JPH05507932A - Imidazopyridine PAF antagonist - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Imi Zopi 1 Jin PAF゛ The present invention relates to imidazopyridines, particularly certain 4-substituted-1-(2-methylimidazo( 0 compounds related to 4,5-c)pyrid-1-yl)-benzene derivatives are human and has clinical utility in the treatment of allergic and inflammatory diseases in animals It is a potent and selective antagonist of platelet activating factor.

Platelet activating factor (PAF, 1-〇-alkyl-2-acetyl-3n-glyceride) (3-phosphorylco, phosphorus) is an ether phospholipid, and its structure is 1979 It was first revealed in . It is produced by many pro-inflammatory cells, platelets and the kidneys. 0 potent platelet aggregation activity released from, and interacting with In addition to sex, PAF can be induced directly or with other strong mediator substances. e.g. induced via the release of thromboxane A8 or leukotrienes. It exhibits a wide spectrum of biological activity, which helps to treat allergies, inflammation and hypersecretion. Multi-symptoms of various conditions including asthma, arthritis, rhinitis, bronchitis and urticaria. Treatment, including circulatory system shock, gastric ulcer, xiatus and angina, thrombosis and stroke It is a PAF inhibitor with strong value in the treatment of cardiovascular diseases.

In European Patent Application No. 0258033, we have identified one A series of 2-substituted 1,4-dihydropyridine derivatives are disclosed. our yo after that In Roppa Patent Application No. 0310386, we present yet another series of dihydro Pyridine PAF antagonists are disclosed in which the substituent at the 2-position is specifically 0 containing a dazo(4,5-c)pyrid-1-yl-phenyl group. formula: (In the formula, R', R'' and R3 are each H or a methyl group, and R4 is a hydrogen atom. , a halogen atom, a 01-C4 alkyl group or a C3-C4 alkoxy group, and n is an integer from 1 to 3) and their pharmaceutically acceptable compounds. The present invention provides another PAF antagonist containing a salt that can be used as a compound.

In the above definition, the term halogen atom means fluorine, chlorine, bromine or iodine atom. means. Alkyl and alkoxy groups with 3 or more carbon atoms are straight-chain or or a branched chain.

Preferred implementation of the invention JI! , R+, Rx and R3 are H and R 4 is preferably a chlorine atom and n is 1 or 2.

When R4 is a branched alkyl or alkoxy group having 4 carbon atoms, the formula ( The compound represented by 1) contains at least one asymmetric center and has a pair of enantiomers. - may exist as Such isomers can be obtained by physical methods, e.g. Fractional crystallization or chromatography of compounds or their appropriate salts or derivatives 0 This invention applies to all enantiomers, whether separated or not. Including Omar.

Pharmaceutically acceptable acid addition salts of the compound represented by formula (1) that form salts include non- those formed from acids that form toxic acid addition salts, e.g. hydrochloride, hydrobromide; , sulfate or hydrogen sulfate, phosphate or acid phosphate, acetate, citrate , fumarate, gluconate, lactate, maleate, succinate and tartrate It's salt.

formula! The compound represented by the following formula: (wherein R', R'', R3, R' and n are as defined above) It can be obtained by cyclizing a compound.

In a typical method, the compound represented by Simply heat for several hours at a temperature above 100° C. in luene or xylene).

The solvent is evaporated and the product is recovered and purified in conventional manner.

The intermediate represented by formula ■ is the following formula: The amine represented by the following formula: It is prepared by reacting with benzoic acid or anhydride derivative represented by

This reaction involves dissolving water or an aqueous solution in the presence of a base (e.g. sodium carbonate). Reacting the amine (II[) with the anhydride in a medium or diimide coupling agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide This is accomplished by reacting benzoic acid with an amine.

Suitable reagents and conditions for these steps can be found in standard reference books and subsequent examples. This can be easily determined by looking at the

The activity of the compounds of the present invention is demonstrated by their ability to inhibit the platelet aggregation activity of PAF in vitro. Demonstrated by ability. The test is carried out as follows: blood samples are placed in rabbits or is taken from any human and added to 0.1 volume of ethylenediaminetetraacetic acid disodium. Centrifuge the sample for 15 minutes to obtain platelet-rich plasma. . Furthermore, the plasma was centrifuged to obtain a platelet pellet, which was mixed with a buffer solution (4mM KH, PO,, 6mM N a x HP O,, roomM NaC1,0,1 % glucose and 0.1% bovine serum albumin, pH 7.25), and The sample (0 , 5a either in vehicle alone or in a vehicle containing the particular compound under test. At the same time, the plate was placed in a Paton agglomerometer at 37°C for 2 minutes with stirring. Incubate. Sufficient concentration to obtain maximal agglutination in the absence of test compound Add PAF (101 to 10-' mol) to inhibit platelet aggregation and increase the light transmittance of the solution. Measured by addition. Repeat the experiment in the presence of a range of concentrations of the test compound; The IC5o value is the compound concentration required to reduce the reaction to 50% of the maximum value of and record it.

The activity of the compound represented by formula (T) also inhibits mice from the lethal effects of PAF injection. It is also demonstrated in vivo by its ability to protect. in 0.9% W/V sodium chloride Mixture of PAF (50x/kg) and DL-propranolol (5mg/kg) is injected into mice via the tail vein (0.2 m), the compound under test is PA Inject into the tail vein immediately before F/propranolol injection or into the stomach 2 hours before injection. Administered orally by tube feeding. The compound was tested by administering several doses to groups of five mice. The dose that reduces the mortality rate by 50% is recorded as the PDso value.

For therapeutic use, compounds of formula (1) are generally prepared according to the intended route of administration or and a pharmaceutical carrier selected in accordance with standard pharmaceutical practice. It will be done. For example, tablet forms containing starch or lactose as excipients, or even alone or capsules or pellets mixed with excipients, or flavorings or colorings. It can be administered orally in the form of a Ulixir formulation or suspension containing the agent. These are also For example, it can be parenterally injected by intravenous, intramuscular or subcutaneous injection. For parenteral administration However, they require the addition of other substances, such as salts or is best used in the form of a sterile aqueous solution containing glucose.

Administration to humans in the treatment or prophylaxis of allergic bronchial diseases and arthritis When used, the oral dosage of the compound is generally 2 times a day for an average adult patient (70 kg). It is in the range of ~1000■. i.e. for the typical adult patient, individual tablets or Capsules contain the active substances 1 to 1 in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration, including 500 μg, are generally given in single doses as needed. It is in the range of 1 to 10 cm. For the treatment of allergic and tracheal palliative symptoms For patients, inhalation via nebulizer or aerosol is the preferred method of drug administration. It is the root. Dosage levels by this route can be adjusted per dose as needed. It is within the range of 0.1 to 50 . In reality, it is up to the doctor to determine the best fit for each individual patient. Determine the practical dose, which will vary depending on the age, weight, and response of the particular patient. It will become. The above dosages are illustrative of the average case and are of course higher or lower. There may be individual cases where a narrower dosage range may be beneficial and these are also within the scope of this invention. It is within the range.

Therefore, from another point of view, the present invention relates to a compound represented by formula (1) or its A pharmaceutical composition comprising a pharmaceutically acceptable salt and a pharmaceutically acceptable diluent or carrier. It provides a product.

The present invention also has applications in medicine, particularly in humans for allergy, inflammation and A compound represented by formula (1) or its compound for use in the treatment of hypersecretion Contains pharmaceutically acceptable salts.

The preparation of intermediates of formula (II) and compounds of formula (I) This will be explained in more detail with reference to the following experimental examples. .

The purity of the compound was determined by thin layer crosslinking using Merck Keyl Gel 60F254 plates. 1) (-Nuclear magnetic resonance spectra were routinely monitored by chromatography. , using either a Nicolet QE-300 or a Plutzker-AC-300 spectrometer. were recorded and in all cases agreed with the proposed structure. The chemical shift is mainly 22m from tetramethylsilane using common abbreviations for the names of peaks of interest. Given downfield: s, - doublet; d, doublet; t, triplet; m, multiplet Heavy line and br, wide.

Example 1 7-chloro-34-dihydro-2-4'-2-methylimizo 45-C bild -1-yl phenyl-5H-1'4-benzodiazepine-5-a) 4- Chloroisatoic anhydride (0.32 g, 1.6 mmol) was dissolved in 2 mL of water (6 dl). -amino-4'-(2-methylimidazoC4,5-c]pyridoenyyl)acetate Tophenone (0.57 g, 1.45 mmol) was added to the solution. average After stirring until uniform consistency, add sodium carbonate (0.19 g, 1.8 mmol). solution was added. After 1 hour, dichloromethane (12 m) was added and the two phases were stirred for 6 Continued again for 6 hours. A mixture of saturated aqueous sodium bicarbonate and dichloromethane distributed between. The organic phase is separated, dried (MgSO, ) and evaporated to form an amorphous A fine solid was obtained. Flash chromatography on silica in ethyl acetate. Elution with 15% and then 25% methanol solution yields 2-amino-5-chloro. -N-(2-C4-(2-methylimidazo(4,5-C)pyrid-1-yl)ph 2-oxoethyl)benzamide as a solid (0.14 g, 23%) m, p, 116-118°C, HNMR (CDsSOCDd: 2.52 (3FI, s), 4.79 (2L d, J5.4Hz), 6. 58　br　exchc2H,s), 6.76(ill, d, J　8.9 Hz), 7.21 (IL dd, i 8.9° 2.2Hz), 7.28 (18, d, J 5.4Hz) + 7.67 (IL d, J 2.2+1z), 7.82 and 8.28 i respectively 2B, d, J 8-4b) + 8.35 (IH, d, J 5.5Hz), 8.85 br exch (IH, t, J 5.4Hzj and and 8.94 (IH, 5) b) In xylene (5 m, containing 2-3 ethanol to promote solubility) The benzamide from (a) (0.11 g, 0.26 mmol) is suspended in The liquid was heated to 140°C for 5 hours. Evaporate the solvent and transfer the residue to a silica flash screen. chromatographed with 10% then 20% methanol solution in ethyl acetate. Purification by elution gave the title product as a pale yellow amorphous solid (0,041 g , 40%). m, p, 225-227°C, actual value: C, 63,5 2; H, 4, 14; N, 16.61. Theoretical value (CzzH+hCI Nso, 0. 751(,0)? C, 63,62; H, 4,25; N, 16.86%.

Example 2 78-dichloro-34-dihydro-2-4'-2-methylimizo 45-c Pi-do-1-yl phenyl-5H-14-benzodiazepine-52t7 a) Repeat the procedure of Example 1(a) but with 4,5-dichloroisatoic anhydride When used as a starting incentive, 2-amino-4,5-dichloro-N-+2-(4 -(2-methylimidazo(4,5-c)pyrid-1-yl)phenyl]-2-o xoethyl)benzamide was obtained.

'HNMR (CDCI+): 2.63 (3H, s), 5.00 (2H,' d, J 4.2 Hz), 5.69 br exch, (QH, s).

6.83 (18, s), 7.18 (2H, m), 7.62 (31, m), 8.33 (2L d, J 8.4Hz), 8.42 (1a, d.

J 5.5H2), 9. IHltl, s).

b) Cyclization of the above product according to the procedure of Example 1(b) yields the title product was obtained with a yield of 58%. m, p, 174-177°C, actual value: C, 58,0 8iH, 3, 41; N, 14.94. Theoretical value (CZ□H+5CItNs○・)! , 0) :C.

5B, 16 ;)! , 3.77; N, 15.40%.

Example 3 79-dichloro-4-dihydro-2-4'-2-methylimizo45-cbi ! Do-yl phenyl-5H-14-bendacyazepine-52-Z a) 2-Amino-4'-(2-methylimida) in dichloromethane (25m) Zo(4,5-c)pyrid-1-yl)acetophenone hydrochloride (0.7g, 1.8 mmol L3.5-dichloro-2-aminobenzoic acid (0.48 g, 2.3 mmol ), N-hydroxybenzotriazole (0.34 g, 2.4 mmol), N -methylmorpholine (1,61m, 16 mmol) and 1-(3-dimethylalcohol) (minopropyl)-3-ethylcarbodiimide hydrochloride (0.89g, 4.7ml The solution in which mol) was dissolved was stirred at 25°C for 3 hours. evaporate all volatiles , and the residue was partitioned between ethyl acetate and water buffered to pH 5. organic layer was separated and dried (MgSQ,) LH. Flash chroma the residue on silica eluting with a 10% methanol solution in ethyl acetate gives the 2-alpha Mino-3,5-dichloroo-N-(2-(4-(2-methylimidazo(4,5- c) Pyrid-1-yl)phenyl]-2-oxoethyl)benzamide is pale yellow Obtained as a gum (0.21 g, 26%). 'B NMR (CDCb) :2.62 (38,s), 4.98 (2fl, d, J 5.7Hz).

6.10 br exch (3B, m), 7.13 (IH, d, J 5. 7Hz), 7.39 (Ill, d, J 2H2), V. 48 (IL d, J 2Hz), 7.57 and 8.30 (2H, d, J 8. respectively). 4Hz), 8.43 (LH, d, J 5.7Hz) and 9.07 (18, s).

b) p-) Luenesulfonic acid hydrate (0.1 g, 0.5 mmol), dichloro Ketoamine (0.21 g, 0.47 mm) from (a) in methane (14 m) to the refluxing solution in which the After 6 hours, the mixture was saturated with dichloromethane. and aqueous sodium bicarbonate solution. Dry the organic layer (MgSO,) Evaporated to a yellow foam. Flash chromatography in silica and vinegar Elution with 5% methanol in ethyl acid gave the title product as an off-white solid ( 0,065g.

33%). m, p, 165-7°C, actual value: C, 58,92, H .

3°85; N, 14.57. Theoretical value (CxzH+5CItNsO, 0.5HzO ,0,5EtOAc): C, 58,91; H, 4,12; N, 14.31%.

Preparation example 2-amino-4'-2-methylimizo 45-c bi-1-do-1-yl A. Z5lZ hydrochloride (a) 4-4-acetylphenyl amino-3-nitroviridine ethanol (4 4-chloro-3-nitropyridine hydrochloride (9.75 g.

50 mmol) dissolved in p-aminoacetate in ethanol (25d). Add to the slurry of phenone (6.76 g, 50 mmol) and let the mixture stand at room temperature. It was stirred overnight. The mixture was quenched in water, the yellow solid was filtered off and dried (10. 1g.

69%), m, P, 197-200°C.

(b) 4-4-acetylphenyl amino-3-aminopyridine 4-(4-acetylphenyl tylphenyl)amino-3-nitropyridine hydrochloride (2.0 g.

78.8 mmol) in aqueous sodium hydroxide solution and dichloromethane (3X20d) distributed between. The collected organic layer was washed with water (20 m) and concentrated under reduced pressure to form a solid. was gotten. Ethanol (201f) was added and the solution was loaded with 5% palladium. Hydrogenated over charcoal (0,2 g) at 50 p, s, i, (3,4 bar) for 3.5 h added. The catalyst was filtered off and the solvent was removed under reduced pressure to give a brown solid (1.8 g, approx. 0%) was obtained, which was used directly in the next step without purification.

4-(4-acetylphenyl) in acetic acid (204af) and acetic anhydride (20Ld) ) Amino-3-aminopyridine (68.0 g, 0.3 mmol) is dissolved The liquid was heated to 95°C for 1.5 hours, then cooled and concentrated under reduced pressure. residue Salt by dissolving in water (500 M1) and adding saturated aqueous ammonia Basicized.

The product was filtered off, washed with water (2X100m) and dried under reduced pressure to give the title compound. (61.0 g, 81%) was obtained as a brown solid, m, p, 155-156 °C (from water).

4-(2-methylimidazo[4,5- c) Pyrid-1-yl-acetophenone (17.5 g, 69.7 mmol) is dissolved The dissolved solution was mixed with dry tetrahydrofuran (35m) and diethyl carbonate ( sodium hydride (3.68 g, 15 It was added to a slurry of 3 mmol) under reflux and stirred for 45 minutes. After another hour, mix The mixture was cooled, hexane (200m) was added and the resulting precipitate was filtered off. Washed with xane (2X100m). Suspend the solid in ethyl acetate (200m) , acetic acid (10.2 g) was added. After stirring for 15 minutes, add water (200ml) and then The organic layer was separated. The aqueous phase was extracted with ethyl acetate (100 m) and the combined organic The solution was washed with water (200 m), dried (MgSO, ) and concentrated to give the title product. Obtained as a mush (17.3 g, 77%). Furthermore, flash chromatography Purification by filtration (eluted with ethyl acetate/methanol (7:1)) yielded the title The compound was obtained as a white solid, m, P, 111-112°C.

Sodium nitrite (3.3 g, 47 mmol) dissolved in water (40 m) The solution was diluted with ethyl 4'-(2-methylimidazo[ 4゜5-C]pyrid-1-yl)benzoyl acetate (12.6g, 39ml Mole) was added one by one to the solution in which it was dissolved. After 1.5 hours, the mixture was dissolved in dichloromethane. Distributed between tongue and brine. The organic layer was washed again with brine and then saturated bicarbonate. Wash with aqueous sodium solution, dry (MgSOn), and evaporate to form an oil. This crystallized immediately upon addition of ether (9.61 g, 70%) ( 2:1 mixture of syn/anti isomers), m, P, 168-170<0>C.

, the product from e) above (6g) in acetic acid (33m) and acetic anhydride (9m).

17 mmol) dissolved in the solution was heated at 30°C for 5 hours at 50 p, s, i, (3 , 45 bar) over 5% palladium on charcoal (1 g). mixture Filter through a filter pad, wash the cake with methanol and evaporate the filtrate.

The residue was chromatographed with methanol and then 10% methane in ethyl acetate. Elution with a bottle gave a colorless foam (6.1 g, 94%). m, p, 7 1-73℃.

(g) 2-Amino-4'--methylimizo 5-c pylx-yl acetate Fenon d Product from r) above (1.2 g, 3.2 mmol) in 2M hydrochloric acid (30 af) The solution in which was dissolved was heated under reflux for 3 hours. When the solution is evaporated to dryness, the amine hydrochloride is Obtained as a colorless foam (1.35 g), which was stored under reduced pressure.

Summary book Formula ■: (In the formula, R1, Rf and R1 are each H or a methyl group, and R4 is a hydrogen atom. , a halogen atom, a CI-C-alkyl group, or an auto-C4 alkoxy group, and and n is an integer from 1 to 3) are used for the treatment of allergic and inflammatory conditions. It is a PAF antagonist used.

international search report Kon 488115

Claims (1)

[Claims] 1. The following formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (II) (In the formula, R1, R2 and R3 are each H or a methyl group, and R4 is a hydrogen atom. , a halogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group, and n is an integer from 1 to 3) A compound represented by or a pharmaceutically acceptable salt thereof. 2. R1, R2 and R3 are H, R4 is a chlorine atom, and n is 1 or less. or 2. The compound according to claim 1, which is 3. The compound: 7-chloro-3,4-dihydro-2-[4'-(2-methylimidazo[4,5- c]pyrid-1-yl)phenyl]-5H-1,4-penzodiazepine-5-o hmm, 7.8-Dichloro-3,4-dihydro-2-[4'-(2-methylimidazo[4 ,5-c]pyrid-1-yl)phenyl]-5H-1,4-benzodiazebin- 5-on, or 7.9-dichloro-3,4-dihydro-2-[4'-(2-methylimidazo[4 ,5-c]pyrid-1-yl)phenyl]-5H-1,4-benzodiazepine- 5-on, The compound according to claim 2. 4. The following formula: ▲There are mathematical formulas, chemical formulas, tables, etc. (I) Is it possible to cyclize the compound represented by ▼? A method for preparing a compound represented by formula (I) according to claim 1. 5. The compound represented by formula (1) according to any one of claims 1 to 3 compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable diluent or carrier. A pharmaceutical composition comprising: 6. Allergy, inflammation and hypersecretion, especially in humans, for use in medicine. The method according to any one of claims 1 to 3 for use in treating multiple symptoms. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof. 7. The following formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (II) The following formula consists of cyclizing the compound represented by: ▲There are mathematical formulas, chemical formulas, tables, etc. ▼(I) (In the formula, R1, R2 and R3 are each H or a methyl group, and R 4 is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, or a C1-C4 alkoxy and n is an integer of 1 to 3). 8. R1. R2 and R3 are H, R4 is a chlorine atom, and n is 1 or less. or 2. The method according to claim 7. 9. The compound represented by formula (I) to be produced is: 7-chloro-3,4-dihydrogen Dro-2-[4'-(2-methylimidazo[4,5-c]pyrid-1-yl)ph phenyl]-5H-1,4-benzodiazepin-5-one, 7,8-dichloro-3,4-dihydro-2-[4'-(2-methylimidazo[4 ,5-c]pyrid-1-yl)phenyl]-5H-1,4-benzodiazepine- 5-on, or 7,9-dichloro-3,4-dihydro-2-[4'-(2-methylimidazo[4 ,5-c]pyrid-1-yl)phenyl]-5H-1,4-benzodiazepine- 5-on, The method according to claim 8.