WO2003035653A1

WO2003035653A1 - Pyridothienopyrimidine compound and salt thereof

Info

Publication number: WO2003035653A1
Application number: PCT/JP2002/011028
Authority: WO
Inventors: Hirokazu Yamada; Seiichi Uchida; Nobuhiro Umeda; Mitsumasa Takata; Seiichi Ikeyama; Yasuyuki Shiinoki
Original assignee: Nippon Soda Co.,Ltd.
Priority date: 2001-10-26
Filing date: 2002-10-24
Publication date: 2003-05-01
Also published as: JPWO2003035653A1

Abstract

A novel thienopyrimidine compound represented by the formula (1), which is useful as a medicine, especially a cGMP-PDE inhibitor: (1) wherein A represents optionally substituted pyridyl or pyrazolyl; and B represents amidino, di(C1-6 alkyl)carbamoyl, di(C1-6 alkyl)sulfamoyl, or a group represented by the formula -Y-G (wherein Y represents carbonyl or sulfonyl; and G represents an optionally substituted, 5- or 6-membered, (un)saturated heterocyclic group containing one to three nitrogen, oxygen, or sulfur atoms).

Description

Specification

Pyridothienopyrimidine compounds and salts thereof

The present invention relates to pyridothienopyrimidine compounds and salts thereof useful as cGMP-specific phosphodiesterase (cGMP-PDE) inhibitors, and methods for producing them. Background technology:

c GMP is a substance that plays an important role as a second messenger in the signal transduction pathway in the living body, and its degrading enzyme, c GMP-PDE inhibitor, increases the intracellular c GMP concentration. , Hypertension, heart failure, myocardial infarction, angina, arteriosclerosis, restenosis after PTCA, cardiac edema, pulmonary hypertension, renal failure, renal edema, hepatic edema, asthma, bronchitis, dementia, immune deficiency, endocarditis Or it is useful for prevention and / or treatment of impotence and the like.

On the other hand, a compound represented by the following formula has been reported as a cGMP-PDE inhibitor having a thieno [2,3-d] pyrimidine skeleton in WO 98/06722 and EP 728759.

Here, X is a cycloalkyl group, a phenyl group or a heterocyclic group which may have a substituent.

Further, compounds represented by the following general formula are reported in WO 98 17668, W099Z28325 and W099 / 55708.

Here, X represents alkylene, cycloalkyl, or the like, substituted with a carboxylic acid, a carboxylic acid amide, or the like.

WO 00/59912 also discloses pyridothienopyrimidine compounds similar to the compounds of the present invention. Are described, but the compound of the present invention is not described!

DISCLOSURE OF THE INVENTION:

The present invention provides novel thienopyridine compounds that are useful as pharmaceuticals, particularly as cGMP-PDE inhibitors.

That is, the present invention provides:

[In the formula, A represents a pyridyl group which may be substituted with a hydroxyl group or a halogen atom, or a pyrazolyl group;

B is amidino group, di C - ₆ alkyl force Rubamoiru group, di-C ₆ alkylsulfamoyl group, or a group of the formula: - represents a Y- group represented by G.

(Here, Y represents a carbonyl group or a sulfonyl group, and G represents a 56-membered saturated or unsaturated nitrogen atom, oxygen atom or sulfur atom, which may be substituted with R. Represents a saturated heterocyclic group, and R represents a halogen atom, a hydroxyl group, a Ci- ₄ alkyl group, a formyl group, a C ₄ alkylcarbonyl group or a C alkoxyl group.)] A thienopyrimidine compound represented by the following formula: And a pharmaceutically acceptable salt thereof, preferably in the above formula (1)

B is, amidino group, dimethylcarbamoyl group, dimethylsulfamoyl group, one C OGx, -YG ₂ or is an Y- G _3, compound and pharmaceutically acceptable salts thereof.

[Where Y represents the same meaning as described above, represents one of the following groups,

(Wherein, X is, 0 SS 0 ₂ or represents N-R _3, is also a hydrogen atom represents a hydroxyl group, R ₃ is a hydrogen atom, a methyl group, a formyl group, was Asechiru group or tert -Represents a butoxycarbonyl group.) G ₂ represents any of the groups shown below,

(Here, R ₂ represents a hydrogen atom, a methyl, a formyl group, an acetyl group or a tert-butoxycarbonyl group.)

G ₃ represents a pyridyl group optionally substituted with a hydroxyl group or a halogen atom, or a pyrazolyl group optionally mono- or di-substituted with a methyl group. In the compound of the present invention represented by the formula (1),

A represents a pyridyl group or a pyrazolyl group which may be substituted with a hydroxyl group or a halogen atom, and more specifically, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-chloro-5- Pyridyl, 2-hydroxy-5-pyridyl, 3-birazolyl and the like.

B is an amidino group; a di-C i-6 alkyl sulfamoyl group such as dimethylcarbamoyl and getylcarbamoyl; a diCi-6 alkylsulfamoyl group such as dimethylsulfamoyl and getylsulfamoyl; formula: —Y — G (where Y represents a carbonyl group or a sulfonyl group, and G is a 5- or 6-membered saturated group containing 13 nitrogen, oxygen or sulfur atoms, which may be substituted with R. Alternatively, it represents an unsaturated heterocyclic group.

Examples of the heterocyclic group include pyridyl, pyrazolyl, pyrrolyl, piberidinyl, piperazinyl, pyrrolidinyl, morpholino, tetrahydrofuranyl, tetrahydrothenyl, tetrahydrothiaviranyl, tetrahydroviranyl, and the like. Halogen atoms such as black and bromo; hydroxyyl groups; oxo; methyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl groups _ ₄ alkyl group; formyl group; Asechiru group, C ₄ alkylcarbonyl group or main butoxycarbonyl group such as propionyl group, ethoxycarbonyl group, optionally substituted with C i _ ₄ alkoxycarbonyl group such as a tert- butoxycarbonyl group Is also good.

When the hetero ring has two or more substituents, they may be the same or different.

Examples of the pharmaceutically acceptable salts include salts of compounds represented by the general formula (1) with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid; Queen Examples include salts of organic acids such as acids, benzoic acid, salicylic acid, nicotinic acid, and heptagluconic acid.

The starting compound and the compound (1) of the present invention have optical isomers, and not only the racemic form but also the optically active form are included in the compound of the present invention.

The compound of the present invention has a c-GMP-specific phosphodiesterase inhibitory action. In particular, the following compounds show excellent PDE selectivity and antianginal action and are promising as pharmaceuticals. That is, a compound in which B is an amidino group, a dimethylcarbamoyl group, a dimethylsulfamoyl group, one COG ^ —Y—G ₂ or one Y—G ₃ .

Here, represents one of the groups shown below.

(Where represents a hydrogen atom or a hydroxyl group, X is 0, S, S 0 _2, or represents N-R _3, R ₃ is a hydrogen atom, a methyl group, a formyl group, were or Asechiru group Represents a tert-butoxycarbonyl group.)

G ₂ represents any of the groups shown below.

N 0 — N N — R — N

G ₃ represents a pyridyl group optionally substituted with a hydroxyl group or a halogen atom, or a pyrazolyl group optionally mono- or di-substituted with a methyl group. Next, the production method of the present invention and the production method of a novel compound as an intermediate or the like will be described.

Manufacturing method 1

In the general formula (1), the compound (la) in which B is one CO—G ′ (G ′ has the same meaning as described above or G ₂ ) can be produced according to the following formula.

(In the formula, A and G ′ represent the same meaning as described above.)

Compound (la) can be obtained by subjecting compound (2) and compound G'-COOH to dehydration condensation by a conventional method.

The dehydration-condensation reaction is not particularly limited as long as it is a commonly performed method, but a method using a condensing agent is preferable.

Examples of the condensing agent include 1,3-dicyclohexylcarpoimide, 11- (3-dimethylaminopropyl) -13-ethylcarpoimide, and 2-ethoxy-11-ethoxycarbonyl. 1,2-dihydroquinoline and the like can be used.

In this reaction, if N-hydroxysuccinimide, 1-hydroxybenzotriazole or 3,4-dihydro-13-hydroxy-4-oxo-1,2,3-benzotriazine, etc., coexist, the reaction will proceed. Proceed more quickly.

The solvent is not particularly limited as long as it is inert to the reaction. Examples thereof include ethers such as getyl ether, THF, and 1,4-dioxane, and aromatic hydrocarbons such as benzene, toluene, and xylene. For example, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc., acetonitrile, DMF, DMS0, pyridine and the like can be used.

The reaction temperature is from about 15 ° C to about the boiling point of the solvent, preferably from 0 to 80 ° C. Manufacturing method 2

In the general formula (1), a compound in which B is —Y—G ″ (G ”has the same meaning as G ₂ or G ₃ ) can be produced according to the following formula.

(In the formula, A, Y and G "represent the same meaning as described above.)

Compound (lb) can also be produced by condensing compound (2) with compound G "—Y—C1 by a conventional method.

The condensation reaction is not particularly limited as long as it is a commonly performed method, but the reaction can proceed more quickly by coexisting a base. As the base, inorganic bases such as sodium hydrogen carbonate and potassium carbonate, and amines such as triethylamine and pyridine can be used.

The solvent is not particularly limited as long as it is a solvent inert to the reaction, and examples thereof include ethers such as getyl ether, THF, 1,4-dioxane, and aromatic hydrocarbons such as benzene, toluene, and xylene. Halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc., acetonitrile, DMF, DMS 0 and the like can be used. The reaction temperature is from about 15 ° C to about the boiling point of the solvent, preferably from 0 to 80 ° C. Manufacturing method 3

In the general formula (1), the compound in which B is an amidino group (—C (= NH) NH ₂ ) can be produced according to the following formula.

(In the formula, A represents the same meaning as described above.)

Compound (lc) can be obtained by reacting compound (2) with compound (c) in a solvent such as DMF or DMSO at room temperature to about the boiling point of the solvent, preferably at 50 to 120 ° C.

In the present invention, after completion of the reaction, the desired product can be obtained by performing ordinary post-treatment.

The structure of the compound of the present invention was determined from IR, NMR, MS and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described more specifically with reference to examples.

Example 1

5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl) -7- (3-tetrahydrofuroyl) pyrido [4 ', 3 ': 4,5] Thieno [2,3-d] pyrimidine (Compound No. 8)

5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl) pyrid [4 ', 3'4,5] thieno Dissolve 3 g of [2,3-d] pyrimidine in 30 ml of DMF, and add 1.6 g of 1- (3-dimethylaminopropyl) -3-ethylcarposimid hydrochloride, 1-hydroxybenzotriazole To the mixture were added 1.lg of hydrochloride, 0.8 g of triethylamine, and 0.9 g of tetrahydrofuran-3-carboxylic acid, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into water, and the precipitated crystals were separated by filtration and washed with water. The obtained crystals were dried and purified by silica gel column chromatography (cloth form: methanol = 20: 1) to obtain 2.6 g of the desired compound. Melting point 201-205 ° C Example 2

5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -7-morpholinosulfonyl-2- (4-pyridyl) pyrido [4 ', 3' : 4,5] Cheno [2,3-pyrimidine production (Compound No. 40) ■

5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl) pyrid [4 ', 3': 4,5] 0.3 g of thieno [2,3-d) pyrimidine and 0.2 g of triethylamine were dissolved in MFlOml, and 0.4 g of morpholinosulfonyl chloride was added at room temperature, followed by stirring at room temperature for 2 hours. The reaction solution was poured into water, and the precipitated crystals were separated by filtration and washed with water. The obtained crystals were dried and purified by silica gel column chromatography (form: methanol = 10: 1) to obtain 0.3 g of the desired compound. Melting point 265-267 ° C Example 3 5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl) pyrid [4 ', 3': 4,5] Production of thieno [2,3-d] pyrimidine-7-carboxamidine (Compound No. 48)

5,6,7,8-tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl) pyridide [4 ', 3': 4,5] thieno 0.3 g of [2,3-d] pyrimidine and 0.3 g of 3,5-dimethylvirazole-11-carboxamidine nitrate were dissolved in 5 ml of DMF and stirred at 100 ° C for 2 hours. The reaction solution was poured into water, and the precipitated crystals were separated by filtration and washed with water. The obtained crystals were dried and purified by silica gel column chromatography (cloth form: methanol = 10: 1) to obtain 0.08 g of the desired compound. Melting point 247 ° C Dec. Representative examples of the compound of the present invention including the above Examples are shown in Table 1. Table 2 shows the NMR data.

In the table, Ac represents an acetyl group, and B0c represents a tert-butoxycarbonyl group.

Table 1

91

Z0ll / Z0 <if / X3d CS9S £ 0 / C0 O

8L

Z0ll / i0df / X3d CS9S £ 0 / C0 OAV

Table 2

Industrial applicability:

Next, the pharmacological activity of the compound of the present invention is shown.

Pharmacological test example 1 Inhibitory effect of phosphodiesterase

c GMP-specific phosphodiesterase (hereinafter referred to as PDE 5) was obtained from human platelets according to the method of Thampson et al. (Thompson WJ, eta 丄., Advancesin Cyclic Nucleotide Research 10, 69-92, 1979). — Cellulose column chromatography (Whatman, DE-52, 3.2 x 13 cm), 70-: LOO OmM Sodium acetate was separated and purified by concentration gradient elution. Photoreceptorc GMP-specific phosphodiesterase (hereinafter PDE 6) was prepared from rod outer segments of the retina. The PDE activity was measured by partially modifying the method of Thamps0n et al. That is, 1〃M (for PDE 5) or 100〃 M (for PDE 6) [3H] -1c GMP is decomposed by PDE, and the generated 5,1 GMP is treated with snake venom (Sima V 7000). This reaction solution was added to an anion exchange resin (Bio-Rad, AG 1-X8), and unadsorbed guanosine was measured by a liquid scintillation counter. From the concentration inhibition curve, the concentration (IC50) at which the enzyme activity was inhibited by 50% was determined. Table 3 shows the results. Table 3

PDE inhibitory activity

Compound P D E 5

I C 50 (nM)

Number selectivity

P D E 5 P D E 6

2 0.28

7 0.56

8 0.62 .68 110 Eight

29 0.24

44 0.37

45 0.85

65 0. 33

127 0. 17

128 0. 21

137 0. 10

138 0-052

144 0.23

148 0.25

Control drug 14 77 5.5

PDE 5 selectivity = (PDE 6 inhibitory activity (I C 50))

/ (PDE5 inhibitory activity (I C 50))

Control drug: s i 1 de n a f i 1 Pharmacological test example 2 Antianginal effect

The antianginal effect using rat (male Crj: CD (SD) IGs rat, Nippon Chillers' River) was demonstrated by Sakai et al. (J Pharmacol Methods, _5). , 325, 1981) by partially modifying the method described below. After the rat was fixed in the dorsal position under urethane anesthesia, the trachea was exposed and a tracheal force neura was inserted. A polyethylene force neuron (SP-28, Natsume Seisakusho) filled with parin saline to 100 U / m 1 from the right internal carotid artery was placed near the coronary artery opening near the aortic valve, and was treated with angina pectoris. A certain metacholine (A-2251, Sigma) was used for coronary artery administration. A blood pressure measurement force neuron was inserted through the right femoral artery and placed, and the other end was connected to a pressure transducer. A forcenula (PE-50, Clay Adams) filled with saline was placed in the right femoral vein for administration of the test drug.

A second electrocardiogram was derived with a bioelectric amplifier through electrodes attached to the limbs, and the heart rate was measured from the R wave. The ST change of the electrocardiogram was recorded on a thermal recorder at a high speed of 5 Omm / mV with high sensitivity (S OmmZ seconds) or recorded on a data recording and analysis system (PowerLab, Bioresearch Center) and analyzed. In addition, the electrocardiogram, heart rate and blood pressure waveform were drawn on a thermographic recorder via a polygraph (Nihon Kohden).

After surgery, blood pressure, heart rate, etc. become stable, methacholine 2-6 g is administered several times, The force neuron was fixed at the position where the ST elevation of the fixed ECG was obtained. Approximately 10 minutes before administration of the test substance (100 zg / kg) and 2, 10, and 30 minutes after administration, methacholine was injected into the coronary artery and compared with the electrocardiogram before administration of methacholine. The difference between the S-wave magnitude from the baseline immediately before the administration of methacholine and the S-wave magnitude at the time when the increase of the S-wave after the administration of methacholine was the maximum was defined as the increase in the S-wave. Small ST gain (approximately when ST gain is less than 0.2 mV) Individuals were not subjected to the experiment. The evaluation of the antianginal effect was the change rate of ST increase calculated by the following formula. Table 4 shows the results.

ST change rate at each time point (%) =

(Increase in ST at each time point-Increase in ST before test substance administration)

/ (Increase in ST before administration of test substance) X 100 Table 4

Controls: s i 1 d e n a f i 1

: The test substance was intravenously administered at 100 g / kg.

**: a compound represented by the following formula and described in WO00Z59912

As described above, the compound of the present invention has a strong PDE 5 inhibitory activity and a high PDE 5 selectivity c GMP-specific PDE (PDE 5) inhibitory action, an antianginal action, such as hypertension, heart failure, Prevention of myocardial infarction, angina, arteriosclerosis, restenosis after PTCA, cardiac edema, pulmonary hypertension, renal failure, renal edema, hepatic edema, asthma, bronchitis, dementia, immunodeficiency, glaucoma or impotence Or useful for treatment.

Claims

The scope of the claims

1. Equation (1)

[Wherein, A represents a pyridyl group optionally substituted with a hydroxyl group or a halogen atom, or a pyrazolyl group optionally substituted with a methyl group,

B is amidino group, di C i_ ₆ alkyl force Rubamoiru group, di (: -: represents a group represented by a Y- G ₆ alkylsulfamoyl group, or a group of the formula.

(Where Y represents a carbonyl group or a sulfonyl group, and G represents a 5- to 6-membered saturated group containing 1 to 3 nitrogen, oxygen or sulfur atoms which may be substituted with R. or a heterocyclic group of the unsaturated. R Table with a halogen atom, a hydroxyl group, an CI- ₄ alkyl group, formyl groups, C I ₄ alkyl group or a C i_ ₄ alkoxy force Lupo two Le group.)] Thienopyrimidine compounds and their pharmaceutically acceptable

<^ Then ¾.

2. In equation (1),

B is, amidino group, dimethylcarbamoyl group, dimethylsulfamoyl group, one C OG ^ -YG ₂ or, - Y- A compound according to claim 1 G _3.

[In the formula, represents one of the groups shown below.

(Where represents a hydrogen atom or a hydroxyl group, X is 0, S, S_〇 ₂ or represents N-R _3, R ₃ is a hydrogen atom, a methyl group, a formyl group, were or Asechiru group Represents a tert-butoxycarbonyl group.)

G ₂ represents any of the groups shown below.

— NP-N jN- R ₂ — N, — (Here, R ₂ represents a hydrogen atom, a methyl, a formyl group, an acetyl group or a tert-butoxycarbonyl group.)

G ₃ represents a pyridyl group optionally substituted with a hydroxyl group or a halogen atom, or a pyrazolyl group optionally substituted with a methyl group. ]

3. The compound according to claim 1, wherein B is CO—, wherein G 1 has the same meaning as in claim 2.

4. The compound according to any one of claims 1 to 3, selected from the following list.

5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl)-

7-(3-tetrahydrofuroyl) pyrido [4 ', 3': 4,5] cheno [2,3-pyrimidine

5, 6, 7, 8-tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl) -7- (2-tetrahydrofuroyl) pyrid [4 ', 3 ': 4,5] Cheno [2,3- (1) pyrimidine

5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl) -7- (4-pyridylcarbonyl) pyrid [ 4 ', 3': 4,5] Cheno [2,3- (1) pyrimidine

5,6,7,8-tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl) -7- (3-pyridylcarbonyl) pyrid [ 4 ', 3': 4,5] Cheno [2,3- (1) pyrimidine

5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl) -7- (4-hydroxy-2-pyrrolidone Dinylcarbonyl) pyrido [4 ', 3': 4,5] cheno [2,3- (1) pyrimidine

5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl) -7-dimethylcarbamoylpyrido [, 3 ': 4,5 Thieno [2,3-d] pyrimidine

5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl) -7-morpholinocarbonylpyrido [4 ', 3': 4,5] Ceno [2,3-dipyrimidine

5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl) -7-morpholinosulfonyl bilide [4 ', 3 ': 4,5] thieno [2,3-d) pyrimidine

5,6,7,8-Tetrahydroxy-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl) -7- (2-oxo-5-tetrahydrofuroyl) pyri De [4 ', 3': 4,5] thieno [2,3-d] pyrimidine

5,6,7,8-tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (4-pyridyl) -7- (2-oxo-5-pyrrolidinecarbonyl ) Pyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine

5, 6, 7, 8-tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (3-pyridyl) -7-dimethylcarbamoylpyrido [4 ', 3': 4 , 5] thieno [2,3-d] pyrimidine

5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (3-pyrazolyl) -7- (2-tetrahydrofuroyl) pyrido [ 4 ', 3': 4,5] Cheno [2,3- (1) pyrimidine 5,6,7,8-Tetrahydro-4-[(3-chloro-4-Methoxy) benzylamino] -2- (3-virazolyl) -7- (3-tetrahydrofuroyl) pyrido [4 ' , 3 ': 4,5] Cheno [2,3- <1] pyrimidine

5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (3-pyrazolyl) -7-dimethylcarbamoylpyrido [4 ', 3': 4,5] Ceno [2,3- (1) pyrimidine

5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (3-pyrazolyl) -7-morpholinocarbonylpyrido [4 ', 3': 4,5] thieno [2,3-d] pyrimidine

5,6,7,8-Tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (3-pyrazolyl) -7-dimethylsulfamoylpyrido [4 ', 3 ': 4,5] thieno [2,3-d] pyrimidine

5, 6, 7, 8-tetrahydro-4-[(3-chloro-4-methoxy) benzylamino] -2- (3-virazolyl) -7- (2-oxo-5-tetrahydrofuroyl) pyri C [4 ', 3': 4,5] Cheno [2,3- (1) pyrimidine