JP2828548B2 - Novel 2-piperidinecarboxylic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel 2-piperidinecarboxylic acid derivatives having a broad antitumor spectrum.

[0002]

2. Description of the Related Art Recently, malignant tumors mainly composed of cancer have become the leading mortality in various countries, and the development of a therapeutic method therefor is the most desired medically. Currently, the mainstream is surgical removal of tumors, treatment with radiation, and subsequent maintenance treatment with antibiotics, plant alkaloids, and synthetic anticancer drugs, but a satisfactory treatment for solid cancer has been established. It has not been. The present inventors have conducted repeated research on novel compounds effective for various tumors using microbial metabolites and synthetic compounds.
The present inventors have found that piperidine carboxylic acid derivatives have a wide range of excellent antitumor activity, and have completed the present invention. The origin of the research of the present invention is based on the fact that the present applicant has found that a microbial metabolite SF2698 substance, which has been applied for a patent as an antifungal agent (Japanese Patent Application No. 2-129049), has an antitumor effect (No. 1991). Proceedings of the 50th Annual Meeting of the Japanese Cancer Society 2065).

[0003]

The present invention provides a compound of the general formula (I)

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(Wherein X represents an oxygen atom, a sulfur atom or a nitrogen atom bonding to a hydrogen atom, and the configuration of the carbon atom bonding to the carboxyl group is (S), (R), or (S), ( R) and a pharmaceutically acceptable salt thereof.When X is an oxygen atom or a sulfur atom, the salt includes Na, K, Ca and the like. In the case where X is a nitrogen atom bonded to hydrogen, the salt may be any of salts such as hydrochloric acid, bromic acid, citric acid, and oxalic acid. The compound represented by the general formula (I) is typically produced by the method shown in the following process diagrams 1 to 3. In the general formula (I) of the present invention, the compound represented by X = oxygen is a process chart. It is manufactured by the process shown in FIG.

[0005]

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First, L-homoserine, which is a starting material, is sequentially protected with an amino group and a carboxyl group in accordance with a conventional method of amino acid chemistry. The amino-protecting group is preferably a group that can be deprotected under mild conditions, such as a benzyloxycarbonyl group, t-
A butyloxycarbonyl group is preferred. The protecting group for the carboxyl group may be an ordinary alkyl ester protection, and methyl ester and ethyl ester are preferred. Preferably,
As illustrated, treatment with di-tert-butyl dicarbonate, protection of the amino group with a t-butoxycarbonyl group (Boc), followed by methyl esterification of the carboxyl group by treatment with dimethyl sulfate. The resulting protected L-homoserine The next step is to oxidize the primary hydroxyl group of to obtain the aldehyde compound 2. Oxidation methods include oxidation with various chromic acids and chromium derivatives, Pfitzner-Moffatt oxidation with dimethyl sulfoxide and dicyclohexylcarbodiimide, dimethyl sulfoxide and oxalyl. Sw by chloride
ern oxidation can be applied. Reference: JE Baldwin
Et al., Tetrahedron Letters; Vol. 28, No. 31, page 3
Compound 2 is also prepared by the method of 605-3608, 1987.

Subsequently, the compound 2 is subjected to a usual unsaturated bond forming reaction with phosphorus ylide. Wittig reaction, Horn
The er-Emmons reaction and the like are preferable, and as exemplified, the olefin compound 3 is obtained by reacting with triphenylphosphoranylideneacetic acid t-butyl ester. Unsaturated bonds formed by Wittig reaction or the like are usually obtained as a mixture of cis- and trans-forms. In addition, as described below, a method for selectively producing a cis-form,
Thus, an efficient manufacturing method is also possible. Olefin compound 3 is subjected to a Michael addition reaction with various mercaptan or selenium compounds. Preferably, phenylmercaptan and benzylmercaptan may be used. For example, phenylmercaptan is added in the presence of an organic base,
Compound 4 was heated to 50 ° C to 100 ° C for several hours.
give.

Compound 4 is subjected to deprotection and cyclization of t-butyl ester group and Boc group without purification. That is, deprotection by treatment with aqueous trifluoroacetic acid,
Then, after neutralization and concentration, the dehydration cyclization reaction easily proceeds,
This gives cyclic compound 5. Compound 5 is led to dihydro-2-pyridone compound 6 by an oxidation and elimination reaction. The oxidizing agent is preferably a mild oxidizing agent that oxidizes sulfides to sulfoxides, and is preferably iodine, periodic acid, aqueous hydrogen peroxide, or peracetic acid. Give body. The sulfoxide elimination reaction proceeds by heating in a high-boiling solvent such as toluene or xylene. For example, a sulfoxide intermediate is dissolved in xylene and heated to 140 ° C. for 1 hour to give compound 6. Hydrolysis of the methyl ester group of compound 6 yields a compound of the general formula (I) of the present invention wherein X = oxygen atom. The hydrolysis may be a conventional hydrolysis with an acid or an alkali, preferably an alkaline hydrolysis with caustic soda.

Incidentally, one of the structural features of the compound of the present invention represented by the general formula (I) is a cis-olefin on a piperidine ring, and in the above-mentioned production method, a mixture of cis and trans-olefins (compound 3 ) Was synthesized by Michael addition reaction followed by cyclization and elimination reaction to lead to cis-olefin. In a more efficient production method, a cis-olefin is selectively synthesized from Intermediate 2 described above. A method for the selective synthesis of cis-olefins is described in J. Am. K. Sti
II, Tetrahedron Letters, 24, 41
No., pages 4405-4408, 1983. Further, R. K. Boeckmann Jr. Is bistrifluoroethylphosphonoacetic acid allyl ester, Compound 7 was prepared using the method of Journal of American Chemical Society, Vol. 111, pp. 8036-8037, 1989.
Reported in the year.

The compound 7 and the compound 2 described in this document
Compound 8 was obtained in a yield of 6 by the donor-Emmons reaction.
Obtained at 5%. The allyl protecting group of compound 8 is 2
Treatment with tetrakistriphenylphosphine palladium in an organic solvent in the presence of potassium ethylhexanoate gave the free acid compound 9. The cyclization reaction from compound 9 to compound 6 is carried out in the same manner as the above-mentioned cyclization from compound 4 to compound 5. That is, compound 9 was treated with hydrous trifluoroacetic acid, and the resulting free amino acid intermediate was dehydrated and condensed to give compound 6 almost quantitatively. Among the compounds of the present invention represented by the general formula (I), the compound in which X is a sulfur atom is produced by the method shown in FIG.

[0011]

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The oxygen atom of the amide carbonyl group of compound 6 is first converted to a sulfur atom. This conversion reaction is carried out in an inert organic solvent in phosphorus pentasulfide or Lawesson's reagent, 2,4-
Bis (4-methoxyphenyl) -1,3-dithia-2,
It proceeds by heating with 4-diphosphetane-2,4-disulfide. For example, heating compound 6 to phosphorus pentasulfide in toluene at 60 ° C. for 1 hour easily gives compound 1
Give 0. Next, the methyl ester of the compound 10 is hydrolyzed to obtain a compound represented by the formula (I) and represented by X = sulfur atom. As for the hydrolysis of the compound 10, alkali hydrolysis with caustic soda is suitable as in the above-mentioned hydrolysis of the compound 6 to the compound of the formula (I) where X = oxygen atom.

The compound represented by the general formula (I), wherein X is a nitrogen atom bonding to a hydrogen atom, and the configuration of * is (S) is a natural compound obtained by culturing the above-mentioned actinomycete SF2698 strain. SF2698 substance. However, * is a novel substance that cannot be obtained by culturing (R) or a mixture of (R) and (S). These novel substances are produced by the synthesis method of the inventor by the method shown in FIG. As an example, a method for producing a mixture of (R) and (S) will be described below.

[0014]

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The starting material 1, the intermediates 2, 8, and 9 are the compounds exemplified in the process diagrams 1 and 2, respectively. The configuration indicated by * is a mixture of (R) and (S), and Active. This intermediate is prepared by the above-mentioned synthesis method using DL-homoserine as a starting material. The synthesis of a compound represented by the general formula (I), wherein X is a nitrogen atom bonding to a hydrogen atom, is synthesized from compound 9 by synthesizing a compound having a nitrile group and a free amino group as an intermediate, and synthesizing the compound with a cyclic amidine. Apply the law. As a method for synthesizing a cyclic amidine compound, R.I. S. Garigipatai, Tetrahedron Letters, Vol. 31, No. 14, p. 1969-
1972, 1990 are preferred.

After activating the free carboxyl group of compound 9, the compound is treated with ammonia to obtain an amide intermediate. The activation may be performed by a general method such as an acid chloride method or a mixed acid anhydride method, preferably a mixed acid anhydride method, for example, treatment with butyl chlorocarbonate to form an acid anhydride, and then ammonia Treatment with water gives the amide intermediate. The amide intermediate gives the nitrile compound 11 by a dehydration reaction. The dehydration of the amide form may be carried out by a conventional method. For example, tosylate chloride is added in the presence of pyridine, and the mixture is heated to obtain Compound 11. Next, the amino-protecting group and t-butyloxycarbonyl group (Boc) of the compound 11 were removed by hydrochloric acid treatment to obtain an intermediate 12 having a desired nitrile group and a free amino group. Compound 12 was converted to Garigipat.
According to the method of ai, the mixture was stirred at room temperature in an organic solvent in the presence of trimethylaluminum. After the reaction, excess trimethylaluminum was decomposed with hydrochloric acid to obtain a cyclic amidine intermediate 13. The ester protecting group of compound 13 is removed by hydrolysis with hydrochloric acid, and the compound is purified and purified to obtain the desired compound represented by the general formula (I) of the present invention.
X is a nitrogen atom bonding a hydrogen atom,
A compound in which * is a mixture of (R) and (S) was obtained.

The method for preparing the compound in which * of the intermediate 9 is (S) has already been described in FIG. When a cyclic amidine is synthesized using this intermediate, a compound represented by the general formula (I) and * is (S), that is, SF269
Eight substances are obtained. Therefore, the present invention also provides a chemical production method of SF2698 substance as shown in the examples. When the compound of the present invention is used as an antitumor agent, it is administered parenterally or orally. In the case of parenteral administration, it is used as an injection such as intravenous injection and intramuscular injection. In that case, the drug is administered as a solution or suspension. The daily dose in mammals including humans is 10 to 10 kg / kg body weight.
It should be in the range of 400 mg, preferably 10-200 mg. As an oral preparation, for example, a mixture with a pharmaceutically acceptable excipient or the like and use in a gelatin capsule if desired, or a drug, starch, a lubricant and other pharmaceutically acceptable excipients as desired. The mixture of excipients is prepared so as to contain the active ingredient in an amount of 20 mg to 2000 mg, and used by tableting.

[0018]

[Test Example] Next, a test example will be shown on the antitumor effect of the compound of the present invention. Test Example 1 Antitumor Effect on Various Mouse Tumor Cells The effect of the compound of the present invention was determined using various mouse tumor strains that can be subcultured and clearly form tumors when transplanted into mice. The P388 strain and the L1210 strain are cells derived from mouse leukemia, the MethA strain is a solid cancer, the 3LL strain is a Lewis lung cancer, and the B16 strain is a cell derived from melanoma. A 50% inhibitory concentration (I
_C50 ) is shown in Table 1.

Table 1 Antitumor effect of the compound of the present invention (IC ₅₀ : μg / ml) P388 L1210 MethA 3LL B16 Compound of Example 3 5.0 9.0 11.0 11.0 45 SF2698 substance 120 65 46 51 41 Compound of Example 1 200 130 100 100 90 Test Example 2 Antitumor Effect on Various Human-Derived Tumor Cells The effect of the compound of the present invention was measured using various human-derived tumor cells in the same manner as in the previous test. The HL60 strain is derived from human leukemia, CCRF-CCM is derived from human T cells, and QG56 is derived from human lung cancer.

Table 2 Antitumor effect of the compound of the present invention (IC ₅₀ : μg / ml) HL60 CCRF-CEM QG56 Compound of Example 3 20 20 70 SF2698 substance 45 45 80 Compound of Example 1 90 90 Acute toxicity Acute toxicity test compound of the invention 180 Test Example 3 present compound using male BDF mice, i.
v. The administration was performed and observed. Table 3 shows the doses in which all mice survived in three mice per group.

Table 3 Safety of the compound of the present invention (amount without death by administration: iv, mg / kg) Compound of Example 1 1000 mg / kg SF2698 substance 300 mg / kg Compound of Example 3 800 mg / kg Example 4 Hereinafter, the details of the present invention will be described with reference to Examples.

[0022]

【Example】

Example 1 In the general formula (I) of the present invention, X is an oxygen atom,
The compound in which * is (S) is produced as follows according to the flow chart 1 in the text. 10.4 g (87 mmol) of L-homoserine
Dissolve 7.34 g of NaHCO _{3 in} 50 ml of H ₂ O and 75 ml of dioxane.
Add t-butyl dicarbonate, 21 g of Boc ₂ O and add 1 at room temperature.
Stir for 6 hours. The reaction solution was completely concentrated to dryness, and the residue was triturated with ether. Powder dimethylformamide 6
The residue was dissolved in 0 ml, dimethylsulfuric acid (12.3 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was added to a mixture of ice-cooled saline (100 ml) and ethyl acetate (100 ml), and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over MgSO ₄ , and concentrated under reduced pressure to obtain N-Boc-L-homoserine.

70.4 ml of pyridine in 700 ml of dichloromethane
And cool with ice, add 43.5 g of CrO _3, and add 1 at the same temperature.
Reacted for hours. The previously obtained N-Boc-L-homoserine was dissolved in dichloromethane and added thereto, followed by stirring for 15 minutes. The supernatant was separated and the residue was washed with dichloromethane. The organic layers were combined, 300 ml of ice-cold water was added, and 6N HCl was added to adjust the pH to 2.0. The organic layer was separated, washed with brine, and concentrated under reduced pressure. The remaining oily substance was washed with Wako Gel C-30.
Purified by column chromatography using 0, 300 g,
The desired product eluted with toluene-ethyl acetate (5: 1) was collected. The eluate was concentrated to give the aldehyde compound, compound 2 19
g was obtained.

Compound 2 (3.8 g) was dissolved in 60 ml of chloroform, 6.4 g of Ph ₃ P = CHCO ₂ t-Bu was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Wako Gel C-
Purification was carried out on 300 and 70 g columns. Ethyl acetate-n-Hexan
All the fractions containing the cis-isomer and the trans-isomer eluted at e 2: 5 were collected, concentrated and crystallized from petroleum ether to obtain a mixture of the cis-isomer and the trans-olefin, a compound 3, 2.6 g.

Compound 3 (trans form) NMR (CDCl ₃ ) δ ppm; 1.41 (9H, s, t-Bu), 1.44 (9H, s,
t-Bu), 2.52 and2.63 (2H, m, -CH _2- ), 3.72 (3H, s, -CH
₃ ), 4.41 (1H, m, -CH-CO ₂ ), 5.01 (1H, broad d, -NH-),
5.76 (1H, dt, J = 15.82, 1.32 Hz, = CHCO), 6.68 (1H,
(dt, J = 15.82, 7.47 Hz, -CH = CH-CO) Dissolve 1.65 g (5 mmol) of the olefin mixture in 15 ml of DMF, add 1.54 ml of thiophenol and 0.5 ml of piperidine and react at 60 ° C for 2 hours. I let it. After cooling, the mixture was diluted with ethyl acetate, washed with brine to remove DMF, and the organic layer was concentrated under reduced pressure to obtain Compound 4.

Compound 4 (diastereomeric mixture) NMR (CDCl ₃ ) δ ppm; 1.40 (18H, s, t-Bu), 1.70-2.15 (2
H, m, -CH _2- ), 2.30-2.72 (2H, m, -CH _2- ), 3.20-3.55 (1
H, m, -CHSPh-), 3.71 (3H, s, CH 3), 4.30-4.80 (1H, m,
-CHCO _2- ), 4.90-4.15 (1H, broad d, -NH-), 7.15-7.60
(5H, m, Ph) To the residue was added 20 ml of 90% trifluoroacetic acid (10% water), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and washed with benzene to remove excess thiophenol. The aqueous layer was concentrated to dryness, the residue was dissolved in water, and neutralized to pH 4.5 with triethylamine. After concentration under reduced pressure, benzene was added to perform azeotropic dehydration. The residue was dissolved in methylene chloride, washed sequentially with dilute hydrochloric acid and a NaHCO3 solution, and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-Hexane to obtain the desired cyclic compound 5 (1.1 g).

Compound 5 (diastereomeric mixture) NMR (CDCl ₃ ) δ ppm; 2.08-2.87 (4H, m, -CH ₂ -CHSPh- CH ₂
-), 3.31-3.70 (1H, m , -CH-), 3.76 (3H, s, CH 3), 3.9
6-4.41 (1H, m, -CHCO _2- ), 6.37 (1H, broads, -NH-), 7.2
2-7.60 (5H, m, Ph) Dissolve cyclic compound 5 in 15 ml of methylene chloride and cool under ice-cooling.
890 mg of 0% AcO ₂ H was added dropwise. The reaction solution was NaHCO ₃ water, 1%-
After washing with NaHSO ₃ water, it was dried with MgSO ₄ . The solution was concentrated under reduced pressure to obtain a sulfoxide intermediate. This sulfoxide intermediate was dissolved in xylene (40 ml),
Heated at 0 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography using 70 g of Wako gel C-300 to obtain chloroform-methanol (20:
Elution with 1) gave cyclic compound 6 (600 mg).

Compound 6 NMR (CDCl ₃ ) δ ppm; 2.70 (2H, m, -CH _2- ), 3.79 (3H, s,
CH ₃ ), 4.22 (1H, ddd, J = 8.57, 6.81. 1.97 Hz, -CHCO
_2- ), 5.90 (1H, dq, J = 9.89, 1.97 Hz, = CHCO-), 6.17
(1H, broad s, -NH-), 6.56 (1H, dt, J = 9.89, 4.12 H
z, -CH = CHCO-) IR (KBr) νcm ^-1 ; 1742, 1681, 1603 [α] D = -135 ° (C 1.57, CHCl ₃ ) mp 80-82 ° C Compound 6 (200 mg) was added to THF (2 ml). )
Under ice cooling, 2.8 ml of NaOH was added and reacted for 10 minutes. The reaction solution was diluted with ethyl acetate and ice-cold water, and extracted with 6N HCl to pH 2.0. The organic layer was washed with brine, dried over MgSO ₄ and concentrated to dryness to give an oily residue. This residue was powdered with hexane. The residue was dissolved in water, neutralized with NaHCO ₃ , purified by column chromatography with DIION HP20 resin (100 ml), and eluted with water. The fraction containing the target substance was concentrated and placed in the general formula (I) to obtain a compound (120 mg) in which X was an oxygen atom and * was (S).

Compound of Example 1 (Compound of general formula (I) wherein X is an oxygen atom and * is (S)) NMR (D ₂ O) δ ppm; 2.59 and 2.73 (2H, m, -CH2- ), 4.08
(1H, dd, J = 7.77, 7.22 Hz, -CHCO-), 5.85 (1H, dt,
J = 9.99, 1.94 Hz, = CH-CO), 6.77 (1H, dt, J = 9.99,
4.16 Hz, -CH = CH-CO) [α] D ²⁵ = −54 ° (C 1.0, H ₂ O) Example 2 The cyclic compound 6 produced in Example 1 is more efficiently produced as follows. Is done.

1.52 g of lithium bromide was added to anhydrous THF 40
dissolved in bis-trifluoroethylphosphone-
, Compound 7 and 7 g were added, and the mixture was stirred at room temperature for 10 minutes.
Subsequently, 2.4 ml of triethylamine was added, the mixture was cooled to -20 ° C, and 2.46 g of the aldehyde compound and the compound were dissolved in a small amount of anhydrous THF and added, followed by stirring at -20 to -10 ° C for 3 hours. Ethyl acetate 100 ml and saline 100 ml
Was added and extracted with stirring. The organic layer was washed with brine and then dried over MgSO4
After drying with, the solvent was distilled off under reduced pressure. The residue was treated with Wako Gel C-
Purified by column chromatography of 300 and 260 g. Eluted with ethyl acetate-n-hexane (= 2: 5)
The is isomer was collected and the solvent was distilled off under reduced pressure to obtain 3.0 g of the desired cis isomer, compound 8.

Compound 8 NMR (CDCl ₃ ) δ ppm; 1.42 (9H, s, t-Bu), 3.04 (2H, dt,
J = 7.03, 1.10Hz, -CH = CH- CH _2- ), 3.68 (3H, s, CH ₃ ),
_{4.34 (1H, m, -CHC0 2} ), 4.58 (2H, m, -CO 2 CH 2 -), 5.10-
5.40 (3H, m, -NH- and -OCH ₂ CH = CH ₂ ), 5.85 (1H, m, -OC
H ₂ CH = CH ₂ ), 5.88 (1H, dt, J = 11.65, 1.10 Hz, -CH = CH C
O _2- ), 6.19 (1H, ddd, J = 11.65,7.03, 6.81 Hz, -CH = C
HCO _2- ) IR (CHCl ₃ ) νcm ^-1 ; 1710, 1645, 1420 [α] D ²⁵ = +46.6 (C 1.55, CHCl ₃ ) Compound 8 (3.0 g) was dissolved in 30 ml of methylene chloride and 2-ethyl 1.75 M ethyl acetate solution of potassium hexanoate
3.3 ml was added, and then 13 mg of tetrakistriphenylphosphine palladium and Pd (PPh ₃ ) ₄ were added, and the mixture was reacted at room temperature for 3 hours. The reaction solution was diluted and extracted with ethyl acetate-ice cold water. The aqueous layer was adjusted to pH 2.0 with 6N HCl, extracted with ethyl acetate, and dried over MgSO ₄ . The solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate-n-hexane to give cis olefin free carboxylic acid, compound 9, 2.3 g.
I got

Compound 9 NMR (CDCl ₃ ) δ ppm; 1.42 (9H, s, t-Bu), 3.10 (2H, bro
ad t, -CH _2- ), 3.71 (3H, s, CH ₃ ), 4.38 (2H, broad q,
-CHCO _2- ), 5.22 (1H, broad s, -NH-), 5.91 (1H, dt, J
= 11.43, 1.38 Hz, = CH-CO _2- ), 6.30 (1H, dt, J = 11.4
3, 7.25, -CH = CH-CO _2- ) IR (KBr) νcm ^-1 ; 1759, 1684, 1645 [α] D ²⁵ = + 60.5 ° (C 1.70, CHCl ₃ ) mp 77-79 ° C Compound 9 It was dissolved in trifluoroacetic acid and reacted at 0 ° C. for 2 hours. The reaction solution was distilled off under reduced pressure, water was added, and the mixture was adjusted to pH 4-5 with triethylamine under ice cooling, and then concentrated again. The residue was dissolved in benzene and azeotropically dehydrated to give the desired product, compound 6, quantitatively. Example 3 In the general formula (I) of the present invention, a compound wherein X is a sulfur atom and * is (S) is produced as follows.

The cyclic compound 6 (60) produced in Example 1
The 0 mg) was dissolved in benzene 10 ml, added P ₂ S ₅ 1.1g, it was heated for 1 hour at 60 ° C.. After cooling to room temperature, the supernatant was separated and the residue was washed with benzene. The organic layer was collected, concentrated under reduced pressure, and then dissolved in methylene chloride.
And dried. After the solvent was distilled off under reduced pressure, Wako Gel C-3 was used.
Purification by column chromatography using 00,40 g with a solvent system; benzene-ethyl acetate (4: 1). The fraction containing the desired product was concentrated under reduced pressure to obtain 10,200 mg of a thioamide cyclic compound.

Compound 10 NMR (CDCl ₃ ) δ ppm; 2.56 (1H, m, -CH _2- ), 2.73 (1H, m,
-CH _2- ), 3.83 (3H, s, CH ₃ ), 4.24 (1H, ddd, J = 11.
54, 6.41, 2.05 Hz, -CHCO _2- ), 6.35 (1H, ddd, J = 9.7
4, 5.38, 3.33 Hz, = CHCS-), 6.45 (1H, ddd, J = 9.74,
3.08, 2.31Hz, -CH = CHCS-) Compound 10, dissolved in 200mg THF 2ml, 0.5N under ice cooling
2.8 ml of NaOH was added, and the mixture was hydrolyzed at the same temperature for 10 minutes.
Dilute the reaction solution with 10 ml of ethyl acetate and 10 ml of ice-cold water, and add 6N
The pH was adjusted to 2.0 with HCl and extracted with stirring. The organic layer was washed with brine, dried over MgSO4, and treated with decolorizing carbon.
The oil remaining after the solvent was distilled off under reduced pressure was dissolved in water using an equivalent amount of NaHCO ₃ , and Diaion HP-20 (manufactured by Mitsubishi Kasei) was used.
To obtain a compound of the formula (I) in which X is a sulfur atom and * is (S).

Compound of Example 3 (Compound of general formula (I) wherein X is a sulfur atom and * is (S)) NMR (D ₂ O) δ ppm; 2.61 (1H, m, -CH _2- ) , 2.71 (1H, m,-
CH _2- ), 4.09 (1H, t, J = 7.82 Hz, -CHCO _2- ), 6.31 (1H,
dt, J = 9.49, 1.80 Hz, -CH = CH CS), 6.51 (1H, dt, J =
9.49, 4.36 Hz, -CH = CHCS) [α] D ²⁵ = −42.3 ° (C 1.50, H ₂ O) Example 4 In the general formula (I) of the present invention, X is a nitrogen atom bonding a hydrogen atom, Compounds where * is a mixture of (R) and (S) are prepared as follows.

When the production methods described in Examples 1 and 3 are produced using DL-homoserine as a starting material, a compound 9 in which * is a mixture of (R) and (S) is obtained. 1.5 g of this compound 9 was treated with methylene chloride 15
and added 0.73 ml of N-methylmorpholine to
Cooled to 25 ° C. 0.86 ml of isobutyl chloroformate was added to this solution, and the mixture was stirred at −25 to −20 ° C. for 30 minutes. Then, 80 ml of ice-cooled 0.7N ammonia water was added with vigorous stirring, and the mixture was reacted for 15 minutes. After separating the organic layer, the aqueous layer was extracted with methylene chloride, and the organic layers were combined.
The residue obtained by distilling off the solvent and the amide intermediate were dissolved in 4.5 ml of pyridine, 1.57 g of tosylic acid chloride was added, and the mixture was stirred at 60 ° C. for 3 hours. Cool the reaction to 5 ° C.
The resulting precipitate was filtered off and the precipitate was washed with ethyl acetate.
The organic layers were combined, saline was added, the pH was adjusted to 2.0 with 6N-HCl, and the mixture was washed. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure, and the resulting residue was purified by column chromatography using 40 g of Wako gel C-300. The fraction eluted with benzene-ethyl acetate (4: 1) was collected and concentrated to obtain 11,1.0 g of the nitrile compound.

Compound 11 NMR (CDCl ₃ ) δ ppm; 1.42 (9H, s, t-Bu), 2.83 (1H, m,
-CH _2- ), 2.89 (1H, m, -CH _2- ), 3.75 (3H, s, CH ₃ ), 4.46
(1H, m), 5.13 (1H, broad d, -NH-), 5.41 (1H, dt, J =
10.99, 1.32 Hz, = CH-CN), 6.46 (1H, ddd, J = 10.99,
7.91, 7.25, -CH = CH-CN) IR (KBr) νcm ^-1 ; 2240, 1735, 1674 Compound 11, 65 mg was dissolved in methylene chloride 0.5 ml,
1 ml of 4N-HCl adjusted with dioxane was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. The residue obtained by concentrating the reaction solution under reduced pressure was treated with ethyl ether to obtain Compound 12 as crystals.

Compound 12 NMR (D_TwoO) δppm; 3.08 (2H, m, -CH_Two-), 3.86 (3H, s, C
H_Three), 4.41 (1H, t, J = 6.37 Hz), -CH-CO_Two), 5.77 (1H,
dt, J = 10.99, 1.32 Hz, = CH-CN), 6.68 (1H, dt, J = 1
0.99, 7.69 Hz,-CH= CH-CN) IR (KBr) νcm^-12210, 1740 Compound 12 was suspended in 1 ml of toluene, and 15%
Add 0.4 ml of hexane solution of chillaluminum,
The reaction was performed at room temperature for 16 hours. 1N HCl 2m under ice cooling after the reaction
l, add aluminum chloride and excess trimethyl
Decomposed aluminum. Separate the aqueous layer and reconstitute the organic layer.
Extracted with 1N HCl. Combine the aqueous layers and add concentrated hydrochloric acid to this.
The solution was then adjusted to a 3N HCl concentration. This solution is kept at 50 ° C
For 2.5 hours to hydrolyze the ester. reaction
The solution is concentrated to a small volume under reduced pressure.
Purified by column chromatography. Column with water
After washing, it was eluted with 30% methanol. Including object
Collect fractions, concentrate to a small volume under reduced pressure, and freeze
By sintering and drying, the compound represented by the general formula (I) of the present invention
X is a nitrogen atom bonding a hydrogen atom, and * is
Compound (hydrochloride) which is a mixture of (R) and (S), 35mg
was gotten.

Compound of Example 4 (in the formula (I), X is a hydrogen atom-bonding nitrogen atom and * is a mixture of R and S (hydrochloride) NMR (D ₂ O) δ ppm; 2.65 (1H , m, -CH _2- ), 2.73 (1H, m,-
CH _2- ), 4.22 (1H, dd J = 7.77, 6.11 Hz, -CH = CH C-NH),
6.01 (1H, ddd, J = 9.98, 2.22, 1.6H Hz, = CH-CN), 6.76
(1H, ddd, J = 9.98, 4.71, 3.89 Hz, -CH = CH-CNH) IR (KBr) νcm ^-1 ; 1730, 1680 UV λmax = 219 nm (ε 8840) Example 5 SF2698 substance, that is, the present invention In the general formula (I), X is a nitrogen atom bonding to a hydrogen atom, and * is (S), and the compound is chemically produced as follows.

The production method of Example 4 is carried out using Compound 9 in which * is (S) obtained by the production methods described in Example 1 and Example 3 as a starting material. Compound 11 (* is S) NMR (CDCl ₃ ) δ ppm; 1.42 (9H, s, t-Bu), 2.83 (1H, m,
-CH _2- ), 2.89 (1H, m, -CH _2- ), 3.75 (3H, s, CH ₃ ), 4.46
(1H, m), 5.13 (1H, broad, d, -NH-), 5.41 (1H, dt, J = 1
0.99, 1.32 Hz, = CH-CN), 6.46 (1H, ddd, J = 10.99,
7.91, 7.25, -CH = CH-CN) IR (KBr) νcm ^-1 ; 2240, 1735, 1674 [α] D ²⁵ = +108 (C 1.38, CHCl ₃ ) mp 75-77 ° C Compound 12 (* is S ) NMR (D ₂ O) δ ppm; 3.08 (2H, m, -CH _2- ), 3.86 (3H, s, C
H ₃ ), 4.41 (1H, t, J = 6.37 Hz, -CH-CO ₂ ), 5.77 (1H, d
t, J = 10.99, 1.32 Hz, = CH-CN), 6.68 (1H, dt, J = 1
0.99, 7.69 Hz, -CH = CH-CN) IR (KBr) νcm-1; 2210, 1740 [α] D ²⁵ = +32 (C 1.03, CH ₃ OH) mp 108-110 ° C SF2698 substance (hydrochloride) NMR (D ₂ O) δppm; 2.65 (1H, m, -CH _2- ), 2.73 (1H, m,-
CH _2- ), 4.22 (1H, dd J = 7.77, 6.11 Hz, = CHC-NH-), 6.01
(1H, ddd, J = 9.98, 2.22, 1.67 Hz, = CH-C-NH), 6.76 (1
H, ddd, J = 9.98, 4.71, 3.89 Hz, -CH = CH-C = NH) IR (KBr) νcm-1; 1730, 1680 UV λmax = 219 nm (ε 8840) [α] D ²⁵ = -26.7 ° (C1.0, H ₂ O)

[0041]

The present invention provides an antitumor agent having a broad antitumor spectrum.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Takayuki Usui 760 Morioka-cho, Kohoku-ku, Yokohama, Kanagawa Prefecture Inside the Pharmaceutical Research Institute, Meiji Seika Co., Ltd. Inside the Pharmaceutical Research Institute, Meiji Seika Co., Ltd. (72) Inventor, Yukizo Nagaoka 760, Shiokaokacho, Kohoku-ku, Yokohama, Kanagawa Prefecture Inside the Pharmaceutical Research Institute, Meiji Seika Co., Ltd. Examiner, Meiji Seika Co., Ltd. Pharmaceutical Research Laboratory Shohide Hoshino (56) References Patent 2594167 (JP, B2) (58) Field investigated (Int. Cl. ⁶ , DB name) C07D 211/90 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A compound of the general formula (Wherein X represents an oxygen atom or a sulfur atom) and a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein the configuration of the carbon atom bonding to the carboxyl group is (S), (R) or a mixture of (S) and (R). 3. An antitumor agent comprising the compound according to claim 1 as an active ingredient. 4. A compound of the formula (Wherein * represents a mixture of (S) and (R)) and a pharmaceutically acceptable salt thereof.