JP3233276B2 - Hydrazide compounds as kappa agonists - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel hydrazide compounds and pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them. The pharmaceutically active compounds of the present invention can be used as selective kappa receptor agonists.

[0002]

BACKGROUND OF THE INVENTION Opioid analgesics, such as morphine, are useful for treatment, but their use is critical because of their side effects (eg, drug dependence and abuse). Is restricted to Therefore,
There is a need for analgesics that are highly convenient and less prone to drug dependence. Considerable pharmacological and biochemical studies have been performed to discover opioid proteins and opioid receptors. And subtypes of opioid receptors in peripheral nerves of various species including humans, for example, μ (mu), δ (delta), κ
(Kappa) 's discoveries set the stage for creating new painkillers. As opioid analgesics (e.g., morphine) are thought to act as mu-receptor agonists, it has been studied to separate kappa-receptor agonist-based responses from mu-receptor agonist-based responses. Recently, from the above viewpoint, κ-
Selective agonists (κ agonists) have been reported (eg, EMD-61753: A. Barber et al.,
Br. J. Pharmacol. , Vol. 113, p
p. 1317-1327). Some of them are actually being studied in clinical trials (Med. Res.
Rev .. , Vol. 12, p. 525, 1992). Selective κ-receptor agonist (or κ agonist)
Various kinds of pyrrolidinyl hydroxamic acid compounds are disclosed in WO 96/30339.

[0003]

According to the present invention, there is provided the following formula (I):

Embedded image [Wherein, R ¹ and R ² each independently represent a hydrogen atom,
(Alkyl having 1 to 4 carbon atoms) -CO- group, 1 to 4 carbon atoms
R ³ is a hydrogen atom, a hydroxy group, a halogen atom or an OY group (Y is a hydroxy protecting group); and R ⁴ is a halogen atom, optionally having 1 to 4 carbon atoms. An alkyl group having 1 to 4 carbon atoms
A phenyl group which may be substituted with 1 to 3 substituents selected from an alkoxy group, or a heterocyclic group selected from a furanyl group, a thienyl group and a pyridinyl group]. Provided are compounds and salts thereof.

The hydrazide compounds of the formula (I) according to the invention exhibit good kappa agonist activity and are therefore useful as analgesics, anesthetics, anti-inflammatory agents or neuroprotective agents in the treatment of mammals, especially humans. Useful and also in arthritis, stroke or functional bowel disease (eg abdominal pain). In particular, these compounds show good analgesic effects in the central nervous system of mammals. Accordingly, the present invention is useful as an analgesic, anesthetic, anti-inflammatory or neuroprotective agent comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically inert carrier, and Provided are pharmaceutical compositions that are also useful in treating diseases. Also, the present invention
The present invention can be used for a method for treating a mammal in a medical condition requiring an agonistic activity for an opioid κ receptor, comprising administering a therapeutically effective amount of a compound represented by the formula (I) to a mammal.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom. As used herein, the term "alkyl having 1 to 4 carbons" means a linear or branched alkyl group, and is not limited to the following groups, but includes methyl, ethyl, n
-Propyl group, isopropyl group, n-butyl group, sec
-Butyl group and tert-butyl group. In the present specification, the “alkoxy group having 1 to 4 carbon atoms” means a linear or branched (alkyl having 1 to 4 carbon atoms) —O— group, and is limited to the following groups. However, examples thereof include a methoxy group, an ethoxy group, a propoxy group, an iso-propoxy group, an n-butoxy group, an iso-butoxy group, and a tert-butoxy group.

As used herein, the term “amino protecting group” refers to
Means a functional group that protects the amino group from undesired reactions during the synthetic procedure, including but not limited to the following groups: trifluoroacetyl, trimethylsilylethoxycarbonyl, benzyloxycarbonyl, and t
tert-butyloxycarbonyl group and the like (preferably,
Benzyloxycarbonyl group and tert-butyloxycarbonyl group). By "hydroxy protecting group" in the present invention is meant a functional group that protects the hydroxy group from undesired reactions during synthetic procedures,
Although not limited to the following groups, benzyl, triphenylmethyl, tetrahydropyranyl, methoxymethyl, and R ⁵ R ⁶ R ⁷ silyl groups (R ⁵ , R ⁶ and R ⁷
Is an alkyl group or a phenyl group each having 1 to 6 carbon atoms), and preferably a methoxymethyl group.

In a preferred group of the κ agonist compounds of the present invention, R ¹ and R ² each independently represent a hydrogen atom, an aliphatic acyl group, an alkyl group having 1 to 4 carbon atoms or tert-
R ³ is a hydroxy group or an OY group (Y is a methoxymethyl group); and R ⁴ is a butoxycarbonyl group;
Is a phenyl group substituted with 1 to 3 substituents selected from a halogen atom, an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms as a substituent. And a compound represented by the formula:

A further preferred group of the invention comprises R ¹ and R ²
Are each independently a hydrogen atom, an acetyl group or a methyl group, R ³ is a hydroxy group, and R ⁴ is
It includes the compound represented by the formula (I), which is a 3,4-dichlorophenyl group.

Preferred specific compounds of the present invention are N '
-Tert-butoxycarbonylamino-2- (3,4
-Dichlorophenyl) -N- [2- (3- (S) -methoxymethoxypyrrolidin-1-yl) -1- (S) -phenylethyl] acetamide; N-amino-2- (3,
4-dichlorophenyl) -N- [2- (3- (S) -methoxymethoxypyrrolidin-1-yl) -1- (S)-
Phenylethyl] acetamide; N-acetamido-2
-(3,4-dichlorophenyl) -N- [2- (3-
(S) -methoxymethoxypyrrolidin-1-yl) -1
-(S) -phenylethyl] acetamide; and N'-
tert-butoxycarbonylamino-2- (3,4-
Dichlorophenyl) -N- [2- (3- (S) -methoxymethoxy-pyrrolidin-1-yl) -1- (S) -phenylethyl] -N'-methylacetamide.

Further preferred specific compounds of the present invention are
N-amino-2- (3,4-dichlorophenyl) -N-
[2- (3- (S) -hydroxypyrrolidin-1-yl) -1- (S) -phenylethyl] acetamide; 2
-(3,4-dichlorophenyl) -N ', N'-dimethylamino-N- [2- (3- (S) -hydroxy-pyrrolidin-1-yl) -1- (S) -phenylethyl] acetamide; N-acetamido-2- (3,4-dichlorophenyl) -N- [2- (3- (S) -hydroxypyrrolidin-1-yl) -1- (S) -phenylethyl]
Acetamide; and 2- (3,4-dichlorophenyl)
-N- [2- (3- (S) -hydroxypyrrolidine-1
-Yl) -1- (S) -phenylethyl] -N- (N '
-Methylamino) acetamide.

General Synthesis The kappa agonist of formula (I) of the present invention can be prepared in a number of ways. For example, the reaction process formula (1)
Can be easily prepared according to the procedure described in (1).

Reaction scheme (1)

Embedded image

The reaction step formula (1) shows the step of producing the hydrazide compound of the present invention. The intermediate 1- (2-
(S) -chloro-2-phenylethyl) -3- (S)-
Methoxymethoxypyrrolidine can be reacted with an N-protected carbazate (eg, NH ₂ NHBOC). The reaction is carried out in a suitable polar solvent, such as methanol (MeOH), ethanol (EtOH), or tetrahydrofuran (THF), at −60 ° C. to the reflux temperature of the solvent, preferably at the reflux temperature of the solvent for 5 minutes to 24 hours. It can be carried out in a time, preferably 5 minutes to 2 hours. After evaporating the solvent, the residue is washed. Desired phenylacetic acid (e.g., 3,4-dichlorophenylacetic acid) can be added to the residue. The above reaction is carried out using a carbodiimide compound [eg, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride; this is a water-soluble carbodiimide (water-solubl).
e carbodiimide) or WSC]. The above reaction can be carried out at about 25 ° C. in methylene chloride (CH ₂ Cl ₂ ) for 5 minutes to 24 hours. Optionally, in the presence of an acid (eg, trifluoroacetic acid), about 2
The N-protecting group (for example, BOC) can be removed by performing ordinary hydrolysis at 5 ° C. to obtain an unsubstituted hydrazide compound.

According to a procedure similar to the procedure shown in the above reaction scheme (1), R ¹ is a hydrogen atom and R ² is an alkyl-O— group having 1 to 4 carbon atoms or a C ¹ to 4 carbon atom. A compound represented by the formula (I), which is an alkyl group of For example, in the step shown in the above reaction scheme (1), instead of tert-butyl carbazate, an acylhydrazide having 1 to 4 carbon atoms [that is, NH
₂ NHCO- (alkyl having 1 to 4 carbons)]
Formula (II):

Embedded image (R is an alkyl group having 1 to 4 carbon atoms), thereby obtaining a mono-acylated hydrazide compound.

Further, 1- (2- (S) -chloro-2-phenylethyl) -3- (S) -methoxymethoxypyrrolidine is reacted with tert-butyl N-alkylcarbazate in the reaction scheme (1). By reacting under the conditions shown in formula (III):

Embedded image (R is an alkyl group having 1 to 4 carbon atoms), that is, R ¹ is a hydrogen atom, and R ² is
Compounds of formula (I), which are alkyl groups of ~ 4, can be prepared.

The intermediate 1- (2- (S) -chloro-
2-Phenylethyl) -3- (S) -methoxymethoxypyrrolidine can be prepared according to the process described in the reaction scheme (2).

Reaction formula (2)

Embedded image In the above reaction scheme, P means a protecting group.

In route 1, first, a compound represented by the formula (IV) is reacted with a substituted styrene oxide represented by the formula (V) to give a compound represented by the formula (VI) and a compound represented by the formula (VII). ) Can be formed. The reaction is carried out in a reaction inert solvent [eg, MeOH, EtOH,
Isopropyl alcohol, THF, dioxane, dimethylformamide (DMF), dimethylsulfoxide (D
MSO), methylene chloride, water, benzene, toluene, n
-Hexane, cyclohexane] in the presence or absence of
-78 ° C to the reflux temperature of the solvent, preferably 0 ° C to 25 ° C
At a temperature of 5 minutes to 48 hours, preferably 0.5 to 12 hours. Subsequently, a mixture of the compound represented by the formula (VI) and the compound represented by the formula (VII) is converted to methanesulfonyl chloride (MsCl) in the presence of a base [eg, triethylamine (Et ₃ N)]. To give intermediate A. According to the above steps, the R and S configurations of the compound represented by the formula (VI) and the compound represented by the formula (VII) can be selectively determined.

Alternatively, Intermediate A can be obtained according to the steps described in Route 2. The compound represented by the formula (X) can be prepared by reacting a compound represented by the formula (VIII) with a compound represented by the formula (IX). Subsequently, the compound represented by the formula (X) can react with MsCl under the same conditions as in Route 1. The compound represented by the formula (VIII) and the compound represented by the formula (IX) are both known compounds, which can be produced by a known method, or compounds similar to the known compounds. Can be manufactured by a method similar to a known method.

The tert-butyl N-alkylcarbazate can be prepared according to the process described in reaction scheme (3).

Reaction Scheme (3) Preparation of t-butyl N-alkylcarbazate

Embedded image

The phthalimide represented by the formula (XII) can be produced from a known compound. For example, the expression (X
Phthalic anhydride and carbazic acid tert-
The compound represented by the formula (XII) can be obtained by reacting butyl with a reaction inert solvent (eg, dichloroethane). Subsequently, the compound represented by the formula (XII) can be reacted with a desired alkyl halide (RX) in the presence of sodium hydride. Subsequently, the compound represented by the formula (XIII) can be reacted with N-methylhydrazine to give tert-butyl N-alkylcarbazate. The above reaction can be carried out using reaction conditions well known to those skilled in the art.

The hydrazide compound of the present invention represented by the general formula (I) in which both R ¹ and R ² are alkyl groups can be obtained from an unsubstituted hydrazide compound prepared according to the process described in the reaction scheme (1). It can be prepared by conventional reductive alkylation. The unsubstituted hydrazide compound can be treated with a desired aldehyde in the presence of a reducing agent, as shown in reaction scheme (4).

Reaction scheme (4) Preparation of disubstituted hydrazide derivative

Embedded image In the above reaction scheme, R and R ′ each have 1 to 1 carbon atoms.
4 alkyl group.

The above-mentioned reduction can be carried out using conditions well known to those skilled in the art. Suitable reducing agents include sodium cyanoborohydride (NaBH ₃ CN), sodium triacetoxyborohydride, and sodium borohydride. The compounds of the formula (I) according to the invention are basic and, therefore, they will form acid addition salts. All such salts are included within the scope of the present invention. However, for administration to mammals, a pharmaceutically acceptable acid addition salt must be used. The acid addition salts are contacted by standard methods, for example, by contacting the basic and acidic compounds in a substantially equivalent ratio in water or an organic solvent (eg, methanol or ethanol), or a mixture thereof. Can be prepared. Said salts can be isolated by crystallization from the solvent or evaporation of the solvent. Typical salts that can be formed are hydrochloride, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumaric acid Salt, gluconate, sugar, benzoate, methanesulfonate, p-toluenesulfonate, oxalate,
And pamoate [ie, 1,1′-methylene-bis-
(2-Hydroxy-3-naphthoic acid) salt].

Further, a bioprecursor (also referred to as a prodrug) of the kappa agonist compound represented by the formula (I) is also included in the scope of the present invention.
Biological precursors of the kappa agonists of formula (I) are chemical derivatives of the kappa agonists and are readily converted back to the original compounds of formula (I) in biological systems. . In particular, the biological precursor of a kappa agonist of formula (I) is administered to a mammal (e.g., a human) and absorbed, and then the original biological formula of formula (I) A conversion back to the compound takes place.

For example, a bioprecursor of the kappa agonist of the present invention represented by the formula (I) wherein one or both of A and OR is a hydroxy group can be produced by forming an ester of a hydroxy group. . If only one of A and OR is a hydroxy group, only a monoester can be formed. If both A and OR are hydroxy groups, monoesters and diesters (which can be the same or different) can be formed. Typical esters are esters of simple alkanoic acids (eg, acetic acid, propionic acid, butyric acid, etc.). Furthermore, A or OR
Is a hydroxy group, the hydroxy group is converted to an acyloxymethyl compound (eg, pivaloyloxymethyl compound) by reaction with an acyloxymethyl halide (eg, pivaloyloxymethyl chloride). , A biological precursor can be produced.

The kappa agonist compounds of the present invention represented by the formula (I) show significant agonist activity for opioid kappa receptors, and are therefore analgesic, anti-inflammatory, diuretic, anesthetic and neuroprotective, or It is useful for treating a mammal requiring a therapeutic agent for seizure or functional bowel disease (for example, abdominal pain), particularly a human, as a therapeutic agent for the mammal.

The activity of the κ-agonist compound of the present invention represented by the formula (I) is indicated by the opioid receptor binding activity. Said activity was demonstrated in homogenates from whole guinea pig brain by Regina, A. et al. By J. Receptor Res. Vol. 12: p.
p. 171-180, 1992 ". Briefly, at 25 ° C. in the presence of labeled ligand and test compound,
Incubate the tissue homogenate for minutes. μ−
The site is (3H)-[D-Ala2, MePhe4, Gl
y-ol5] enkephalin (DAMGO) (1 nM)
And the δ-site is (3H)-[D-Pen2,5].
Labeled with enkephalin (DPDPE) (1 nM) and the κ-site was (3H) -CI-977 (0.5 nM).
Label with. Non-specific binding was determined by CI-977 (κ) (1
μM), DAMGO (μ) (1 μM), and DPDPE
(Δ) Measured using (1 μM). Data is Chen
Expressed as IC ₅₀ values obtained by a non-linear fitting program using g and Prusoff equations. Some compounds prepared in the examples range from 0.01 to 100
It showed low IC ₅₀ values in the nM range.

The activity of the κ agonist compound is Wh
eeler-Aceto, H .; "Psych
opharmology, Vol. 104: pp.
35-44, 1991 ". In this exam,
Male SD rats (80-100 g) are injected subcutaneously with test compound dissolved in 0.1% methylcellulose saline or vehicle. After 30 minutes, 2%
Inject 50 ml of formalin into the hind paws. The number of licks of the injected paw is measured per observation period of 15-30 minutes after formalin injection and expressed as% inhibition compared to the respective vehicle group. Some of the compounds prepared in the following examples were tested according to the above procedure and showed good activity (ie, ED ₅₀ values in the range below 0.1 mg / kg; subcutaneous injection).

The above activity of the kappa agonist is determined by Haye's
s, A. G. FIG. By Br. J. Pharmaco.
l. Vol. 79: pp. 731-736, 1983 "
Can also be shown by the Rotarod test described in In this test, male SD rats (100-12) were tested for their ability to balance on a rotating rod (diameter = 9 cm; rotation speed = 5 rpm).
0g) Select groups of 6-10 animals. Next, the selected rat is injected subcutaneously with the test compound dissolved in 0.1% methylcellulose saline. 30 minutes after treatment,
The animals are tested again; rats that fall off the stick more than twice in 150 seconds are considered to indicate impaired motor performance and their performance [ie time on rotarod] is recorded. I do. This ED ₅₀ value, defined as the dose of the drug that halves the performance time, is observed in the control group.

The kappa agonist compound of the present invention represented by the formula (I) can be administered to mammals by any of oral, parenteral and topical routes. Generally, it is most preferred that these compounds be administered to humans at a dosage ranging from 0.01 mg to 50 mg per day,
It will, of course, vary with the weight and condition of the subject being treated, the condition of the disease being treated, and the particular route of administration chosen. However, it is most desirable to use humans for the treatment of pain in post-operative patients, alone or in divided doses, at dose levels in the range of 0.01 mg to 1 mg / kg (body weight) per day.

The compounds of the present invention can be administered by any of the above routes of administration, alone or in combination with pharmaceutically acceptable carriers or diluents, and the administration can be simple. It can be performed in one or more administrations. In particular, the novel therapeutic agents of the present invention can be administered in a wide variety of different dosage forms. That is, tablets, capsules, lozenges, troches, hard candy, powders, sprays, creams, salves, suppositories, jellies, gels, pastes in combination with various pharmaceutically acceptable inert carriers. , Lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. Further, the pharmaceutical composition for oral administration can be appropriately imparted with sweetness and / or flavor. The therapeutically active compounds according to the invention are generally present in the aforementioned dosage forms in concentration levels in the range from 5% to 70% by weight, preferably from 10% to 50% by weight.

For oral administration, tablets containing various excipients, for example, microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate, and glycine
Various disintegrants, for example starch (preferably corn, potato or tapioca starch), alginic acid,
And some complex silicates
xsilicate), and granular binders such as polyvinylpyrrolidone, sucrose, gelatin, and acacia. In addition, lubricants,
For example, magnesium stearate, sodium lauryl sulfate, and talc are often very useful for tableting purposes. Solid compositions of the same type can also be used as fillers in gelatin capsules;
Preferred materials in this connection also include lactose (or lactose) and high molecular weight polyethylene glycols. If aqueous suspensions and / or elixirs are desired for oral administration, various sweetening or flavoring agents, coloring agents or dyes, and, if desired, emulsifiers and / or
Alternatively, the active ingredient can be combined with a suspending agent and a diluent, for example, water, ethanol, propylene glycol, glycerin, and various mixtures thereof.

For parenteral administration, solutions of a compound of the present invention in sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH> 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions described above are suitable for intra-articular, intramuscular and subcutaneous injection purposes.
The preparation of all these solutions under sterile conditions can be readily accomplished by standard formulation techniques well known to those skilled in the art. Furthermore, for the treatment of inflammatory conditions of the skin, the compounds of the present invention may be administered topically, preferably with creams, jellies, gels, pastes, ointments and the like according to standard pharmaceutical practice. .

[0036]

Examples and Production Examples The present invention will be specifically described below with reference to examples and production examples, but these do not limit the scope of the invention. Melting points were measured on a Buchi micro melting point apparatus and are uncorrected. The infrared absorption spectrum (IR) was measured using a Shimadzu infrared spectrometer (IR-4).
70). Unless otherwise noted, ¹ H and
The nuclear magnetic resonance spectrum (NMR) of ¹³ C is CDCl ₃
In a JEOL NMR spectrometer (JNM-GX270,
270 MHz), and the peak position is pp
m (parts per million) (downfield from tetramethylsilane). The shape of the peak is shown as follows. s = single line; d = double line; t
= Triplet; m = multiplet; br = broad.

Example 1 N'-tert-butoxycal
Bonylamino-2- (3,4-dichlorophenyl) -N
-[2- (3- (S) -methoxymethoxypyrrolidine-
1-yl) -1- (S) -phenylethyl] acetami
De methylene chloride (15ml) solution of 1- (2- (S) - hydroxy-2-phenylethyl) -3- (S) - methoxymethoxy pyrrolidine (503 mg, 2 mmol) and triethylamine (0.33 ml, 2.4 mmol) To a solution of was added mesyl chloride (0.19 ml, 2.4 mmol) at 0 ° C., and the resulting mixture was stirred at ambient temperature for 17 hours. The mixture was washed with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated to give 491 mg of an oil. Tert-butyl carbazate (31 in ethanol (5 ml))
A mixture of 7 mg, 2.4 mmol) and 1- (2- (S) -chloro-2-phenylethyl) -3- (S) -methoxymethoxypyrrolidine (491 mg, 2 mmol) was refluxed with stirring for 0.5 hour. did. After distilling off the ethanol, the resulting residue was methylene chloride (10 ml).
And washed with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated to give 676 mg of a yellow clear oil. The oil (676 mg, 1.8 in methylene chloride (10 ml)).
2 mmol) and 3,4-dichlorophenylacetic acid (44
9 mg, 2.19 mmol) in WSC (420
mg, 2.19 mmol) at room temperature. After stirring for 0.5 hour, the mixture was diluted with methylene chloride (10 ml) and washed with water and brine. After drying (sodium sulfate) and filtration, the filtrate was concentrated to an oil 1.1.
13 g were obtained. This was subjected to column chromatography (silica gel: 60 g, eluent = methylene chloride / methanol:
50/1) Purification by treatment to give a colorless oil 682m
g (61.7%). ¹ H NMR (270 MHz, CDCl ₃ ) δ 4.60
_{(2H, s, MeOC H 2} OCH -), 4.25-4.
_{15 (1H, m, MeOCH 2} OC H -), 3.76
(1H, d, J = 15.4 Hz, NCOC H ₂ Ar),
3.37 (3H, s, C H 3 OCH 2 O), 1.46 (9
H, s, NHCO ₂ C (CH ₃ ) ₃ ) MS (EI) m / z (rel int) 555 (0.
5, [M + 4] ⁺ ), 553 (1.1, [M + 2] ⁺ ),
551 (1.2, [M] ⁺ ), 524 (1.8, [M +
4-OMe] ⁺ ), 522 (7.3, [M + 2-OM
e] ⁺ ), 520 (10, [M-OMe] ⁺ ), 478.
(10), 404 (8.9), 365 (39), 321
(12), 234 (100)

Example 2: N-amino-2- (3,4-di
Chlorophenyl) -N- [2- (3- (S) -methoxy
Methoxypyrrolidin-1-yl) -1- (S) -phenyl
[Ethyl] acetamide N'-tert-butoxycarbonylamino-2- (3,4-dichlorophenyl) in methylene chloride (5 ml)
To a solution of -N- [2- (3- (S) -methoxy-methoxypyrrolidin-1-yl) -1- (S) -phenylethyl] acetamide (672 mg, 1.22 mmol),
Trifluoroacetic acid (2 ml) was added at room temperature. After stirring for 2 hours, the solvent was distilled off. The residue is basified with aqueous ammonia (NH ₃ ) and methylene chloride (2
0 ml). The extract was washed with brine, dried (sodium sulfate), filtered, and concentrated to give 551 mg of an oil. This was subjected to column chromatography (silica gel: 30 g, methylene chloride / methanol: 3).
Purification by treatment from 0/1 to 15/1) gave 225 mg (40.8%) of the title compound as a pale yellow oil. ¹ H NMR (270 MHz, CDCl ₃ ) δ7.45-
7.23 (7H, m), 7.18 (1H, dd, J =
1.8, 8.1 Hz), 5.94 (1H, dd, J =
5.1, 12.5 Hz), 4.62 (1H, d, J =
7.0 Hz), 4.58 (1H, d, J = 6.6H)
z), 4.20-4.10 (1H, m), 4.13 (1
H, d, J = 13.9 Hz), 3.84 (2H, s),
3.77 (1H, d, J = 13.9 Hz), 3.35
(3H, s), 3.30 (1H, dd, J = 12.1,
12.5 Hz), 2.90-2.75 (2H, m),
2.64 (1H, dd, J = 5.1, 12.5 Hz),
2.57 (1H, dd, J = 2.9, 9.9 Hz),
2.50-2.35 (1H, m), 2.10-2.00
(1H, m), 1.80-1.65 (1H, m) As a compound having a higher polarity, des-M of the title compound was used.
194 mg (39%) of the OM compound was also recovered.

Example 3 N-amino-2- (3,4-di
Chlorophenyl) -N- [2- (3- (S) -hydroxy
Cipyrrolidin-1-yl) -1- (S) -phenylethyl
Acetamide N-amino-2- (3,4-dichlorophenyl) -N-
[2- (3- (S) -methoxymethoxypyrrolidine-1
A mixture of -yl) -1- (S) -phenylethyl] acetamide (215 mg, 0.48 mmol) and methanol dissolved in HCl gas (2 ml) was stirred at room temperature. 1
After stirring for hours, the reaction mixture was concentrated, the residue was basified with aqueous ammonia and methylene chloride (10 m
Extracted in l). The extract is dried (sodium sulfate)
Filtration and concentration gave 173 mg of a white amorphous solid. This was subjected to column chromatography (silica gel:
20 g, eluent = methylene chloride / methanol: 30/1
To 10/1) to give 125 mg (64.4%) of a white amorphous solid. ¹ H NMR (270 MHz, CDCl ₃ ) δ7.45-
7.13 (8H, m), 5.94 (1H, dd, J =
5.1, 12.1 Hz), 4.30-4.20 (1H,
m), 4.10 (1H, d, J = 13.9 Hz), 3.
80 (2H, s), 3.78 (1H, d, J = 13.9)
Hz), 3.31 (1H, dd, J = 12.1, 12.
5Hz), 2.98-2.55 (5H, m), 2.38
-2.26 (1H, m), 2.18-2.02 (1H,
m), 1.70-1.55 (1H, m) IR (film): 3400, 3350, 1630 cm
^-1 The free amine (110 mg) was treated with HCl gas-dissolved methanol (2 ml) and concentrated to a white powder, which was washed with ether to give 103 mg of a white powder.
(Melting point = 232-233 ° C.). MS (ESI) m / z: 408 (M + H) + C 20 H 23 C
l ₂ N ₃ O ₂ · HCl theoretical value for: C, 54.01; H, 5.44 ; N, 9.45 Found: C, 53.77; H, 5.43 ; N, 9.49

[0040]Example 4: 2- (3,4-dichlorophenyl)
) -N ', N'-dimethylamino-N- [2- (3-
(S) -Hydroxy-pyrrolidin-1-yl) -1-
(S) -phenylethyl] acetamide N-amino-2- (3,4-) in methanol (4 ml)
Dichlorophenyl) -N- [2- (3- (S) -hydro
Xypyrrolidin-1-yl) -1- (S) -phenyle
Tyl] acetamide (140 mg, 0.34 mmol
l), 37% formaldehyde (0.24 ml, 3 mm
ol) and sodium cyanoborohydride (63
mg, 1 mmol) in a stirred solution of HCl gas.
Methanol was added dropwise at room temperature to give yellow (bromocresol).
Green was used as an indicator). 17 hours disruption
After stirring, the reaction mixture is concentrated and the residue obtained is concentrated.
Is basified with a saturated aqueous sodium hydrogen carbonate solution,
Extract with ren (20 ml) and dry (sodium sulfate)
And filtered. Concentrate the filtrate to a blue viscous oil
147 mg were obtained. This oil was purified by preparative TLC (chloroform
Purified by treatment with Tylene / methanol: 10/1)
This gave 55 mg (37.2%) of a colorless viscous oil.¹ 1 H NMR (270 MHz, CDCl_Three) Δ7.50-
7.10 (8H, m; 1H at 7.37 ppm,
d, including J = 2.2 Hz; 1 at 7.36 ppm
H, d, J = 8.1 Hz included; 7.12 ppm
3H, dd, J = 2.2, 8.1 Hz).
57 (1H, t, J = 7.0 Hz), 4.30-4.2
5 (1H, m), 3.81 (1H, d, J = 14.3H)
z), 3.73 (1H, d, J = 14.3 Hz);
34 (2H, d, J = 7.0 Hz), 2.98-2.8
8 (1H, m), 2.78 (1H, br.d, J = 9.
9Hz), 2.59 (1H, dd, 4.8, 9.5H)
z), 2.48 (3H, s), 2.40 (3H, s),
2.40-2.30 (1H, m), 2.18-2.05
(1H, m), 1.81 (1H, br.s), 1.75
-1.64 (1H, m) IR (film): 3400, 1645 cm^-1 MS (EI) m / z (rel int) 439 (0.
4, [M + 4]⁺), 437 (1.1, [M + 2]⁺),
435 (1.2, [M]⁺), 393 (1.2, [M +
2-NMe_Two]⁺), 391 (1.8, [M-NM
e_Two]⁺), 349 (13.8), 292 (8.2), 2
33 (18.2), 190 (97.6), 161 (10
0) This free amine (55 mg) was dissolved in HCl gas in methanol.
(1 ml) and concentrated. The residue
Solidified from ether by clutching, yellow non-
40 mg of a crystalline solid were obtained. C_{twenty two}H₂₇Cl_TwoN_ThreeO_Two・ HCl ・ 1.5H_TwoTheory for O: C, 52.86; H, 6.25; N, 8.41 Found: C, 52.94; H, 6.10; N, 8.82.

Example 5: N-acetamido-2- (3,
4-dichlorophenyl) -N- [2- (3- (S) -me
Toximethoxy-pyrrolidin-1-yl) -1- (S)
-Phenylethyl ] acetamide The title compound was prepared according to the method of Example 1 using acetic hydrazide instead of t-butyl carbazate. The yield was 57.7%. ¹ H NMR (270 MHz, CDCl ₃ ) δ 9.09 and 7.53 ( ¹ H in total, both br.s, NH A
c), 7.45-7.25 (7H, m, Ar), 7.1
4-7.05 (1H, m, Ar), 5.94 and 5.6
1 (1H in total, dd, J = 4.4, 12.5
Hz, PhC H NCO), 4.59 (2H, br.s,
_{MeOC H 2 O), 4.30-4.08 (} 1H, m, M
eOCH ₂ OC H), 3.37 and 3.36 (total 3
H, both s, Me OCH ₂ O), 2.02 and 1.
18 (3H in total, all s, NHCO Me ) IR (film): 3500, 3280, 1710-1
630 cm ^-1

Example 6: N-acetamido-2- (3,
4-dichlorophenyl) -N- [2- (3- (S) -H
(Droxypyrrolidin-1-yl) -1- (S) -phenyi
[Rethyl] acetamide The title compound was prepared according to the method described in Example 3. The yield was 62.7%. ¹ H NMR (270 MHz, CDCl ₃ ) δ 9.10 and 8.05 (1H in total, both br.s, NH A
c), 7.50-7.25 (7H, m, Ar), 7.1
5-7.05 (1H, m, Ar), 4.35-4.20
(1H, m, HOC H ), 2.02 and 1.15 (3H in total, all s, NHCO Me ) IR (film): 3450, 1650 cm ⁻¹ MS (EI) m / z 450 (M ⁺ ), 391,363,
290, 190, 160 hydrochloride: amorphous solid IR (KBr): 3400, 1675 cm ^-1 C ₂₂ H ₂₅ Cl ₂ N ₃ O ₃ .HCl _2.2 H ₂ O Theoretical value: C, 50.19; N, 7.98 Found: C, 50.16; H, 5.87; N, 7.80.

Production Example 1: N-methylcarbazic acid ter
Phthalic anhydride (2.9) in t-butyldichloroethane (40 ml).
A mixed suspension of 6 g, 20 mmol) and tert-butyl carbazate (2.64 g, 20 mmol) was refluxed for 14 hours with stirring. After cooling to room temperature,
The white solid was collected by filtration, washed with ether, and dried to give 3.82 g (72.9) of a white solid.
%). This solid (2.6 in DMF (20 ml))
NaH (60% oil suspension, 0.60 g, 15 mmol) was added to a solution of 2 g, 10 mmol) at 0 ° C.
After stirring at room temperature for 1 hour, methyl iodide (2.13 g, 15 mmol) was added to the orange mixed suspension at room temperature. After stirring for 1 hour, the reaction mixture was
(60% oil suspension, 0.20 g, 5 mmol) was added. DMF was distilled off and the residue was extracted with methylene chloride. Wash the extract with water and dry (sodium sulfate)
And concentrated to give 4.427 g of a yellow oil which was purified by column chromatography (silica gel: 100
g, hexane / ethyl acetate: 4/1) to give 1.287 g (46.6%) of a white solid. This solid (1.28 g, methylene chloride (10 ml),
(4.6 mmol), N-methylhydrazine (0.23 g, 5 mmol) was added at room temperature. After stirring for 2 hours, a white precipitate was removed by filtration.
The filtrate was concentrated to 0.836 g of a mixture of an oil and a solid.
Was obtained, which was suspended in ether, and the white solid was removed again by filtration. The filtrate was concentrated to obtain 697 mg of a pale yellow oil. This was used for the next reaction without purification. ¹ H NMR (270 MHz, CDCl ₃ ) δ 4.15
(2H, almost horizontal br.s), 3.06 (3H,
s), 1.48 (9H, s)

Example 7: N'-tert-butoxycal
Bonylamino-2- (3,4-dichlorophenyl) -N
-[2- (3- (S) -methoxymethoxy-pyrrolidine
-1-yl) -1- (S) -phenylethyl] -N'-
Methylacetamide of 2- (3- (S) -methoxymethoxypyrrolidin-1-yl) -2- (R) -phenylethanol (1.26 g, 5 mmol) and triethylamine (1 ml, 7 mmol) in methylene chloride (5 ml). To the solution was added mesyl chloride (0.46 ml, 6 mmol) at 0 ° C. After stirring at room temperature for 5 hours, the reaction mixture was washed with methylene chloride (1
0 ml), washed with saturated aqueous sodium bicarbonate and dried (sodium sulfate). After filtration, the filtrate was concentrated to give 1.295 g of a brown oil. This oil (1.295) in ethanol (5 ml)
g, 4.8 mmol), N-methylcarbazic acid ter
A mixture of t-butyl (697 mg, 4.6 mmol) and triethylamine (0.7 ml, 5 mmol) was added to 1
Refluxed for 5 hours. The ethanol was distilled off and the residue obtained was dissolved in methylene chloride (20 ml), washed with saturated aqueous sodium hydrogen carbonate solution and dried (sodium sulfate). After filtration, the filtrate was concentrated to give 1.664 g of a brown oil. Methylene chloride (20 ml)
Oil (1.66 g), 3,4-dichlorophenylacetic acid (0.94 g, 4.6 mmol) and WSC
(0.96 g, 5 mmol) was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium bicarbonate, dried (sodium sulfate) and filtered. The filtrate was concentrated to a brown oil 3.11
g, which was subjected to column chromatography (silica gel: 100 g, methylene chloride / methanol: 40/1).
Purification by workup gave 1.049 g (40
%). ¹ H NMR (270 MHz, CDCl ₃ ) δ7.50-
7.05 (8H, m, Ar), 5.65 and 5.40
(Total 1H, both m, PhC H NCO), 4.7
0-4.50 (2H, m, MeOC H 2 O), 4.25
_{-4.10 (1H, m, MeOCH 2} OC H), 3.2
7 (3H, s, Me OCH 2 O), 1.50 and 1.4
3 (9H in total, all s, NHCO ₂ t- Bu )

[0045]Example 8: 2- (3,4-dichlorophenyl)
Ru) -N- [2- (3- (S) -hydroxypyrrolidine
-1-yl) -1- (S) -phenylethyl] -N-
(N'-methylamino) acetamide N'-tert-butoxyca in ethyl acetate (4 ml)
Rubonyl-2- (3,4-dichlorophenyl) -N-
[2- (3- (S) -methoxymethoxypyrrolidine-1
-Yl) -1- (S) -phenylethyl] -N'-methyl
Luacetamide (1.049 g, 1.85 mmol)
The mixture with 4N HCl was stirred at room temperature for 1 hour. Real
The same operation as in Example 3 was performed, and 710 mg of a brown amorphous solid was obtained.
Obtained. This was subjected to column chromatography (silica gel:
100 g, methylene chloride / methanol: 20/1) treatment
Purified and labeled as pale brown clear viscous oil
406 mg of the compound was obtained. The yield was 52%.¹ 1 H NMR (270 MHz, CDCl_Three) Δ7.45-
7.10 (8H, m), 5.79 (0.8H, dd, J
= 5.5, 11.4 Hz), 4.82 (0.2H, d
d, J = 4.4, 9.2 Hz), 4.30-4.25
(1H, m), 4.02 (0.8H, d, J = 13.9)
Hz), 3.80-3.70 (1.2H; 3.77pp)
0.8H, d, J = 14.0Hz at m),
3.55-3.40 (2H, m), 3.00-2.65
(4H, m), 2.59 (0.6H, s), 2.41
(2.4H, s), 2.40-2.30 (2H, m),
2.20-2.08 (1H, m), 1.75-1.60
(1H, m) IR (film): 3400, 3300, 1635 cm
^-1 MS (FAB) m / z 422 (MH⁺) HCl salt: amorphous solid C_{twenty one}H_{twenty five}Cl_TwoN_ThreeO_Two・ HCl 1.6H_TwoFor O: C, 51.73; H, 6.04; N, 8.62 Found: C, 51.51; H, 5.81; N, 9.02.

The chemical structures of the compounds prepared in Examples 1 to 8 are summarized in the following table.

[Table 1]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 25/28 A61P 25/28 29/00 29/00 C07D 207/06 C07D 207/06 401/12 401/12 405/12 405 / 12 409/12 409/12 (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 207/12 A61K 31/40 A61K 31/44 C07D 207/06 C07D 401/12 C07D 405/12 C07D 409 / 12 CA (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. A compound of formula (I): [Wherein, R ¹ and R ² each independently represent a hydrogen atom,
(Alkyl having 1 to 4 carbon atoms) -CO- group, 1 to 4 carbon atoms
R ³ is a hydrogen atom, a hydroxy group, a halogen atom or an OY group (Y is a hydroxy protecting group); and R ⁴ is a halogen atom, optionally having 1 to 4 carbon atoms. An alkyl group having 1 to 4 carbon atoms
A phenyl group which may be substituted with 1 to 3 substituents selected from an alkoxy group, or a heterocyclic group selected from a furanyl group, a thienyl group and a pyridinyl group]. A compound or a salt thereof. 2. R ¹ and R ² each independently represent a hydrogen atom, an aliphatic acyl group, an alkyl group having 1 to 4 carbon atoms or t.
R ³ is a hydroxy group or an OY group (Y is a methoxymethyl group); and R ⁴ is a halogen atom, an alkyl group having 1 to 4 carbon atoms, and an alkyl group having 1 to 4 carbon atoms. The compound according to claim 1, which is a phenyl group substituted with 1 to 3 substituents selected from the alkoxy group of the above. 3. The method according to claim ² , wherein R ¹ and R ² are each independently a hydrogen atom, an acetyl group or a methyl group; R ³ is a hydroxy group; and R ⁴ is a 3,4-dichlorophenyl group. Item 7. The compound according to Item 2. 4. N'-tert-butoxycarbonylamino-2- (3,4-dichlorophenyl) -N- [2-
(3- (S) -methoxymethoxypyrrolidin-1-yl) -1- (S) -phenylethyl] acetamide; N
-Amino-2- (3,4-dichlorophenyl) -N-
[2- (3- (S) -methoxymethoxypyrrolidine-1
-Yl) -1- (S) -phenylethyl] acetamide; N-acetamido-2- (3,4-dichlorophenyl) -N- [2- (3- (S) -methoxymethoxypyrrolidin-1-yl)- 1- (S) -phenylethyl] acetamide; and N'-tert-butoxycarbonylamino-2- (3,4-dichlorophenyl) -N- [2
-(3- (S) -methoxymethoxy-pyrrolidine-1-
3. The compound according to claim 2, wherein the compound is selected from yl) -1- (S) -phenylethyl] -N'-methylacetamide. 5. N-amino-2- (3,4-dichlorophenyl) -N- [2- (3- (S) -hydroxypyrrolidin-1-yl) -1- (S) -phenylethyl] acetamide; 2- (3,4-dichlorophenyl) -N ′,
N'-dimethylamino-N- [2- (3- (S) -hydroxy-pyrrolidin-1-yl) -1- (S) -phenylethyl] acetamide; N-acetamido-2-
(3,4-dichlorophenyl) -N- [2- (3-
(S) -Hydroxypyrrolidin-1-yl) -1-
(S) -phenylethyl] acetamide; and 2-
(3,4-dichlorophenyl) -N- [2- (3-
(S) -Hydroxypyrrolidin-1-yl) -1-
4. The compound according to claim 3, selected from (S) -phenylethyl] -N- (N'-methylamino) acetamide.