JPH08157363A - Anti-cancer drug - Google Patents

Abstract

(57) [Summary] [Structure] As an active ingredient, the compound of the general formula (I); [In the formula, X represents a sulfur atom, R ₁₁ represents an oxo group or an imino group, R ₁₂ represents a methylthio group or a methylsulfinyl group, R ₁₃ represents a hydrogen atom or a halogen atom, and R ₁₅ represents a methyl group. ] Or the general formula (II); [In the formula, X represents a nitrogen atom, R ₂₁ represents a chlorine atom, R ₂₂ represents a methylthio group or a methyl group,
R ₂₃ represents a hydrogen atom, a halogen atom, a methoxy group or a nitro group, and R ₂₅ represents a hydrogen atom. ] A carcinostatic agent comprising a fused pyridine derivative represented by the above or a salt thereof. [Effects] The above-mentioned condensed pyridine derivatives, which are chemically modified in the pyridine ring moiety as an active ingredient, have an unprecedented structure and exhibit an excellent carcinostatic action, and can be used in combination with other chemotherapeutic agents. It becomes a possible and useful anticancer agent.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an anticancer agent containing a condensed pyridine derivative as an active ingredient, and in particular, various derivatives in which the condensed pyridine ring is a thiazolo [3,2-a] pyridine ring, or The fused pyridine ring is imidazo [1,2-a]
The present invention relates to a carcinostatic agent containing various derivatives having a pyridine ring as an active ingredient. The condensed pyridine derivative contained in the anticancer agent of the present invention as an active ingredient exhibits a useful anticancer effect when used in chemotherapy for various cancers such as leukemia, lung cancer, and melanoma.

[0002]

2. Description of the Prior Art For the treatment of cancer, in addition to surgical means, chemotherapy such as 5-FU and adriamycin, OK
Immunotherapy such as 432, radiation therapy, hyperthermia, etc. are used. These therapies have been tried for the treatment of various cancers, but have not yet achieved a sufficient therapeutic effect. In particular, various drugs have been proposed as chemotherapeutic agents, but only a few drugs show sufficient effects as a single agent, and in actual clinical practice, it is possible to use several chemotherapeutic agents in combination. Treatment is being advanced.

Chemotherapy for cancer requires drugs that inhibit multiple sites of action or have the same mechanism of action but completely different structures. That is, cancer cells are basically different from each patient, and there are differences in the degree of effect of a specific anti-cancer drug, and there are patients who are effective and those who are not. . Therefore, it is necessary to select and use from among various anticancer agents having different structures according to the patient. For example, as a single agent, taxol, which is said to have the highest anticancer activity, has been reported to have an efficacy rate of about 30%. Under such circumstances, it has been desired to develop a new anticancer agent having a chemical structure different from those of various conventionally proposed anticancer agents and having a compound having an anticancer activity as an active ingredient.

[0004]

The present invention is to solve the above problems. That is, an object of the present invention is to provide a novel anti-cancer agent having a chemical structure different from those of various conventionally proposed anti-cancer agents and having an anti-cancer effect as an active ingredient. A further object of the present invention is to provide a novel condensed pyridine derivative which is an active ingredient of such an anticancer agent.

[0005]

Against this background, the present inventors have aimed to create various compounds having a novel structure,
We also conducted intensive research to develop useful means for synthesizing compounds having various structures. As a result, the present inventors and their co-workers have developed suitable means for the synthesis of fused pyridine derivatives and have developed them in Pharmaceutical Journal, 113 32-39 (1993) and Pharmaceutical Journal, 113861-869 (1993). Reported the outline of the method. Based on the above-mentioned synthetic means, the present inventors proceeded with the development of a synthetic method for a novel condensed pyridine derivative, investigated the physiological action of the created condensed pyridine derivative, and found a series of compounds having an anticancer action. The present invention has been completed.

That is, the present invention provides a compound [group A] having a thiazolo [3,2-a] pyridine ring represented by the following general formula (I) as an active ingredient and an imidazo compound represented by the general formula [II].
The present invention relates to an anticancer agent containing at least one condensed pyridine derivative selected from the group consisting of compounds having a [1,2-a] pyridine ring [Group B] or a pharmaceutically acceptable salt thereof. [Group A] General formula (I);

Embedded image [In the formula, X represents a sulfur atom, R ₁₁ represents an oxo group or an imino group, R ₁₂ represents a methylthio group or a methylsulfinyl group, R ₁₃ represents a hydrogen atom or a halogen atom, and R ₁₅ represents a methyl group. ] [Group B] General formula (II);

[Chemical 4] [In the formula, X represents a nitrogen atom, R ₂₁ represents a chlorine atom, R ₂₂ represents a methylthio group or a methyl group,
R ₂₃ represents a hydrogen atom, a halogen atom, a methoxy group or a nitro group, and R ₂₅ represents a hydrogen atom. The halogen atom of the above-mentioned group R ₁₃ or R ₂₃ is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The imidazo [1,2-a] pyridine derivative obtained by substituting the chloro group at the 5-position shown in the general formula (II) has the general formula (III);

Embedded image [In the formula, X represents an imino group, R ₆ represents an oxo group, R ₃₃ represents the same group as R _{23 in the} general formula (II),
R ₃₅ represents the same group as R _{25 in} formula (II). ] The 1-position S atom of the imidazo [1,2-a] pyridine derivative represented by the following formula, that is, the thiazolo [3,2-a] pyridine derivative represented by the above general formula (I), is replaced with an NH group. Is derived from an imidazo [1,2-a] pyridine derivative corresponding to the following compound by further substituting the oxo group at the 5-position with a chloro group.

As a condensed pyridine derivative suitable as an active ingredient to be contained in the carcinostatic agent of the present invention, a thiazolo [3,2-a] pyridine derivative of [group A] and an imidazo [1,2 of [group B] are used.
-a] Pyridine derivatives are roughly classified into two groups. The former [Group A]
Examples of the thiazolo [3,2-a] pyridine derivative belonging to the category include the following compounds. 8-benzoyl-6-
Cyano-3-methyl-7-methylthio-5-oxo-5
H-thiazolo [3,2-a] pyridine, 6-cyano-8- (4
-Fluorobenzoyl) -3-methyl-7-methylthio-5-oxo-5H-thiazolo [3,2-a] pyridine, 8-
Benzoyl-6-cyano-3-methyl-7-methylthio-5-imino-5H-thiazolo [3,2-a] pyridine, 6-
Cyano-8- (4-fluorobenzoyl) -5-imino-3-methyl-7-methylthio-5H-thiazolo [3,2-
a] Pyridine, 8-benzoyl-6-cyano-3-methyl-7-methylsulfinyl-5-oxo-5H-thiazolo [3,2-a] pyridine, 6-cyano-8- (4-fluorobenzoyl)- 3-methyl-7-methylsulfinyl-
5-oxo-5H-thiazolo [3,2-a] pyridine and the like.

Further, imidazo [1,2-a] of [group B]
The following compounds can be illustrated as a pyridine derivative. 8-benzoyl-6-cyano-5-chloro-7-
Methylthio-imidazo [1,2-a] pyridine, 6-cyano-
5-chloro-8- (4-fluorobenzoyl) -7-methylthio-imidazo [1,2-a] pyridine, 6-cyano-5
-Chloro-8- (4-chlorobenzoyl) -7-methylthio-imidazo [1,2-a] pyridine, 6-cyano-5-chloro-8- (4-methoxybenzoyl) -7-methylthio-imidazo [1 , 2-a] Pyridine, 6-cyano-5-chloro-7-methylthio-8- (4-nitrobenzoyl)-
Imidazo [1,2-a] pyridine, 8-benzoyl-6-cyano-5-chloro-7-methyl-imidazo [1,2-a] pyridine and the like.

In particular, 8-benzoyl-6-cyano-3-
Methyl-7-methylthio-5-imino-5H-thiazolo
[3,2-a] pyridine and the like are preferable.

Among the above-exemplified condensed pyridine derivatives, several compounds, that is, 8-benzoyl-6-cyano-3-methyl-7-methylthio-5-oxo-5H-thiazolo [3,2-a] are used. ] Pyridine (compound of Example 1), 8-benzoyl-6-cyano-3-methyl-7-methylthio-
5-Imino-5H-thiazolo [3,2-a] pyridine (Compound of Example 3), 8-benzoyl-6-cyano-3-methyl-7-methylsulfinyl-5-oxo-5H-thiazolo [3, 2-a] pyridine (compound of Example 5), 8-benzoyl-6-cyano-5-chloro-7-methylthio-imidazo [1,2-a] pyridine (compound of Example 7) was previously prepared as Documents published by the inventors and their collaborators (Pharmaceutical Journal, 113 32-39 (1993) and Pharmaceutical Journal, 113 861-86
9 (1993)), the synthetic method and the measurement results of the physical properties necessary for identification have been reported due to their interest in synthetic chemistry, but their physiological properties and pharmacological properties have not been discussed at all. Not not.

On the other hand, the novel fused pyridine derivative of the present invention is represented by the above general formula (I), wherein X is a sulfur atom, R ₁₁ is an oxo group or imino group, and R ₁₂ is a methylthio group. Or a methylsulfinyl group, a halogen atom for R ₁₃ and a methyl group for R ₁₅ , and a series of thiazolo [3,2-a] pyridine derivatives or pharmaceutically acceptable salts thereof; Is represented by the general formula (II),
X is a nitrogen atom, R ₂₁ is a chlorine atom, R ₂₂ is a methylthio group or a methyl group, R ₂₃ is a halogen atom, a methoxy group or a nitro group, and R ₂₅ is a hydrogen atom. ₂₁ a chlorine atom, R ₂₂ a methyl group, R ₂₃
Is a hydrogen atom and R ₂₅ is a hydrogen atom, and is a group of imidazo [1,2-a] pyridine derivatives or a pharmaceutically acceptable salt thereof. The halogen atom of the above-mentioned group R ₁₃ or R ₂₃ is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The condensed pyridine derivative used in the anticancer agent of the present invention can be synthesized by the following method. The outline of the process for forming a condensed pyridine ring is described in the above-mentioned literature (Pharmaceutical Journal, 113 32-39 (1993) and Pharmaceutical Journal, 113 861-869 (1
993)) can be referred to.

[Step 1] 2-benzoylmethylthiazo
Derivative (or 2-benzoylmethylimidazole derivative)
Conductor) preparation Knaus and Cassity method (G. Knaus, AI Mayers,
J. Org. Chem., 39, 1192 (1974) and RP Cassity e
t al, J. Org. Chem., 43, 2286 (1978)), and the method of Macco et al. (AA Macco et al, J. Org. Chem.,
43, 2286 (1978)), a 2-benzoylmethyl thiazole derivative (or 2-benzoylmethyl imidazole derivative) as an intermediate raw material can be synthesized by the following reaction.

General formula (IV);

[Chemical 6] [In the formula, X represents a sulfur atom or an imino group, and R ₃₅
Represents a hydrogen atom or a methyl group. ] The thiazole derivative (or imidazole derivative) shown by these, and general formula
(V);

[Chemical 7] [Wherein R ₃₃ is the same as R _{13 in} the above general formula (I),
The same as R _{23 of} the general formula (II) described above. ] Indicated by N,
N-dimethylbenzamides are reacted with n-butyllithium at, for example, -78 ° C to give a compound of the general formula (IV)
The compound was selectively benzoylated at the 2-position methyl group,
General formula (VI);

Embedded image [Wherein X and R ₃₅ represent the same group as in the general formula (IV), and R
₃₃ represents the same group as in the general formula (V). ] 2-
A benzoylmethyl thiazole derivative (or an imidazole derivative) is obtained. The 2-benzoylmethylthiazole derivative (or 2-benzoylmethylimidazole derivative) represented by the general formula (VI) is used as an intermediate raw material in the following steps.

According to the method of [Step 1], N, N-dimethyl-3-pyridinecarboxylic acid amides (instead of N, N-dimethylbenzamides represented by the above general formula (V) N, N-dimethyl-nicotinic acid amides)
Is used to react with a thiazole derivative (or an imidazole derivative) of the general formula (IV) to give a 2- (3-pyridylcarbonyl) methylthiazole derivative having a structure similar to the general formula (VI). It can be prepared.

[Step 2. a ] Thiazolo [3,2-a] pyridi
Obtained in the preparation of emission derivatives wherein step 1 2-benzoyl-methyl thiazolium - Le derivatives: In the formula (VI), a sulfur atom in X, compounds that selectively a methyl group at R ₃₅ wherein, R ₃₃ represents generally Formula (I)
Represents the same group as R _{13 of} . ] And general formula (VII);

[Chemical 9] [In the formula, R ₄ represents a lower alkoxycarbonyl group such as a cyano group or a methoxycarbonyl group. Me represents a methyl group. ] And a polar olefin which is a ketene-dithioacetal group represented by the following formula (I) are reacted in the presence of a base (NaH or the like) to form a pyridine ring, and in the general formula (I), R ₁₁ is an oxo group or imino. It is possible to obtain a thiazolo [3,2-a] pyridine derivative which represents a group and selects a methylthio group for R ₁₂ .

Further, in the obtained general formula (I), R ₁₁
Represents an oxo group or an imino group, and a thiazolo [3,2-a] pyridine derivative in which a methylthio group is selected for R ₁₂ is
CPBA (m-chloroperbenzoic acid, m-chloroperbenzoi
c acid) by the action of, by converting the methylthio group in methylsulfinyl group, in the general formula (I), R ₁₁ represents an oxo or imino group, thiazolo [3 selecting a methylsulfinyl group R ₁₂ , 2-a] pyridine derivative.

The thiazolo [3,2-a] pyridine derivative is substituted with a 3-pyridylcarboxy group at the 8-position of the thiazolo [3,2-a] pyridine skeleton in place of the substituted benzoyl group. As the compound, a 2- (3-pyridylcarbonyl) methylthiazole derivative was used in place of the 2-benzoylmethylthiazole derivative, and the above [Step 2. It can be synthesized according to a].

[Step 2. b] imidazo [1,2-a] pyridi
Obtained in Preparation above step 1 of emissions derivatives 2-benzoyl-methylimidazo -
Le derivative: In the general formula (VI), X is an imino group, R ₃₅
A compound that selects a hydrogen atom for [wherein R ₃₃ is a compound of the general formula (I
It represents the same group as R _{23 in} I). ] And a polar olefin which is a ketene-dithioacetal for selecting a lower alkoxycarbonyl group such as a methoxycarbonyl group for R ₄ in the general formula (VII) in the presence of a base (K ₂ CO ₃ etc.) To form a pyridine ring, the compound of general formula (III);

[Chemical 10] [In the formula, X represents an imino group, R ₆ represents an oxo group, R ₃₃ represents the same group as R _{23 in the} general formula (II),
R ₃₅ represents a hydrogen atom. ] Imidazo [1,2
-a] A pyridine derivative can be obtained. Then, the imidazo [1,2-a] pyridine derivative represented by the general formula (III) is treated with a chlorinating agent such as phosphorus oxychloride (POCl ₃ ) or phosphorus pentachloride (PCl ₅ ) to give the imidazo [1 , 2-a] The oxo group at the 5-position of the pyridine ring skeleton is converted to a chloro group to give a compound of the general formula (II)
To an imidazo [1,2-a] pyridine derivative represented by

The condensed pyridine derivative obtained by the above synthesis method is a 2-benzoylmethylthiazole derivative (or 2-benzoylmethylimidazole derivative) as an intermediate raw material and a ketene-dithioacetal compound. Since it is derived from olefin, its ring structure can be easily specified by nuclear magnetic resonance ( ¹ H-NMR) of hydrogen atoms existing in the condensed pyridine ring. Furthermore, infrared absorption characteristic of the group substituting the pyridine ring portion, or
The structure of the compound can be easily identified by nuclear magnetic resonance ( ¹ H-NMR, ¹³ C-NMR, etc.).

The condensed pyridine derivative used in the anticancer agent of the present invention has a structure which has not been hitherto obtained by chemically modifying the pyridine ring portion. Further, it may be used as a pharmacologically acceptable salt by forming a salt compound with a pharmacologically acceptable acid, for example, hydrochloric acid, using the condensed pyridine ring.
Furthermore, as shown in the test example below, antitumor activity,
It is a useful compound that exhibits excellent properties such as a cancer cell growth inhibitory activity or an effect of prolonging the life of a tumor-bearing animal and has a carcinostatic action.

The carcinostatic agent of the present invention can be prepared by preparing the condensed pyridine derivative of the active ingredient or a pharmacologically acceptable salt thereof into an injectable solution according to a conventional method, and administering the solution by intravenous injection, arterial injection or the like. Alternatively, it may be orally administered in the form of an internal preparation such as tablets and capsules together with pharmacologically acceptable additives. The dose is appropriately determined depending on the administration method, the patient's symptoms, the purpose of treatment and the like, but generally, the dose is appropriately determined and administered to the patient in the range of 2 to 200 mg / kg.

[0024]

INDUSTRIAL APPLICABILITY The carcinostatic agent of the present invention uses a condensed pyridine derivative having an unprecedented structure and a chemically modified pyridine ring portion as an active ingredient, and therefore differs from various conventionally proposed carcinostatic agents. It has the advantage of becoming an anticancer drug that can be administered in place of the conventional anticancer drug even if it inhibits the site of action or has the same mechanism of action. In addition, the condensed pyridine derivative serving as an active ingredient exhibits excellent properties such as antitumor activity, cancer cell growth inhibitory activity, or life-prolonging effect in tumor-bearing animals, and is used in combination with other chemotherapeutic agents or as a single agent. It has the advantage of becoming a useful anti-cancer agent when administered.

In the following, the method for synthesizing the condensed pyridine derivative used as an active ingredient in the anticancer agent of the present invention will be shown by examples, and the antitumor action of the condensed pyridine derivative will be described with reference to test examples.

[0026]

Example 1 8-Benzoyl-6-cyano-3-methyl-7-methylthio-5-oxo-5H-thiazolo [3,2-a] pyridine According to [Step 1] above, 2,4- 2-Benzoylmethyl-4-benzoylated 2-methyl group from dimethylthiazole and N, N-dimethylbenzamide
Methyl-thiazole was preliminarily synthesized as an intermediate raw material (for detailed synthetic method, see Pharmaceutical Journal, 113 32-39 (1993)).

2-benzoylmethyl-4-methyl-thiazole 500 mg (2.3 mmol), 1-cyano, 1-methoxycarbonyl-2,2-dimethylthioethylene 467 mg
(2.3 mmol), 50% NaH as base 221 mg (4.6 mmol)
Was added to the solvent DMSO (10 ml) and the mixture was stirred at room temperature for 3 days. Ice water was added to the reaction solution, and 10% hydrochloric acid was added to make the solution acidic, and the precipitated crystals were collected by filtration. After washing the filtered crystals with water,
Crystals recrystallized from chloroform-methanol and purified
547 mg was obtained. The compound of this crystal has the following melting point,
The compound of interest 8-benzoyl-
It was confirmed to be 6-cyano-3-methyl-7-methylthio-5-oxo-5H-thiazolo [3,2-a] pyridine. The yield of the purified crystal with respect to the intermediate raw material 2-benzoylmethyl-4-methyl-thiazole was 7
It was 0%.

Melting point: 234 to 236 ° C. It should be noted that, referring to Pharmaceutical Journal, 113 32-39 (1993), it is reported that the following spectroscopic characteristic values are exhibited. IR (KBr) cm: 2200 (-CN), 1670 (C = O), 1630 (C =
O) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.46 (3H, s, SMe), 2.94 (3H,
s, Me), 6.72 (1H , s, C2-H), 7.34-7.74 (5H, m, C 6 H 5) Elemental _{analysis: C 17 H 12 N 2 O} 2 S 2: theoretical value: C; 59.98, H; 3.55, N; 8.23 Found: C; 59.73, H; 3.69, N; 8.26

[0029]

Example 2 6-Cyano-8- (4-fluorobenzoyl) -3-methyl-7-methylthio-5-oxo-5H-thiazolo
[3,2-a] Pyridine According to the method of Example 1 described above, 2,2-dimethylthiazole and N, N-dimethyl-4-fluorobenzamide were used to benzoylate the methyl group at the 2-position. -(4
-Fluorobenzoylmethyl) -4-methyl-thiazo-
Was preliminarily synthesized as an intermediate raw material.

According to the method of Example 1, 2-benzoylmethyl-4-methyl-thiazole was replaced with 2- (4-fluorobenzoylmethyl) -4-methyl-thiazole to give 1- Cyano, 1-methoxycarbonyl-2,2
-Reacted with dimethylthioethylene to give 6-cyano-8-
Purified crystals of (4-fluorobenzoyl) -3-methyl-7-methylthio-5-oxo-thiazolo [3,2-a] pyridine were obtained. The compound of this crystal shows the following melting point and spectroscopic characteristic values, and the desired compound 6-cyano-8-
It was confirmed to be (4-fluorobenzoyl) -3-methyl-7-methylthio-5-oxo-5H-thiazolo [3,2-a] pyridine. The yield of the purified crystal was 83% based on the intermediate raw material 2- (4-fluorobenzoylmethyl) -4-methyl-thiazole.

Melting point: 233-235 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.47 (3H, s, SMe), 2.92 (3H,
d, J = 1Hz, Me), 6.73 (1H, d, J = 1Hz, C2-H), 7.15 (2H, t, J =
8Hz, C-3 ', 5'-H), 7.72 (2H, dd, J = 5.9Hz, C-2', 6'-H)

[0032]

Example 3 8-Benzoyl-6-cyano-3-methyl-7-methylthio-5-imino-5H-thiazolo [3,2-a] pyridine According to the method of Example 1, 1-cyano, 1 -Methoxycarbonyl-2,2-dimethylthioethylene instead of 1,
1-Dicyano-2,2-dimethylthioethylene was used to react with 2-benzoylmethyl-4-methyl-thiazole to give 8-benzoyl-6-cyano-3-methyl-
7-Methylthio-5-imino-5H-thiazolo [3,2-a]
Purified crystals of pyridine were obtained.
See also 113 32-39 (1993)). The compound of this crystal is
The melting point and the spectroscopic characteristic values shown below are shown, and the target compound 8
It was confirmed to be -benzoyl-6-cyano-3-methyl-7-methylthio-5-imino-5H-thiazolo [3,2-a] pyridine. The yield of the purified crystal was 83% with respect to the intermediate starting material 2-benzoylmethyl-4-methyl-thiazole.

Melting point: 166 to 168 ° C. It is reported that the following spectroscopic characteristic values are shown with reference to Pharmaceutical Journal, 113 32-39 (1993). IR (KBr) cm: 3400 (NH), 2200 (-CN), 1630 (C = O) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.31 (3H, s, Me), 2.57 (3H , s,
SMe), 7.20 (1H, s , C2-H), 7.24-7.34 (5H, m, C 6 H 5) Elemental _{analysis: C 17 H 12 N 3 OS} 2: theoretical value: C; 60.15, H; 3.86 , N; 12.36 Found: C; 60.07, H; 3.99, N; 12.36

[0034]

Example 4 6-Cyano-8- (4-fluorobenzoyl) -5-imino-3-methyl-7-methylthio-5H-thiazolo
[3,2-a] Pyridine According to the method of Example 3, 2-benzoylmethyl-4-
Using 2- (4-fluorobenzoylmethyl) -4-methyl-thiazole instead of methyl-thiazole,
Reacted with 1-dicyano-2,2-dimethylthioethylene to give 6-cyano-8- (4-fluorobenzoyl) -5
Purified crystals of -imino-3-methyl-7-methylthio-5H-thiazolo [3,2-a] pyridine were obtained. The compound of this crystal shows the following melting point and spectroscopic characteristic values, and the desired compound 6-cyano-8- (4-fluorobenzoyl)
It was confirmed to be -5-imino-3-methyl-7-methylthio-5H-thiazolo [3,2-a] pyridine. The yield of the purified crystal was 92% with respect to the intermediate raw material 2- (4-fluorobenzoylmethyl) -4-methyl-thiazole.

Melting point: 158-160 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.32 (3H, s, SMe), 2.90 (3H, d,
J = 1Hz, Me), 6.64 (1H, d, J = 1Hz, C2-H), 7.10 (2H, t, J = 9.4
Hz, C-3 ', 5'-H), 7.65 (2H, dd, J = 9.4Hz, C-2', 6'-H) Elemental analysis: C ₁₇ H ₁₂ FN ₃ OS ₂ : Theoretical value: C ; 57.13, H; 3.38, N; 11.76, S; 17.94 Measured value: C; 56.94, H; 3.46, N; 11.62, S; 17.88

Reference Example 1 6-Cyano-8- (3-carbonylpyridyl) -5-imino-3-methyl-7-methylthio-5H-thiazolo
[3,2-a] Pyridine According to the above-mentioned [Step 1], 2,4-dimethylthiazole and N, N-dimethyl-3-pyridinecarboxylic acid amide were used to convert 3-pyridyl to the 2-position methyl group. 2- (3-Carbonylpyridyl) -4-methyl-thiazole substituted with a carbonyl group was preliminarily synthesized as an intermediate raw material.

According to the method of Example 3, 2- (3-) was substituted for 2-benzoylmethyl-4-methyl-thiazole.
Carbonylpyridyl) -4-methyl-thiazole is reacted with 1,1-dicyano-2,2-dimethylthioethylene to give 6-cyano-8- (3-carbonylpyridyl) -5-imino-3. -Methyl-7-methylthio-5H
-Purified crystals of thiazolo [3,2-a] pyridine were obtained. The compound of this crystal shows the following melting point and spectroscopic characteristic values, and the desired compound 6-cyano-8- (3-carbonylpyridyl) -5-imino-3-methyl-7-methylthio-
It was confirmed to be 5H-thiazolo [3,2-a] pyridine. The yield of the purified crystal was 81% based on the intermediate raw material 2- (3-carbonylpyridyl) -4-methyl-thiazole.

Melting point: 172-174 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.33 (3H, s, SMe), 2.91 (3H, d,
J = 1Hz, Me), 6.68 (1H, d, J = 1Hz, C2-H), 7.36 (2H, dd, J = 8.
5Hz, C-5'-H), 7.91 (1H, d, J = 8Hz, C-4'-H), 8.68-8.79 (2
(H, m, C-2 ', 6'-H) Elemental analysis: C ₁₆ H ₁₂ N ₄ OS ₂ : Theoretical value: C; 56.45, H; 3.55, N; 16.46, S; 18.84 Actual value: C; 56.31 , H; 3.63, N; 16.37, S; 18.78

[0039]

Example 5 8-Benzoyl-6-cyano-3-methyl-7-methylsulfinyl-5-oxo-5H-thiazolo [3,2-a] pyridine Compound of Example 1 492 mg (1.5 mmol), m -CPBA 259 mg
(1.5 mmol) was dissolved in 10 ml of dichloromethane and 2
Stir at room temperature for days. The reaction solution was washed with a 5% sodium carbonate solution, and the dichloromethane layer was evaporated under reduced pressure. The crystal obtained as a residue was recrystallized from chloroform-methanol to obtain 490 mg of a purified crystal (for the synthetic method, see Pharmaceutical Journal, 113 32-39 (1993)). The compound of this crystal shows the following melting point and spectroscopic characteristic values, and the desired compound 8-benzoyl-6-cyano-3-methyl-7-methylsulfinyl-5-oxo-5H-thiazolo [3,2- a]
It was confirmed to be pyridine. The yield of the purified crystals with respect to the compound of Example 1 as a raw material was 95%.
Met.

Melting point: 252 to 254 ° C. It is reported that the following spectroscopic characteristic values are exhibited with reference to Pharmaceutical Journal, 113 32-39 (1993). IR (KBr) cm: 2200 (-CN), 1680 (C = O), 1640 (C =
O) ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.81 (3H, s, Me), 2.98 (3H,
s, SOMe), 7.36 (1H , s, C2-H), 7.40-7.90 (5H, m, C6H5) Elemental _{analysis: C 17 H 12 N 2 O} 3 S 2: theoretical value: C; 57.29, H; 3.39 , N; 7.86 Found: C; 57.58, H; 3.51, N; 7.79

[0041]

Example 6 6-Cyano-8- (4-fluorobenzoyl) -3-methyl-7-methylsulfinyl-5-oxo-5H-thiazolo [3,2-a] pyridine The compound of Example 1 was replaced. Using the compound of Example 2,
According to the method of Example 5, 6-cyano-8- (4-fluorobenzoyl) -3-methyl-7-methylsulfinyl-5 in which a methylthio group was converted to a methylsulfinyl group.
Purified crystals of oxo-5H-thiazolo [3,2-a] pyridine were obtained. The compound of this crystal shows the following melting point and spectroscopic characteristic values, and the desired compound 6-cyano-8- (4-
Fluorobenzoyl) -3-methyl-7-methylsulfinyl-5-oxo-5H-thiazolo [3,2-a] pyridine was confirmed. The yield of the purified crystals with respect to the compound of Example 2 as a raw material was 87%.

Melting point: 214-216 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.82 (3H, s, Me), 3.00 (3H, d, J
= 1Hz, SOMe), 7.35-7.73 ( 5H, m, C2,2 ', 3', 5 ', 6'-H) Elemental _{analysis: C 17 H 11 FN 2 O} 3 S 2: theoretical value: C; 54.54 , H; 2.96, N; 7.48 Found: C; 54.09, H; 2.99, N; 7.41

[0043]

Example 7 8-Benzoyl-6-cyano-5-chloro-7-methylthio-imidazo [1,2-a] pyridine As described above [Step 1].
According to the above, 2-methyl-imidazole and 2-benzoylmethyl-imidazole obtained by benzoylating the methyl group at the 2-position were preliminarily synthesized from 2-methylimidazole and N, N-dimethylbenzamide. , Pharmaceutical Journal, 113 861-
869 (1993)).

2-benzoylmethyl-imidazole 465
mg (2.5 mM), 1-cyano-1-methoxycarbonyl-
508 mg (2.5 mM) of 2,2-dimethylthioethylene and 690 mg (5 mM) of potassium carbonate as a base were added to 20 ml of DMSO, and the mixture was stirred at room temperature for 3 days. Ice water was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals collected by filtration were washed with water, recrystallized from chloroform-methanol, and purified to give purified 8-benzoyl-6-cyano-5-oxo-7-methylthio-5H-.
595 mg of crystals of imidazo [1,2-a] pyridine were obtained. The yield of the purified crystal based on 2-benzoylmethyl-imidazole as an intermediate raw material was 77%.

Then, the 8-benzoyl-6-cyano-5-oxo-7-methylthio-5H-imidazo [1,2-a]
Pyridine 495 mg (1.6 mM) crystals were added to phosphorus oxychloride 20
Add to ml and heat to reflux for 1 hour. Then, the solvent was distilled off under reduced pressure, a saturated sodium hydrogen carbonate solution was added to the residue to make it basic, and the mixture was extracted with chloroform. The solvent chloroform was distilled off under reduced pressure from the extraction layer, and the residue was chloroform-methano-
The crystals were recrystallized to give 461 mg of purified crystals. The compound of this crystal has the following melting point and spectroscopic characteristic values, and is the target compound 8-benzoyl-6-cyano-5-chloro-7-methylthio-5H-imidazo [1,2-a] pyridine. It was confirmed. It should be noted that 8-benzoyl-6-cyano-5-oxo-7 as a raw material in the purified crystal was used.
The yield based on -methylthio-5H-imidazo [1,2-a] pyridine was 88%.

Melting point: 183-185 ° C. Incidentally, referring to Pharmaceutical Journal, 113 861-869 (1993),
It is reported to exhibit the following spectroscopic property values. IR (KBr) cm: 2100 (CN), 1670 (C = O) ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.45 (3H, s, SMe), 7.80 (1H, d,
J = 2Hz, C2-H), 7.91 (1H, d, J = 2Hz, C3-H), 7.54-7.70
(5H, m, C ₆ H ₅ ) Elemental analysis: C ₁₆ H ₁₀ N ₃ ClOS: Theoretical: C; 58.63, H; 3.08, N; 12.82, S; 9.78 Found: C; 58.48, H; 3.19, N; 12.63, S; 9.53

[0047]

Example 8 6-Cyano-5-chloro-8- (4-fluorobenzoyl) -7-methylthio-imidazo [1,2-a] pyridine According to the method of Example 7, 2-methylimidazole was used. When,
From N, N-dimethyl-4-fluorobenzamide, 2
2- (4-fluorobenzoyl) methyl-imidazole in which the methyl group at the position was benzoylated was preliminarily synthesized as an intermediate raw material.

According to the method of Example 7, the intermediate raw material 2-
Using 2- (4-fluorobenzoyl) methyl-imidazole instead of benzoylmethyl-imidazole, the desired compound 6-cyano-5-chloro-8- (4-fluorobenzoyl) -7-methylthio- Purified crystals of imidazo [1,2-a] pyridine were obtained. The compound of this crystal shows the following melting point and spectroscopic characteristic values,
Cyano-5-chloro-8- (4-fluorobenzoyl)
It was confirmed to be -7-methylthio-imidazo [1,2-a] pyridine. In addition, in the purified crystal, the intermediate raw material 2
The yield based on-(4-fluorobenzoyl) methyl-imidazole was 61%.

Melting point: 144-146 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.48 (3H, s, SMe), 7.15 (2H, t, J
= 8Hz, C3 ', 5'-H), 7.82 (1H, d, J = 1Hz, C2-H), 7.91 (1H, d, J
= 2Hz, C3-H), 7.86 (2H, t, J = 9Hz, C2 ', 6'-H)

[0050]

Example 9 6-Cyano-5-chloro-8- (4-chlorobenzoyl) -7-methylthio-imidazo [1,2-a] pyridine According to the method of Example 7, 2-methylimidazole was used. When,
2- (4-chlorobenzoyl) methyl-imidazole in which the methyl group at the 2-position was benzoylated was preliminarily synthesized from N, N-dimethyl-4-chlorobenzamide as an intermediate raw material.

According to the method of Example 7, the intermediate raw material 2-
Using 2- (4-chlorobenzoyl) methyl-imidazole instead of benzoylmethyl-imidazole, the desired compound 6-cyano-5-chloro-8- (4-chlorobenzoyl) -7-methylthio- Purified crystals of imidazo [1,2-a] pyridine were obtained. The compound of this crystal shows the following melting point and spectroscopic characteristic values, and the desired compound 6-cyano-5-chloro-8- (4-chlorobenzoyl) -7-
It was confirmed to be methylthio-imidazo [1,2-a] pyridine. The intermediate raw material 2- (4
The yield based on -chlorobenzoyl) methyl-imidazole was 67%.

Melting point: 163-165 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.48 (3H, s, SMe), 7.44 (2H, d,
J = 9Hz, C2 ', 6'-H), 7.78 (2H, d, J = 8Hz, C3', 5'-H), 7.81 (1
H, d, J = 2Hz, C2-H), 7.91 (1H, d, J = 2Hz, C3-H) Elemental analysis: C ₁₆ H ₉ Cl ₂ N ₃ OS: Theoretical value: C; 53.05, H; 2.50 , N; 11.60 Found: C; 53.11, H; 2.60, N; 11.62

[0053]

Example 10 6-Cyano-5-chloro-8- (4-methoxybenzoyl) -7-methylthio-imidazo [1,2-a] pyridine According to the method of Example 7, 2-methylimidazole was used. When,
From N, N-dimethyl-4-methoxybenzamide, 2
2- (4-methoxybenzoyl) methyl-imidazole in which the methyl group at the position was benzoylated was preliminarily synthesized as an intermediate raw material.

According to the method of Example 7, the intermediate raw material 2-
Using 2- (4-methoxybenzoyl) methyl-imidazole instead of benzoylmethyl-imidazole, the desired compound 6-cyano-5-chloro-8- (4-methoxybenzoyl) -7-methylthio- Purified crystals of imidazo [1,2-a] pyridine were obtained. The compound of this crystal shows the following melting point and spectroscopic characteristic values,
Cyano-5-chloro-8- (4-methoxybenzoyl)
It was confirmed to be -7-methylthio-imidazo [1,2-a] pyridine. In addition, in the purified crystal, the intermediate raw material 2
The yield based on-(4-methoxybenzoyl) methyl-imidazole was 55%.

Melting point: 162-164 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.48 (3H, s, SMe), 3.87 (3H, s, O
Me), 6.93 (2H, d, J = 9Hz, C2 ', 6'-H), 7.81 (2H, d, J = 9Hz, C
3 ', 5'-H), 7.81 (1H, m, J = 2Hz, C2-H), 7.89 (1H, d, J = 2Hz, C
3-H) Elemental _{analysis: C 17 H 12 ClN 3 O} 2 S: theory: C; 57.06, H; 3.38 , N; 11.74 Found: C; 56.99, H; 3.45 , N; 11.83

[0056]

Example 11 6-Cyano-5-chloro-7-methylthio-8- (4-
Nitrobenzoyl) -imidazo [1,2-a] pyridine According to the method of Example 7, 2-methylimidazole,
2- (4-Nitrobenzoyl) methyl-imidazole in which the methyl group at the 2-position was benzoylated was preliminarily synthesized from N, N-dimethyl-4-nitrobenzamide as an intermediate raw material.

According to the method of Example 7, the intermediate raw material 2-
Using 2- (4-nitrobenzoyl) methyl-imidazole instead of benzoylmethyl-imidazole, the desired compound 6-cyano-5-chloro-8- (4-nitrobenzoyl) -7-methylthio- Purified crystals of imidazo [1,2-a] pyridine were obtained. The compound of this crystal shows the following melting point and spectroscopic characteristic values, and the desired compound 6-cyano-5-chloro-7-methylthio-8- (4-nitrobenzoyl) -imidazo [1,2-a] It was confirmed to be pyridine. The intermediate raw material 2- (4
The yield based on -nitrobenzoyl) methyl-imidazole was 53%.

Melting point: 143-145 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.49 (3H, s, SMe), 7.82 (1H, d,
C2-H), 7.94 (1H, d, C3-H), 8.24 (2H, d, J = 9Hz, C2 ', 6'-H),
8.32 (2H, d, J = 2Hz, C3 ', 5'-H) Elemental _{analysis: C 16 H 9 ClN 4 O} 3 S: theory: C; 51.55, H; 2.43 , N; 15.03 Found: C; 51.82, H; 2.58, N; 14.74

[0059]

Example 12 8-Benzoyl-6-cyano-5-chloro-7-methyl-imidazo [1,2-a] pyridine According to the method of Example 7, 8-benzoyl-6-cyano-5-oxo. -8-Methylthio-imidazo [1,2-a] pyridine was replaced with 8-benzoyl-6-cyano-5-oxo-7-methyl-5H-imidazo [1,2-a] pyridine, and phosphorus oxychloride was used. To give purified crystals of the target compound 8-benzoyl-6-cyano-5-chloro-7-methyl-imidazo [1,2-a] pyridine. The compound of this crystal shows the following melting point and spectroscopic characteristic values, and the desired compound 8-benzoyl-6-cyano-5-chloro-
It was confirmed to be 7-methyl-imidazo [1,2-a] pyridine. It should be noted that 8-benzoyl-6-cyano-5-oxo-7-methyl-5H used as a raw material in the purified crystal
-The yield based on imidazo [1,2-a] pyridine was 47%.

Melting point: 219 to 221 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.45 (3H, s, Me), 7.36-7.90 (7
(H, m, C ₆ H ₅ ,, C 2,3 -H) Elemental analysis: C ₁₆ H ₁₀ ClN ₃ O: Theoretical value: C; 64.98, H; 3.41, N; 14.21 Actual value: C; 65.00, H; 3.43 , N; 14.20

In order to verify the carcinostatic action of the condensed pyridine derivatives used in the carcinostatic agent of the present invention, the following antitumor activity and cancer cells were prepared using the compounds shown in the above Examples 1 to 12 and Reference Example. A test was conducted to evaluate the growth inhibitory activity and the life-prolonging effect on tumor-bearing mice.

[Test Example 1] Antitumor activity CEA producing human colon cancer cell FCC, human lung cancer cell KN by SDI method
S, rat ascites hepatoma cells AH66 in 24-well plate 1
× 10 ⁵ cells (1 ml / well) were picked up and cultured at 37 ° C. in a 5% CO ₂ incubator for 1 day. The concentration of each test substance
5 μl of a test substance solution prepared to have a concentration of 2 mg / ml was added to each well and incubated for 3 days. next,
50 μl of 0.4% MTT and sodium succinate (0.1 M) were added and incubated for 3 hours. Aspirate the supernatant and remove
Add 1 ml each of N-KOH aqueous solution and DMSO, and add 1 at room temperature.
The mixture was stirred overnight, and the absorbance at 565 nm was measured. The control without addition of the test substance was set to 100% survival rate,
Viability was calculated and expressed as an index of cytotoxicity.

As an example, Table 1 shows the results of evaluation of the antitumor activity of the compounds of Examples 1 to 12 and Reference Example described above. From these results, it can be seen that the compounds of Examples 1 to 12 and Reference Example 1 all have excellent antitumor activity. Furthermore, it is found that it exhibits antitumor activity against a wide range of cancer cells.

[0064]

[Table 1] ────────────────────────── Survival rate of targeted cancer cells (%) ────────── ───────────────── Test substance FCC KNS AH66 Example 1 95.3 93.0 60.5 Example 2 91.4 98.8 67.7 Example 3 15 8.8 15.1 11.3 Example 4 10.1 10.1 10.1 9.5 Example 5 9.4 10.1 10.1 0.5 Example 6 13.5 23.4 43.5 Example 7 10.2 9.5 9.6 Example 8 11.6 13.5 15.8 Example 9 13.1 28.7 12.2 Example 10 24.2 30.5 35.6 Example 11 9.3 11. 6 8.7 Example 12 12.5 17.6 22.3 Reference Example 1 9.9 10.4 9.6 ────────────────────── ───

Test Example 2 In Vitro Cell Proliferation Inhibitory Activity
1 × 10 ⁴ cells / 100 μl / well of sexual cancer cells in a 96-well plate. Incubate at 37 ° C for 24 hours, and add 100 µl of the test substance solution of the specified concentration. Incubate at 37 ℃ for 20 hours, ³
Add 20 μl of H-thymidine (1 μCi / well). Incubate at 37 ° C for 4 hours to harvest cells. A liquid scintillator is added and the incorporated radioactivity is measured. When the concentration of the test substance is 0, the cell growth rate is 100%,
Calculate the cell growth rate. The cancer cells include L1210,
B16, Sarcoma 180 was used. The cell growth inhibitory activity of the test substance was evaluated as IC ₅₀ : the concentration of the test substance in the solution, which reduces the cell growth rate to 50%. As an example, Table 2 shows the cell growth inhibitory activity IC ₅₀ of the compounds of Examples 3 and 7. From these results, it can be seen that the condensed pyridine derivatives used in the anticancer agent of the present invention show cell growth inhibitory activity against a wide range of cancer cells. In particular, the compound of Example 3 and the like are found to have excellent cell growth inhibitory activity.

[0066]

[Table 2] ─────────────────────────────── Cell growth inhibitory activity IC ₅₀ (μg / ml) Target cancer Cell Test substance L1210 B16 Sarcoma 180 ─────────────────────────────── Example 3 0.8 NTNT Example 7 1. 7 10.2 10.2 ─────────────────────────────── NT: Not tested

[Test Example 3] L1210 tumor-bearing mice
Life-prolonging effect of L12 in the abdominal cavity of 6-week-old male CDF1 mice (6 mice per group)
Transplant 1 x 10 ⁵ 10 floating cells. A predetermined dose of the test substance is intraperitoneally administered every day for 6 days from the day of transplantation. The test substance is 10% DMSO and 10% t which dissolve the prescribed dose.
It was prepared as a ween85 aqueous solution and used for administration. The dosage is
It was set to 10 mg / kg and 50 mg / kg. The survival rate is calculated by setting the dose-free group as the control group and setting the average survival time after transplantation of the control group as 100%.

As an example, Table 3 shows the evaluation results of the compound of Example 3, the average number of days to survive and the survival rate after transplantation of cancer cells L1210. From these results, it can be seen that the condensed pyridine derivative used in the anticancer agent of the present invention has a life prolonging effect on animals transplanted with cancer cells. In particular, the compound of Example 3 and the like have antitumor activity and cell growth inhibitory activity,
It can be seen that the effect of prolonging the life when the cancer cells are transplanted is also excellent.

[0069]

[Table 3] ────────────────────────────────── Test substance Dose (mg / kg) Mean survival time Life extension rate (%) ────────────────────────────────── (control) 0 6.6 ± 0 .2 100 Example 3 10 10.5 ± 0.4 159 50 11.2 ± 0.2 170 ─────────────────────────── ────────

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshiro Matsuda 1-9-13 Yanohira, Nagasaki City, Nagasaki Prefecture

Claims (8)

[Claims] 1. A thiazolo [3,2 represented by the following general formula (I):
-a] a condensed pyridine derivative selected from the group consisting of a compound having a pyridine ring and a compound having an imidazo [1,2-a] pyridine ring represented by the general formula (II) or a pharmaceutically acceptable salt thereof. An anticancer agent contained as an active ingredient. Embedded image [In the formula, X represents a sulfur atom, R ₁₁ represents an oxo group or an imino group, R ₁₂ represents a methylthio group or a methylsulfinyl group, R ₁₃ represents a hydrogen atom or a halogen atom, and R ₁₅ represents a methyl group. ] [Chemical 2] [Wherein, X represents a nitrogen atom, R ₂₁ represents a chlorine atom, R ₂₂ represents a methylthio group or a methyl group, and R
₂₃ represents a hydrogen atom, a halogen atom, a methoxy group or a nitro group, and R ₂₅ represents a hydrogen atom. ] 2. A compound represented by the general formula (I), wherein X is a sulfur atom, R ₁₁ is an imino group, R ₁₂ is a methylthio group, and R is
The anticancer agent according to claim 1, which is a thiazolo [3,2-a] pyridine derivative compound in which ₁₃ is a hydrogen atom and R ₁₅ is a methyl group. 3. A condensed pyridine derivative is represented by the general formula (I), wherein X is a sulfur atom, R ₁₁ is an oxo group or an imino group, and R ₁₂ is a methylthio group or a methylsulfinyl group. The anticancer agent according to claim 1, which is a thiazolo [3,2-a] pyridine derivative obtained by selecting a halogen atom for ₁₃ and a methyl group for R ₁₅ . 4. A condensed pyridine derivative is represented by the general formula (II), wherein X is a nitrogen atom, R ₂₁ is a chlorine atom, and R _{22 is}
A methylthio group or a methyl group, R ₂₃ is a halogen atom,
The anticancer agent according to claim 1, which is an imidazo [1,2-a] pyridine derivative obtained by selecting a methoxy group or a nitro group and a hydrogen atom for R ₂₅ . 5. A condensed pyridine derivative is represented by the general formula (II), wherein X is a nitrogen atom, R ₂₁ is a chlorine atom, and R _{22 is}
The anticancer agent according to claim 1, which is an imidazo [1,2-a] pyridine derivative obtained by selecting a methyl group for R ₂₃ , a hydrogen atom for R _23, and a hydrogen atom for R ₂₅ . 6. A compound represented by the above general formula (I), wherein X is a sulfur atom, R ₁₁ is an oxo group or an imino group, R ₁₂ is a methylthio group or a methylsulfinyl group, and R ₁₃ is a halogen atom. A fused pyridine derivative which is a thiazolo [3,2-a] pyridine derivative obtained by respectively selecting an atom and a methyl group for R ₁₅ or a pharmaceutically acceptable salt thereof. 7. A compound represented by the above general formula (II), wherein X is a nitrogen atom, R ₂₁ is a chlorine atom, R ₂₂ is a methylthio group or a methyl group, and R ₂₃ is a halogen atom, a methoxy group or A condensed pyridine derivative which is an imidazo [1,2-a] pyridine derivative obtained by selecting a nitro group and a hydrogen atom for R ₂₅ , or a pharmaceutically acceptable salt thereof. 8. A compound represented by the above general formula (II), wherein X is a nitrogen atom, R ₂₁ is a chlorine atom, R ₂₂ is a methyl group, and R _{23 is}
A condensed pyridine derivative which is an imidazo [1,2-a] pyridine derivative in which R is a hydrogen atom and R ₂₅ is a hydrogen atom, or a pharmaceutically acceptable salt thereof.