JPH093096A - New n-methylproline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new N-methylproline derivative by replacing the N end of a specific peptide extracted from Dolabella auricularia as a sea Mollusca, having an inhibitory action on cell growth and an antineoplastic action, useful as an anti-cancer agent, an antitumor agent, etc. SOLUTION: This new N-methylproline derivative (salt) comprises a peptide derivative (salt) shown by formula I A is N or a group of formula II [Y is H or a group of the formula COR1 (R1 is OH, a lower alkoxy, an aralkyloxy, etc.); B is phenyl which may be optionally replaced with a halogen, hydroxy, a lower alkyl, a lower alkoxy, etc.)}. The N-methylproline derivative (salt) has an inhibitory action on cell growth and/or an antineoplastic action and is useful as an anti-cancer agent, an antitumor agent, etc. The peptide derivative is obtained by replacing Dolavaline (N,N-dimethylvaline) at the N end of dolastatin 10 as a pentapeptide separated from Dolabella auricularia of a sea hare analog as a sea Mollusca with N-methylproline.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel peptide compound. The compound of the present invention has a cell growth inhibitory action and / or an anti-neoplastic action, and is useful as an anticancer or antitumor agent.

[0002]

2. Description of the Related Art Several compounds having cell growth inhibitory activity and / or anti-neoplastic activity have been isolated from the sea mollusc Aplysia vulgaris (Dolabella auricularia). Are called dolastatins 1-15. Among these, dolastatin 10 is a pentapeptide having the following structural formula extracted from Indian Ocean snails by Pettit et al. In 1987, and is known as a compound having the strongest cell growth inhibitory action among known compounds. (Petit et al., Journal of the American Chemical Society, Vol. 109, page 6883, 1987 and JP-A-2
-167278).

[0003]

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Recently, the total synthesis of dolastatin 10 was also reported (US Pat. No. 4,978).
744 specification).

On the other hand, the present inventors have previously disclosed certain dolastatin 10 derivatives (International Publication WO93).
/ 03054 pamphlet).

[0006]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention [Means for Solving the Problems] This time, the present inventors have proposed a certain method in which N-methylproline is substituted for dovastatin (N, N-dimethylvaline) at the N-terminus of dolastatin 10. It was found that the dolastatin 10 derivative of the above has a far stronger antitumor effect than dolastatin 10.

Therefore, according to the present invention, the general formula (I)

[0008]

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In the formula, A is a hydrogen atom or

[0010]

[Chemical 6]

Wherein Y is a hydrogen atom or --CO
Represents R _1, R ₁ is hydroxy group, a lower alkoxy group,
Aralkyloxy group or

[0012]

[Chemical 7]

(Here, R ₂ and R ₃ are the same or different and each is a hydrogen atom, a lower alkyl group, a phenyl group or a 4 to 7 membered member containing 1 or 2 heteroatoms selected from S, O and N. Represents a heterocyclic group of, or R
₂ and R ₃ together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring which may further contain one heteroatom selected from S, O and N. And B represents a phenyl group which may be optionally substituted with a halogen atom, a hydroxy group, a lower alkyl group or a lower alkoxy group, or an N-methylproline derivative represented by or a salt thereof. .

In the present specification, the term "lower" means that the group or compound to which the term is attached has 6 or less carbon atoms, preferably 4 or less carbon atoms.

In the above formula (I), examples of the "lower alkyl group" include methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-hexyl group and the like,
Examples of the "lower alkoxy group" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy groups and the like. Further, the “aralkyloxy group” means an aryl-lower alkyloxy group, and includes, for example, benzyloxy, phenethyloxy group and the like,
“Halogen atom” includes fluorine, chlorine, bromine and iodine atoms.

When R ₂ or R ₃ represents “a 4- to 7-membered heterocyclic group containing 1 or 2 heteroatoms selected from S, O and N”, examples of the heterocyclic group are: , Azetidinyl, furyl, thienyl, pyridyl, piperidinyl,
Azepinyl, thiazolyl, imidazolyl, oxazolyl, pyrimidinyl, pyridazinyl groups, etc., while R ₂ and R ₃ are “in combination with the nitrogen atom to which they are bonded, a hetero atom selected from S, O and N. When the “4 to 7-membered heterocyclic ring optionally containing atoms” is represented, examples of the heterocyclic ring include azetidino, pyrrolidino, piperidino, 1-perhydroazepinyl, piperazino, morpholino, thiol. A morpholino group etc. can be mentioned.

Then,

[0018]

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Examples of radicals of 1 are amino, methylamino, ethylamino, isopropylamino, tert-butylamino, dimethylamino, diethylamino, phenylamino, N-methyl-N-phenylamino, furylamino, pyridylamino, 2- Examples thereof include thiazolylamino, imidazolylamino, pyrimidinylamino, pyrrolidino, piperidino and morpholino groups.

The "phenyl group optionally substituted by a halogen atom, a hydroxy group, a lower alkyl group or a lower alkoxy group" represented by the symbol B means an unsubstituted phenyl group or one halogen atom, It means a phenyl group substituted with a hydroxy group, a lower alkyl group or a lower alkoxy group, for example, phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 3-iodophenyl, 4-
Fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 2-hydroxyphenyl, 4-hydroxyphenyl, 2-methylphenyl, 4-ethylphenyl, 2-
Examples thereof include methoxyphenyl and 4-ethoxyphenyl groups.

A preferred group of compounds of the invention are compounds of the above formula (I) in which A represents a hydrogen atom and B represents a phenyl group optionally substituted by a halogen atom, especially a fluorine atom. is there.

Another preferred group of compounds of the invention are those wherein A represents a 2-thiazolyl group optionally substituted with N-lower alkylcarbamoyl and B represents an unsubstituted phenyl group. It is a compound of formula (I) above.

In the compound of the above formula (I) of the present invention, the carbon atom to which the isopropyl group, sec-butyl group, methoxy group and methyl group are respectively bonded is an asymmetric carbon atom, so that they are optional. (R)-or (S)
The compounds having the same configuration as dolastatin 10 are preferable from the viewpoint of pharmacological activity, though they can have the configuration of −, and they are all included in the scope of the present invention.

The peptide compound of formula (I) above also comprises
It can exist as a salt, and examples of such salt include hydrochloride, hydrobromide, trifluoroacetate, p-
Examples thereof include toluene sulfonate and acetate.

According to the present invention, the peptide compound of the above formula (I) can be obtained, for example, by a liquid phase synthesis method well known in the field of peptide chemistry (E Schläder and Kay Lübke "The Peptize" Vol. 76-136, 1965 Academic Press issue), it can be produced by condensing each amino acid or peptide fragment.

For example, in order to avoid racemization during condensation, the following formula (II)

[0027]

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A tripeptide fragment of the following formula (III)

[0029]

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In the formula, A and B have the above-mentioned meanings, and are preferably synthesized by condensation with a fragment of.

In order to efficiently synthesize many compounds of the present invention, the following formula (IV)

[0032]

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A tetrapeptide fragment of the following formula (V)

[0034]

[Chemical 12]

In the formula, A and B have the above-mentioned meanings, preferably by condensation with a fragment of

The condensation reaction is generally carried out in an inert solvent such as chloroform, ethyl acetate, tetrahydrofuran (TH
F), dimethylformamide (DMF), acetonitrile and the like, in the presence of an organic base such as triethylamine, N-methylmorpholine and diisopropylethylamine (DIEA) as necessary, a condensing agent such as dicyclohexylcarbodiimide (DCC). , Diphenylphosphoryl azide (DPPA), diethyl cyanophosphate (DEPC), BOP reagent and the like.

The reaction temperature is usually from -10 ° C to room temperature, preferably around 0 ° C, and the ratio of the compound of the formula (III), the organic base and the condensing agent to the compound of the formula (II) is as follows. II mole of the compound of formula (III)
Is at least 1 mol, preferably 1.0 to 1.1
It is advantageous to use a molar amount, an organic base of about 1 to 2 mol, and a condensing agent of an equimolar amount.

The reaction of the compound of formula (IV) with the compound of formula (V) is also carried out by reacting the compound of formula (II) with the compound of formula (II).
It can be carried out under the same conditions as the reaction with the compound of I).

The compound of formula (I) when Y represents a carboxy group can also be produced by hydrolyzing the compound of formula (I) when Y represents a lower alkoxycarbonyl group with an alkali. .

The peptide compound of formula (I) thus obtained can be isolated and purified from the reaction mixture by recrystallization, ion exchange chromatography, gel filtration, high performance liquid chromatography and the like.

The compounds of the above formulas (II), (III) and (IV) used as starting materials in the above reaction are novel compounds which have not been described in the conventional literature, but are the constituent components of each. It can be easily produced by condensing an amino acid by a liquid phase synthesis method.

The peptide compound of the formula (I) of the present invention has a stronger antitumor activity than dolastatin 10 and has a large therapeutic ratio, for example, leukemia, non-small cell lung cancer, small cell lung cancer, colon cancer. , CNS cancer, melanoma, ovarian cancer, kidney cancer, gastric cancer, bladder cancer and the like are useful for treatment or therapy.

The antitumor activity of the compound of formula (I) of the present invention can be measured as follows.

Mouse leukemia P388 cells (0.1 ml, 10 ⁶ cells / mouse) were intraperitoneally transplanted into 7-week-old CDF1 mice. The drug was intraperitoneally administered on the first day (the day after the transplantation) and the fifth day of the transplantation, and the survival rate (ILS,%) was calculated by the following formula from the result of observing the life and death of the mouse for 60 days. In the formula below, T means the median survival days of the drug administration group, and C means the median survival days of the control group.

[0045]

[Equation 1]

The results are shown in the table below. The antitumor effect was expressed as a relative ratio when the survival rate of dolastatin 10 was set to 1.

[0047] When the compound according to the present invention is used as a drug, it may be in a solid form (for example, tablets, hard capsules, soft capsules, granules, powders, fine granules, pills, troches, etc.) depending on its use It can be prepared and used in the form of preparation in either solid form (eg suppository, ointment etc.) or liquid form (injection, emulsion, suspension, lotion, spray etc.). Thus, as non-toxic additives that can be used in the above formulation, for example, starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, gum arabic, Examples thereof include polyethylene glycol, p-hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycol, petrolatum, carbowax, glycerin, sodium chloride, sodium sulfite, sodium phosphate, citric acid and the like. The agent can also contain other therapeutically useful agents.

The content of the compound of the present invention in the drug varies depending on the dosage form, but is generally at a concentration of 0.1 to 50% by weight in the solid and semi-solid forms, and in the liquid form. Is preferably contained in a concentration of 0.05 to 10% by weight.

The dose of the compound of the present invention can be widely varied depending on the type of warm-blooded animal including human being, the route of administration, the severity of symptoms, the diagnosis of a doctor, etc.
Generally, it can be about 0.01 to 50 mg / kg per day. However, it is of course possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range depending on the severity of the patient's symptoms and the doctor's diagnosis. The above dose can be administered once or several times a day.

[0050]

EXAMPLES The present invention will be further described below with reference to Examples and Examples.

For the structures of the compounds corresponding to the compound numbers used in Reference Examples and Examples, refer to Flow Sheets 1 and 2 below. Here, Bu ^t is tert- butyl group, Boc is tert- butoxycarbonyl group, Bzl a benzyl group, Z is benzyloxycarbonyl group, Me represents a methyl group, B and Y are as defined above.

[0052]

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[0053]

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[0054]

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Reference Example 1 0.85 g (1.73 mmol) of Compound 1 was dissolved in 15 ml of t-butanol-water (9: 1), 0.1 g of 5% palladium carbon was added, and the mixture was stirred under a hydrogen stream. After reacting for 3 hours, the catalyst is filtered off and washed, and the filter wash solution is dried under reduced pressure.
The residue is dissolved in 20 ml of benzene and dried under reduced pressure, and this operation is repeated once more to obtain an oily substance. This oil was combined with 0.48 g (1.93 mmol) of Z-proline and 0.31 g (1.90 mmol) of diethyl cyanophosphate (DEPC) to obtain 10 m of dimethylformamide (DMF).
Dissolve in 1 and 0.19 g of triethylamine with stirring under ice cooling
A solution of (1.88 mmol) in 1 ml of DMF is added dropwise.

After continuing stirring at 0 ° for 4 hours and at room temperature overnight, the clear reaction solution was sufficiently diluted with ethyl acetate, washed with ice-cooled 2N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. This gives 1.01 g of an oil. Purification by silica gel column chromatography (eluent: ethyl acetate-hexane (2: 1)) gave the target compound 2 as a colorless foam. 0.97 g (yield 95.1%).

[Α] ²⁷ _D -81.7 ° (c = 1.025, MeOH) ¹ H-NMR (CDCl ₃ , δ) 0.75-1.05 (12H, m), 1.46 (9H, s),
1.8-2.2 (4H, m), 2.3-2.4 (2H, m), 2.96 (3H, s), 3.34
(3H, s), 3.4-3.6 (2H, m), 3.8-4.0 (1H, m), 4.2-4.4 (1
H, m), 4.73 (1H, dd, J = 8.9Hz, 6.3Hz), 5.17 (2H, br.
s), 7.32 (5H, s).

Reference Example 2 0.50 g (0.85 mmol) of Compound 2 was dissolved in 20 ml of methanol, 1.0 g of 37% formalin and 0.4 g of 5% palladium carbon were added, and stirring was continued for 48 hours under a hydrogen stream. The catalyst is filtered off, washed with methanol, the filter wash solution is evaporated to dryness under reduced pressure, the resulting oily substance is dissolved in ethyl acetate-hexane (1: 1), and the insoluble matter is filtered off. The filtrate was evaporated to dryness under reduced pressure, and the residual oily substance was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane (2: 1)) to obtain the target compound 3 as a colorless oily substance. 0.3
6 g (yield 90.0%).

[Α] ²⁵ _D −76.2 ° (c = 1.10, MeOH) ¹ H-NMR (CDCl ₃ , δ) 0.7-1.05 (12H, m), 1.46 (9H, s),
1.6-1.9 (4H, m), 2.31 (3H, s), 2.3-2.45 (2H, m), 2.99
(3H, s), 3.36 (3H, s), 3.75-4.0 (1H, m), 4.73 (1H, d
d, J = 9.8Hz, 7.1Hz), 7.81 (1H, br. d).

Reference Example 3 310 mg (0.66 mmol) of Compound 3 was dissolved in 50% trifluoroacetic acid / dichloromethane at 0 °, and the mixture was stirred at room temperature for 1 hour and dried under reduced pressure.

On the other hand, 263 mg (0.70 mmol) of Compound 4 was dissolved in 4N hydrogen chloride / dioxane at 0 °, stirred at room temperature for 1 hour and then dried under reduced pressure. The residue is D
Dissolve in 3 ml of MF, and under ice cooling, triethylamine 0.9 m
l was added and the mixture was dried under reduced pressure. The residue was dissolved in 3 ml of DMF, and 136 mg (0.83 mmol) of DEPC under ice cooling.
And triethylamine 0.11 ml (0.79 mmol)
And are added and stirring is continued overnight.

The reaction solution was ethyl acetate-benzene (4: 1).
The mixture was diluted, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried, and the solvent was evaporated under reduced pressure to give an oil 449 mg.
This was subjected to silica gel column chromatography (eluent:
Purification with dichloromethane-methanol (30: 1 → 10: 1) gave the desired compound 5 as a colorless oil. 1
85 mg (yield 41.5%).

[Α] _D nd ¹ H-NMR (CDCl ₃ , δ) 0.7-1.1 (m), 1.27 (3H, d, J = 7.0H
z), 1.5-2.3 (m), 2.34 (3H, s), 2.3-2.9 (m), 3.00 (3H,
s), 3.30 (3H, s), 3.35 (3H, s), 3.85-4.3 (m), 4.68 (1
H, dd, J = 8.7Hz, 4.9Hz), 5.13 (2H, s), 7.34 (5H, s).

Reference Example 4 185 mg of Compound 5 was added to t-butanol-water (9: 1).
Dissolve in 3 ml, add 40% of 5% palladium carbon, and stir under a hydrogen stream for 5 hours. The catalyst was filtered off and washed, and the filtrate was dried under reduced pressure to give the desired compound 6 as a colorless oil. 155 mg (yield 97.1%).

[Α] _D −83.3 ° (c = 0.365, MeOH) Example 1 23.4 mg (40 μmol) of Compound 6 and 12.1 mg (100 μmol) of phenethylamine were added to D
Dissolve in 0.5 ml of MF, DEPC 9.6m under stirring with ice cooling
g (59 μmol) and triethylamine (8 μl) were added, and stirring was continued overnight. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried, and the solvent was evaporated to obtain 23.0 mg of residue. This was subjected to column chromatography on Sephadex LH-20 (eluent: hexane-methanol-dichloromethane (4:
5:15)) to obtain the desired compound 7-A (a compound 7 in which B is a phenyl group) as a colorless wax. 18.8 mg (yield 68.6%).

[Α] ²⁵ _D -61.0 ° (c = 0.39, MeOH) ¹ H-NMR (CDCl ₃ , δ) 0.7-1.1 (m), 1.21 (3H, d, J = 7.0H
z), 1.5-2.2 (m), 2.38 (3H, s), 2.83 (2H, t, J = 7.0H
z), 3.01 (3H, s), 3.32 (3H, s), 3.36 (3H, s), 3.2-3.6
(m), 3.84 (1H, dd, J = 7.9Hz, 2.2Hz), 3.9-4.2 (m), 4.7
1 (1H, dd, J = 9.2Hz, 7.0Hz), 6.3-6.6 (1H, m), 7.23 (5
H, s), 7.7-8.1 (1H, m).

Compound 6 was reacted with a phenethylamine derivative in the same manner as in Example 1 to obtain the compounds of Examples 2-4.

Example 2 Compound 7-B (Compound 7 in which B is a 2-fluorophenyl group) Wax-like substance (yield 73.0%) [α] ²⁸ _D -61.7 ° (c = 0.326, MeOH ) ¹ H-NMR (CDCl ₃ , δ) 0.7-1.1 (m), 1.21 (3H, d, J = 7.1H
z), 1.5-2.3 (m), 2.33 (3H, s), 2.3-2.6 (m), 2.88 (2H,
t, J = 7.3Hz), 3.01 (3H, s), 3.32 (3H, s), 3.37 (3H, s)
s), 3.2-3.7 (m), 3.84 (1H, dd, J = 8.0Hz, 2.5Hz), 3.9-
4.2 (br), 4.5-4.9 (1H, m), 6.4-6.6 (1H, m), 6.8-7.3 (4
H, m), 7.6-8.1 (1H, m).

Example 3 Compound 7-C (Compound 7 in which B is a 3-fluorophenyl group) Amorphous powder (yield 70.9%) [α] ²⁸ _D -56.4 ° (c = 0.287, MeOH ) ¹ H-NMR (CDCl ₃ , δ) 0.7-1.1 (m), 1.22 (3H, d, J = 7.0H
z), 1.5-2.2 (m), 2.34 (3H, s), 2.3-2.7 (m), 2.84 (2H,
t, J = 6.8Hz), 3.02 (3H, s), 3.32 (3H, s), 3.36 (3H, s)
s), 3.3-3.6 (m), 3.83 (1H, dd, J = 8.4Hz, 2.2Hz), 3.9-
4.3 (m), 4.5-4.9 (m), 6.5-6.7 (1H, m), 6.8-7.2 (4H,
m), 7.7-8.1 (1H, m).

Example 4 Compound 7-D (Compound 7 in which B is a 4-fluorophenyl group) Amorphous powder (yield 72.7%) [α] ²⁸ _D -55.9 ° (c = 0.285, MeOH ) ¹ H-NMR (CDCl ₃ , δ) 0.7-1.1 (m), 1.22 (3H, d, J = 7.3H
z), 1.5-2.2 (m), 2.34 (3H, br.s), 2.80 (2H, t, J = 7.0
Hz), 3.01 (3H, s), 3.32 (3H, s), 3.36 (3H, s), 3.2-3.
6 (m), 3.75-3.95 (1H, m), 3.95-4.3 (m), 4.5-4.9 (m),
6.4-6.6 (1H, m), 6.8-7.2 (4H, m).

Example 5 To 14.8 mg (32 μmol) of Compound 3 was added 0.4 ml of 50% trifluoroacetic acid / dichloromethane under ice cooling, and the mixture was stirred at room temperature for 4 hours and flushed with nitrogen gas to dryness. . On the other hand, 14.3-mg (30 micromol) of compound 8-A (compound in which Y is a hydrogen atom in compound 8) is similarly treated with 0.4 ml of 50% trifluoroacetic acid / dichloromethane and then dried. Both were combined and dissolved in 1 ml of DMF, and triethylamine 8 was added under ice cooling.
Add 5 μl and dry under reduced pressure. DMF again
Dissolve in 0.4 ml, DEPC 6.7 mg under ice cooling stirring
(41 μmol) and 10 μl of triethylamine (7
2 μmol) and continue stirring overnight.

The reaction mixture is dried under reduced pressure, the residue is dissolved in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried. The residue obtained by distilling off the solvent is purified by preparative TLC (developing solvent: dichloromethane-methanol (10: 1)) to obtain the target compound 9-A (compound 9 in which Y is a hydrogen atom). Obtained as a white powder. 14.5m
g (62.0% yield).

[Α] ²⁵ _D- 92.4 ° (c = 0.218, MeOH) ¹ H-NMR (CDCl ₃ , δ) 0.7-1.2 (m), 1.22 (3H, d, J = 7.0H
z), 1.5-2.0 (m), 2.35 (3H, s), 3.01 (3H, s), 3.33 (3H,
s), 3.36 (3H, s), 3.89 (1H, dd, J = 7.0Hz, 2.2Hz), 4.
0-4.3 (1H, m), 4.66 (1H, dd, J = 7.9Hz, 6.6Hz), 5.5-5.
7 (1H, m), 7.21 (5H, s), 7.73 (1H, d, J = 3.3Hz).

Example 6 Compound 3 was reacted with compound 8-B (a compound in which Y is a methoxycarbonyl group in compound 8) in the same manner as in Example 5 to give compound 9-B (wherein in compound 9, Y was methoxy). A compound having a carbonyl group) was obtained as an amorphous solid (yield: 78.2%).

[Α] _D nd ¹ H-NMR (CDCl ₃ , δ) 0.7-1.1 (m), 1.11 (3H, d, J = 7.0H
z), 1.5-2.1 (m), 2.35 (3H, s), 3.02 (3H, s), 3.32 (3H, s)
s), 3.33 (3H, s), 3.95 (3H, s), 3.8-4.3 (m), 4.70 (1
H, dd, J = 7.5Hz, 6.8Hz), 5.4-5.8 (1H, m), 7.23 (5H,
s), 8.05 (1H, s).

Example 7 To a solution of Compound 9-B (38.7 mg, 47 μmol) was added a 70% aqueous ethylamine solution under ice-cooling. Preparative TL for residue
C (developing solvent: dichloromethane-methanol (10:
1)) and then Sephadex LH-using hexane-methanol-dichloromethane (4: 5: 15) as the eluent.
Purification by column chromatography of 20 gave the desired compound 9-C (a compound 9 in which Y is an N-ethylcarbamoyl group) as an amorphous solid. 34.8m
g (yield 88.5%).

[Α] ²⁸ _D -81.4 ° (C = 0.309, MeOH) ¹ H-NMR (CDCl ₃ , δ) 0.7-1.1 (m), 1.11 (3H, d, J = 7.3H
z), 1.26 (3H, t, J = 7.3Hz), 1.5-2.2 (m), 2.36 (3H,
s), 3.02 (3H, s), 3.33 (6H, s), 3.2-3.7 (m), 3.8-4.0
(1H, br.dd), 4.0-4.3 (m), 4.69 (1H, dd, J = 8.8Hz, 6.
8Hz), 5.3-5.7 (1H, m), 7.24 (5H, s), 7.95 (1H, s).

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Akihiro Sugimura 1-2-22-12 Shimootachu, Nakahara-ku, Kawasaki-shi, Kanagawa (72) Inventor Motohiro Kobayashi 458-2, Sentsu-ku, Kawasaki-shi, Kanagawa 458-2

Claims (4)

[Claims] 1. A compound of the general formula In the formula, A is a hydrogen atom or Wherein Y represents a hydrogen atom or —COR ₁ , R ₁ represents a hydroxy group, a lower alkoxy group, an aralkyloxy group or (Here, R ₂ and R ₃ are the same or different and each contains a hydrogen atom, a lower alkyl group, a phenyl group or 1 or 2 heteroatoms selected from S, O and N.
~ 7-membered heterocyclic group, or R ₂ and R ₃ together with the nitrogen atom to which they are attached may further contain one heteroatom selected from S, O and N Four
~ 7-membered heterocyclic ring may be formed), and B represents a phenyl group optionally substituted by a halogen atom, a hydroxy group, a lower alkyl group or a lower alkoxy group. An N-methylproline derivative or a salt thereof. 2. An N-methylproline derivative or a salt thereof according to claim 1, wherein A represents a hydrogen atom and B represents a phenyl group optionally substituted with a halogen atom. 3. The N-methylproline derivative or a salt thereof according to claim 2, wherein the halogen atom is a fluorine atom. 4. An N-methylproline derivative or a derivative thereof according to claim 1, wherein A represents a 2-thiazolyl group which may be optionally substituted with an N-lower alkylcarbamoyl group, and B represents an unsubstituted phenyl group. salt.