen evolution ceases. Then, 22.4 g of 1-carbamoyl-1-(4-chlorobenzoyl)cyclopropane was added at the same temperature and reacted for 2 hours. After the reaction is completed, the reaction solution is introduced into a mixed solvent of 540 ml of water and 540 ml of ethyl acetate, adjusted to p) 16.0 with 2N hydrochloric acid, and the Ia layer is separated. Then, the organic layer is washed with water, dried over anhydrous magnesium oxide, and then the solvent is distilled off under reduced pressure. Diethyl ether is added to the resulting residue and the crystals are collected to give 2-[1-(carbamoyl)cyclopropan-1-yl]-2-(4-
Chlo]]phenyl)oxirane 21.29 (yield 89
．． 1%).

Melting point 176-178°C (recrystallization solvent: benzene) I
R(KBr) to (H-1; 3480, 3160.1690.1610.149ON
HR (CI) CI3) δ value; 0.60 to 1.95 (411, m), 2.91 (1■,
d, J=5Hz).

3.10 (ltl, d, J=5Hz), 5.40-6.
30 (2tl, bs).

7.20-7.75 (48, m) Similarly, the compounds in Table 4 were added to the stomach.

(Left below) Example 1 2-[1-(carbamoyl)cyclopropan-1-yl]-2-(4-chlorophenyl)oxirane 23.8
After dissolving 1,2,4-triazole sodium salt 13.g in N,N-dimethylformamide 238d.
79 and react at 50-60'C for 5 hours. After the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was diluted with water.
00 ml and 200 ml of ethyl acetate were added and dissolved, and the pH was adjusted to 6.0 with 2N hydrochloric acid. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate.
The solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography (elution solvent: chloroform:methanol = 100:1) to obtain 1-[1-(Leva7yl)cyclopropan-1-yl]-1-(4 -chlorophenyl) -2-(1,2,4-triazole-1-
) ethanol 16.29 (yield 52.8%)
qru.

Melting point 181-182°C (Recrystallization solvent: benzene-ethyl acetate) IR (KBr)
cm-1: 3400, 3330.3160.1655.1485N
MR (d6-DH3O) δ1 direct: 0, 50-1.4
0 (4N, m), 4.77 (2H, S).

6.11 (IH, bs), 6.86 (2M, bs).

7, 10-7.80 (4tl, m), 7.76 (i
ff, s).

8.20 (ill, S) Example 2 Dissolve 27.8 g of 2-(4-chlorophenyl)-2-[1-(N-cyclopropylcarbamoyl-1-yl]oxirane in 250 ml of N,N-dimethylformamide) SA V1 Imidazole 1
After adding 3.6 g and 13.8 cJ of potassium carbonate,
React at 60-70°C for 10 hours. After the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 250 ml of water and 250 ml of ethyl acetate, and then dissolved in 2N
Adjust to 1) H6.0 with hydrochloric acid. The organic layer is separated, washed with water, dried over anhydrous magnesium FA acid, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography (elution solvent; chloroform:methanol = 25:'
If purified by I), 1-(4-chlorophenyl)1-N
16.79 (yield: 48.3%) of -(N-cycloallylcaleva7yl)cyclopropan-1-yl]-2-(imidazol-1-yl)ethanol was converted to j'.

Melting point 187-188°C (Recrystallization solvent: benzene-ethyl acetate) IR (KBr)
nig(-' : 3320, 1630, 1530. 1505(Sh
) NMR (CDCl2 > δ value; 0, 35 to 1.50 (8H, m), 2.2
0 to 2. 70 (IH, m).

4, 08 (IH, d, J=14+Iz), 4.
39 (111, d, J=14Hz).

4, 80-5.60 (1N, nl), 13.40-7
．． 55 (7N, m) Examples 3 to 17 In the same manner as in Example 1, the compounds shown in Table 5 were obtained.

(Left below) 7, / 7・' / Example 18 (1) 2-(4-ri[corophenyl)-2-['l
-(ethoxycarbonyl)cyclopropan-1-yl]
After dissolving 26.7 g of oxirane in 260 d of N,N-dimethylformamide, 189 g of sodium salt of 1,2,4-triazole was added and reacted at 60 to 70'C for 5 hours. After the reaction is completed, the solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 200 ml of water and 200 parts of ethyl acetate, and then adjusted to 1 H6.0 with 2N hydrochloric acid. The organic layer is separated, washed with water, dried over anhydrous magnesium ft acid, and the solvent is distilled off under reduced pressure.

If the resulting residue is purified by column chromatography (elution groove rR: chloroform), 1-(4-chlorophenyl)-1-[1-(ethoxycarbonyl)cyclopropan-1-yl]-2-(L2 .4-triazol-1-yl) ethanol 10.83 (yield 32.1%)
get.

Melting point 73-76°C (recrystallization solvent: IPE) IR (K
Br) cm”: 3280, 2950.1710.1505.1485N
l(R(C[)C10)δ value: 0.50 to 1.55 (7H, m), 4.04 (2tl,
q, J=7Hz).

4, 74 (ltl, d, J=14Hz>, 4.9
5 (IN, bs).

5.36 (IH, d, J=1411z), 7.27
(211, d, J=9tlz).

7, 54 (28, d, J=911z), 7.87
(IH, s) , 8.13 (IH, 5) (2) 1
-(4-chlorophenyl)-1-[1-(ethoxycarbonyl)cyclopropan-1-yl] -2-(1,2
,4-triazol-1-yl)ethanol 33.6g
was added to a mixed solvent of 1N aqueous sodium hydroxide solution 336d and ethanol 336d with stirring, and the mixture was reacted at 25°C for 3 hours. After the reaction is completed, 350 rdl of water and 800 d of ethyl acetate are added, and the pH is adjusted to 113.5 with 2N hydrochloric acid. Then, the organic layer was separated, washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate.

After distilling off the solvent under reduced pressure and adding diethyl ether to the resulting residue, the crystals are taken out and washed with diethyl ether to give 1-[1-(carboxy)cyclopropan-1-yl. ]-1-(4-chlorophenyl)-2-(1
゜2.4-triazol-1-yl) ethanol28.
39 (yield 91.9%) is obtained.

Melting point 175-179°C (recrystallization solvent: IPA) IR
(KBr) cm-1: 3100, 1710.1505.148ONHR(d6
-D) fsO) δ value: 0.20 to 1.40 (4H, m), 4.88 (IH, d
, J=1411z).

5, 30 (IN, d, J=14H7), 7.3
6 (2H, d, J=9H2).

5, 32 (211, d, J=911z), 7.
89 (IH, s), 8.29 (ltl s) Example 19 In the same manner as in Example 18 (1) and (2), each compound was 19.

1-[1-(,ethoxycarbonylpan-1-yl)-1-(2,4-difluorophenyl)-2-(1,2.4-triazol-1-yl)
Ethanol melting point 114-115°C (recrystallization solvent: IPE) IR
(KI3r) to (B-'; 3120, 1720, 1610, 1500, 1
310. 1205 R (CDCI3) δ value; 0, 60-1. 50 (711, m), 4.
08 (2H, q, J=7Hz).

4, 86 (Ill, d, J = 14 Hz), 5.13 (1
fLd, J=14Hz).

5, 16 (IH, bs), 6.30-7. 75
(3H, m).

7, 80 (Ill, s), 8. 13(IN,
s) 1-[1-(carboxy)cyclopropan-1-yl]-1- (2,4-difluorophenyl)-2-
(1,2.4-triazol-1-yl)ethanol Melting point 180-181°C (recrystallization solvent: ethyl acetate) I
R(KBr) to 1B-1: 3320, 1650. 1605, 1580, 1
490, 1320. 118ON)IR(d6-D
) 130 + CDCI 3>δ value: 0, 25 ~ 1.
50 (411, m), 4.95 (IH, d, J = 14H
z).

5.25 (IH, d, J=1411z), 5
．． 75 (211, bs).

6, 45-7. 80 (4H, m>, 8.2
2(IH, s) Example 20 1-(4-chlorophenyl)-1-[1-(ethoxycarbonyl)cyclopropan-1-yl]-2- (L
2,4-triazol-1-yl)ethanol 3.49
was added to 2-aminoethanol 17d, and 150-160
React at ℃ for 3 hours. After the reaction is complete, add 150% water to the reaction solution.
/Ilj and 150% ethyl acetate) into medium d, and adjust the pH to 6.0 with 2N hydrochloric acid.

Then, the organic layer is separated, washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (elution solvent: chloroform:methanol = 20:1).
), 1-(4-chlorophenyl)-1-
(1-[N-(2-hydroxyethyl)carbamoylcocyclopropan-1-yl)-2-(1,2.4-
2.179 (yield: 61.1%) of triazol-1-yl)ethanol are obtained.

Melting point 115.5-116.5°C (Recrystallization solvent; benzene-〇-hexane) IR (KI3
r) cIn-1; 3320, 1625, 1535, 1085.82
0 hearing R (CDCI3) δ1 direct: 0, 50 ~ 1.40 (4tlm), 2, 50 ~ 3.0
0(1tl,m).

3, 00~3. 70 (411, m), 4. 6
5 (IH, d, J=14112).

4, 96 (IH, d, J = 1411z), 5.61 (l
tl, bs).

6 40 ~ 6.90 (IH, m), 7.00 ~ 7.
50 (4N, m).

7, 80 (IH, S), 8, 11 (IH, s)
Example 21 The following compound was obtained in the same manner as in Example 20.

1-(4-chlorophenyl)-1- (1- [N-(
3-Hydroxypropyl)carbamoyl]cyclopropan-1-yl)-2-(1,2.4-triazol-1-yl)ethanol Melting point 107-109°C (Recrystallization solvent: benzene-ethyl acetate) IR (tG3r
) to (B-1: 3370, 3270, 1620. 154ONMI
t(d6-DHSO)δ value: 0, 35 ~1. 60 (6H, m), 2.
60 ~3. 40 (4tLm).

3,95-4,40(IN,m).

4, 64 (IH, d, J = 15 Hz), 4.94 (It
l, d, J = 15tlz).

6, 07 (IH, bS), 6.95 ~ 7.60 (41
, m).

7,77(ill,S),8.25(1H,S)Example 22 1-[1-(carboxy)cyclopropan-1-yl]-1-(4-chlorophenyl)-2-(1,2 ,4-
triazol-1-yl) ethanol 3.1 g and N
- Dissolve 1.29 g of hydroxysuccinimide in 150 d of anhydrous dioxane and react with N,N-1 dicyclohexylcarbodiimide for 3 hours at room temperature. Remove insoluble matter, 5
Addition of 6.1 g of morpholine at ~10″C followed by 2 at room temperature.
React for 00 hours. After the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was mixed with 200 d of water and 20 d of ethyl acetate.
Add 0 d and dissolve. The organic layer is separated, washed twice with saturated brine, dried over 1 ml of anhydrous sulfuric acid magne, and the solvent is distilled off under reduced pressure. The 1q residue was purified by column chromatography (elution solvent: chloroform:methanol-20:1) to give 1-(4-chlorophenyl)-1-[1-(morpholinocarbonyl]-2- (1, 950 ml (yield 25.0%) of 2.4-triazol-1-yl)ethanol are obtained.

Melting point 160.5-161.0°C (Recrystallization solvent; benzene-〇-hexane) IR (KBr
) cm-1: 3400, 3250, 1605, 1430. 1
12ON bolt 1? (CDCl2) δ(direct; 0, 35
~1. ! +0 (4tl, m), 2.50 ~ 3, 90
(8H, m).

4, 84 (lllld, J=14tlz), 5. 11K
ld, J=14Hz).

5, 13 (IH, bS), 6.80 ~ 7.50 (4+
1, m).

7, 80 (11LS), 8.20 (IN, S) Example 2
3-29 In the same manner as in Example 22, the compounds in Table 6 were added to /. l'i
Ta.

Example 30 (1) 1-[1-(carboxy)cyclopropane-
1-yl]-1-(4-chlorophenyl)-2-(1,
2,4-triazol-1-yl)ethanol 1.0
(J and N-hydroxysuccinimide 410 m3
After dissolving in 20 ml of water diquinane and adding 740 mg of N,N-1 dicyclohexylcarbodiimide for 1 hour, the mixture was reacted at a variable temperature for 3 hours. Then, 5-10'C
After adding 1,03% of triethylamine, the seedling temperature was 200%
Time reaction. After the reaction is complete, insoluble materials are removed and the solvent is distilled off under reduced pressure. Water and 50 d of chloroborum are added to the resulting residue to dissolve it.

The organic layer is separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Column chromatography of the resulting residue ()
Exit d) H medium; chloroform: methanol = 50; If prepared *^ with 1), 6-(4-chlorophenyl)-2-oxo-6-[(1,2,4-triazol-1-yl)methyl ]-1-Oxaspiro[3,,2]hexane 650
1 nl (yield 69%) was obtained.

Melting point 108.0-110.0'C (Recrystallization solvent; benzene-〇-hexane-IPE) I
m-' to R(KBr); 1820, 1505.1265.1130.83ONH
R(CDCl2) δ value; 0, 60 to '2.00 (4N, m), 4.83 (2
H,S).

7.10 (2H, d, J=9Hz), 7.39 (
2H, d, J=9tlz).

7.85 (1N, s), 8.10 (III, 5) (2)
6-(4-chlorophenyl)-2-oxo-6-[
(1,2,4-triazol-1-yl)methyl]-1
-7Jki→Nospiro[3,2]hexane 200m! 600 mg l and n-pendelamine in chloroform 5
d and refluxed for 3 hours. After the reaction is completed, the mixture is washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography (elution solvent: chloroform:methanol = 50:1) to obtain 1-(4-chlorophenyl)-1-[1-(N -n-pentylcarbamoyl)cyclopropan-1-yl] -2-(1,2,4
-triazol-1-yl)ethanol 130 my
(yield 50%).

Melting point 96.0-97.5°C (Recrystallization solution W: benzene-〇-hexane-IPE) I
R (KBr) cm-1: 3320, 1625.1530.1260.108ON
MR (C108ONδ value: 0, 20~1.80 (1311, m), 2.70~
3.40 (211, m).

4, 30~5.50 (311, III), 5.80~
6.50 (IN, m).

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ “In the formula, A is CH or N; R^1 is an optionally substituted aryl group; R^2 is a hydroxyl group or a substituted 2-Azolyl-1-cyclopropylethanol derivative and its salt.