KR20060098907A - Pyrrolo[2,3-d]pyridazine derivatives and processes for the preparation thereof - Google Patents

Abstract

The present invention relates to a pyrrolo [2,3-d] pyridazine derivative of Formula 1 having excellent gastric acid secretion inhibitory effect or a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition containing the same.

Formula 1

Where

R ₁ , R ₂ , and R ₃ are each as defined in the detailed description.

Pyrrolo [2,3-d] pyridazine, anti-ulcer agent, proton pump, gastric acid secretion

Description

Pyrrolo [2,3-d] pyridazine derivatives and processes for the preparation according to the present invention

The present invention relates to a novel pyrrolo [2,3-d] pyridazine derivative or a pharmaceutically acceptable salt thereof, and a preparation method thereof and a pharmaceutical composition containing the same, which have excellent gastric acid secretion inhibitory effect.

Peptic ulcers occur when the attackers associated with the secretion of gastric acid are strong or when the gastrointestinal mucosa is weak. Conventional drugs used for the treatment of peptic ulcers include proton pump inhibitors through the development of antacids, anticholinergic drugs, gastric cell protective drugs, and H ₂ -receptor antagonists. Omeprazole has been developed as a drug for proton pump inhibitors and is currently widely used in the treatment of peptic ulcer patients based on its unique mechanism of action that blocks the final stage of gastric acid production.

However, since omeprazole is an irreversible mechanism of action of proton pump, there is a problem about the possibility of causing side effects by causing gastric acid secretion inhibition in the stomach for a long time, and attempts to develop a reversible proton pump inhibitor to overcome this are actively made. have. For example, imidazopyridine derivatives as reversible proton pump inhibitors are disclosed in WO 98/37080 (AstraZeneca AB), WO 00/17200 (Byk Gulden Lomberg Chem.) And US Pat. No. 4,450,164 (Schering Corporation). It is known. In addition, pyrimidine derivatives are known from European Patent No. 0,775,120 (Yuhan Corp.).

The present inventors have conducted a lot of research to develop a reversible proton pump inhibitor, the novel pyrrolo [2,3-d] pyridazine derivatives have a proton pump inhibitory effect and gastric acid secretion inhibitory ability as well as a reversible proton The present invention has been found to have a mechanism of action of pump suppression effect.

It is an object of the present invention to provide a novel pyrrolo [2,3-d] pyridazine derivative or pharmaceutically acceptable salt thereof having excellent gastric acid secretion inhibitory effect.

It is also an object of the present invention to provide a method for preparing a novel pyrrolo [2,3-d] pyridazine derivative or a pharmaceutically acceptable salt thereof.

It is also an object of the present invention to provide a gastric acid secretion inhibiting composition containing a novel pyrrolo [2,3-d] pyridazine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

In accordance with the above object, the present invention provides a pyrrolo [2,3-d] pyridazine derivative represented by Formula 1 below, or a pharmaceutically acceptable salt thereof.

From above

R ₁ is hydrogen, C _1-5 alkyl, C _2-6 alkenyl, — (CH ₂ ) n C _3-6 cycloalkyl or — (CH ₂ ) n-phenyl (where n is an integer from 0 to 3, Alkyl and phenyl as R ₁ may be substituted with one or more halogens);

R ₂ is hydrogen, C _1-5 alkyl or C _3-6 cycloalkyl; And

R ₃ is hydrogen or halogen.

The compound of formula 1 according to the invention preferably comprises the following compounds:

1-cyclopropyl-2- (2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride;

1,4-dimethyl-2- (2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline Hydrochloride;

3-methyl-2- (2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride;

2- (1-allyl-2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride;

2- (1-cyclopropylmethyl-2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride;

2- (2,3-dimethyl-1- H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride;

1-methyl-2- (2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride;

2- [1- (3-fluorobenzyl) -2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl] -1,2,3,4-tetrahydro Isoquinoline hydrochloride;

2- (1-ethyl-2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride;

2- (2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride

The pyrrolo [2,3-d] pyridazine derivatives represented by Formula 1 of the present invention may be in the form of pharmaceutically acceptable salts, which include non-toxic salts commonly used in the field of anti-ulcers, for example For example, it may be in the form of salts generated from non-toxic inorganic or organic acids. Such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, sulfamic acid, phosphoric acid or nitric acid and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, mal Salts prepared from organic acids such as lonic acid, methanesulfonic acid, tartaric acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid or trifluoroacetic acid And the like. In general, salts may be prepared by reacting an organic base in a stoichiometric amount or in excess of the desired salt-forming inorganic or organic acid with a suitable solvent or various combinations of solvents.

The compound of Formula 1 of the present invention is prepared by reacting a compound of Formula 2 with a compound of Formula 3 to produce a compound of Formula 1a, and then reacting the compound of Formula 1a with R ₁ -X, as shown in Scheme 1 below. can do:

In the above formula

R ₁ , R ₂ and R ₃ are the same as defined above and X represents halogen.

In Scheme 1, the compound of Formula 2 and the compound of Formula 3 may be prepared by applying a known method (WO 95/19980; and WO 94/14795).

In Scheme 1, a compound of Formula 1 may be prepared by reacting a compound of Formula 2 with a compound of Formula 3 under anhydrous polar aprotic solvent conditions. At this time, as a solvent usable, anhydrous N , N -dimethylformamide is preferable, and the reaction temperature is preferably reacted at 80 ° C to 140 ° C. In addition, the compound of Formula 1 may be prepared by heating the compound of Formula 2 with the compound of Formula 3 without using a solvent. The compound of formula 1a can be reacted with R ₁ -X under appropriate base and solvent conditions to produce the compound of formula 1. The base that can be used is preferably a metal salt such as sodium hydride, tert -butoxylated, and the like, and tetrahydrofuran and N , N -dimethylformamide are preferable as the solvent, and the reaction temperature is 40 ° C to 100 ° C. Or reaction at room temperature. A catalytic amount of 18-crown-6-ether may be preferably used for improving the progress rate and yield of the reaction.

The present invention includes a gastric acid secretion inhibiting composition comprising a pyrrolo [2,3-d] pyridazine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier. . The composition according to the invention may comprise excipients such as lactose, corn starch and the like, lubricants such as magnesium stearate, emulsifiers, suspending agents, buffers, isotonic agents and the like which are well known and may be used. Flavoring agents may be included.

The compositions according to the invention can be administered orally or parenterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical administration. That is, the composition according to the present invention may be administered in the form of a tablet or capsule, or as an aqueous solvent or suspension. In the case of oral tablets, carriers commonly used include lactose and corn starch, and lubricants such as magnesium stearate can usually be added. Useful diluents for capsule form may include lactose and dry corn powder. If an aqueous suspension is required for oral use, the active ingredient may include emulsifiers and suspensions. If desired, certain sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, a sterile solution of the active ingredient is usually prepared and may contain a buffer that can suitably adjust the pH of the solution. For intravenous administration, the total concentration of the solute is It may include isotonic agents that can be adjusted to impart isotonicity to the formulation. In addition, the composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier such as saline having a pH of 7.4, and may be locally introduced into the patient's intramuscular blood flow in the form of a solution. have.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, this does not limit the scope of the invention.

Example 1. 1-cyclopropyl-2- (2,3-dimethyl-1 H -Pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride

1-cyclopropyl-1,2,3,4-tetrahydroisoquinoline in 7-chloro-2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazine (777 mg, 4.28 mmol) (2.49 g, 15.4 mmol) was added, and the reaction mixture was warmed at 130 ° C. for 24 hours and then cooled to room temperature. The resulting compound was separated and purified using silica gel column chromatography, dissolved in ethyl acetate (1 ml), cooled to 0 ° C., saturated with hydrochloric acid, and the resulting solid was filtered to yield the title compound (4 mg) as a yellow solid. It was.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.79 0.84 (m, 4H), 1.88 1.92 (m, 1H), 2.19 (s, 3H), 2.66 (s, 3H), 2.90 2.95 (m, 2H), 4.01 4.03 (m, 1H), 4.46 4.49 (m, 1H), 5.47 5.49 (m, 1H), 6.92-7.16 (m, 4H), 8.75 (s, 1H)

Example 2. 1,4-dimethyl-2- (2,3-dimethyl-1 H -Pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride

7-chloro-2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazine (850 mg, 4.68 mmol) and 1,4-dimethyl-1,2,3,4-tetrahydro The title compound (10 mg) was prepared in the same manner as in Example 1 using isoquinoline (2.99 g, 18.5 mmol).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.17 (d, 3H), 1.41 (d, 3H), 2.19 (s, 3H), 2.66 (s, 3H), 3.06 ~ 3.07 (m, 1H), 3.82 ~ 3.85 (m, 1H), 4.34-4.36 (m, 1H), 5.85-5.87 (m, 1H), 7.01-7.13 (m, 4H), 8.71 (s, 1H)

Example 3. 3-methyl-2- (2,3-dimethyl-1 H -Pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride

7-chloro-2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazine (714 mg, 3.93 mmol) and 3-methyl-1,2,3,4-tetrahydroisoquinoline ( 1.85 g, 12.6 mmol) was used to prepare the title compound (5 mg) as a yellow solid in the same manner as in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.80 (d, 3H), 2.12 (s, 3H), 2.64 (s, 3H), 2.75-2.79 (m, 1H), 3.31-3.45 (m, 1H), 3.91 ~ 4.08 (m, 1H), 4.40 ~ 4.49 (m, 1H), 4.70 ~ 4.80 (m, 1H), 6.82 ~ 7.00 (m, 4H), 8.66 (s, 1H)

Example 4. 2- (1-allyl-2,3-dimethyl-1 H -Pyrrolo [2,3-d] pyridazin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride

Step 1: 2- (2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline

7-chloro-2,3-dimethyl- 1H -pyrrolo [2,3-d] pyridazine (1 g, 5.5 mmol) and 1,2,3,4-tetrahydroisoquinoline (1 ml) In the same manner as in Example 1, the title compound (300 mg) was prepared as a yellow solid. This compound was used in the next reaction without further purification.

Step 2: 2- (1-allyl-2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride

2- (2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline (15 mg) prepared in step 1 , 0.053 mmol) was dissolved in tetrahydrofuran (0.5 ml), and then tert -butoxylated potassium (5.9 mg, 0.053 mmol) and 18-crown-6 (2 mg, 5.3 umol) were added and stirred at room temperature for 30 minutes. . Allyl iodide (4.8 ul, 0.053 mmol) was added to the reaction mixture and stirred overnight. The solvent was concentrated under reduced pressure, and the residue was separated and purified using silica gel column chromatography. The obtained compound was dissolved in ethyl acetate (0.5 ml), cooled to 0 ° C., saturated with hydrochloric acid, and the resulting solid was filtered to give a pale yellow solid. Compound (8.4 mg) was prepared.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.22 (s, 3H), 2.77 (s, 3H), 3.15 (t, 2H), 4.23 (t, 3H), 5.02 (m, 1H), 5.10 (s, 2H), 5.21 (d, 2H), 5.51 (d, 1H), 5.55 (d, 1H), 7.20 (m, 4H), 9.04 (s, 1H)

Example 5. 2- (1-cyclopropylmethyl-2,3-dimethyl-1 H -Pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride

Example 4 2- (2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline prepared in step 1 (8 mg, 0.044 mmol) and bromomethylcyclopropane (4.27 ul, 0.044 mmol) were prepared in the same manner as in Step 2 of Example 4, to obtain the title compound (2.1 mg) as a white solid.

¹ H-NMR (400 MHz, MeOD) δ 0.58 (m, 2H), 0.71 (m, 2H), 1.53 (m, 1H), 2.35 (s, 3H), 2.55 (s, 3H), 3.12 (t, 2H ), 4.04 (t, 2H), 4.39 (d, 2H), 4.93 (s, 2H), 7.24 (m, 4H), 9.36 (s, 1H)

Example 6. 2- (2,3-dimethyl-1- H -Pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride

7-chloro-2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazine (30 mg, 0.165 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.5 ml) To obtain the title compound (2.8 mg) in a slightly yellow solid in the same manner as in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.21 (s, 3H) 2.43 (s, 3H), 3.01 (t, 2H), 3.82 (t, 2H), 4.71 (s, 2H), 7.03 (m, 1H ), 7.09 (m, 1H), 8.90 (s, 1H)

Example 7. 2- (2,3-dimethyl-1 H -Pyrrolo [2,3-d] pyridazin-7-yl) -1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride

7-chloro-2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazine (120 mg) and 1-methyl-1,2,3,4-tetrahydroisoquinoline (0.5 ml) To prepare the title compound (9.4 mg) in a slightly yellow solid in the same manner as in Example 1.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.45 (d, 3H) 2.22 (s, 3H), 2.40 (s, 3H), 2.87 (m, 1H), 2.90 (m, 1H), 3.69 (m, 1H ), 4.20 (m, 1H), 5.30 (q, 1H), 7.17 (m, 4H), 8.94 (s, 1H)

Example 8. 2- [1- (3-fluorobenzyl) -2,3-dimethyl-1 H -Pyrrolo [2,3-d] pyridazin-7-yl] -1,2,3,4-tetrahydroisoquinoline hydrochloride

To 1,2-3,4-tetrahydroisoquinoline (1 ml) in 7-chloro-2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazine (1.0 g, 5.5 mmol) Added. The reaction mixture was warmed at 120 ° C. for 2 hours and then cooled to room temperature. Separation and purification using silica gel column chromatography gave 300 mg of a pale brown solid compound. The prepared solid compound (15 mg, 0.053 mmol) was dissolved in tetrahydrofuran (3 ml), tert -butoxypotassium potassium (5.9 mg, 0.053 mmol), 18-crown-6 (2 mg, 5.3 umol) was added thereto, and room temperature. Stir for 30 minutes. 3-fluorobenzyl bromide (6.5 ul, 0.053 mmol) was added to the reaction mixture and stirred overnight at room temperature. The solvent was concentrated under reduced pressure, and the residue was separated and purified using silica gel column chromatography. The obtained compound was dissolved in ethyl acetate (0.5 ml), cooled to 0 ° C. and saturated with hydrochloric acid, and the resulting solid was filtered to give a pale yellow solid. Compound (1.9 mg) was prepared.

¹ H-NMR (400 MHz, MeOD) δ 2.25 (s, 3H), 2.57 (s, 3H), 3.11 (t, 2H), 4.22 (t, 2H), 5.03 (s, 2H), 5.58 (s, 2H ), 7.20 (m, 6H), 7.32 (m, 2H), 8.51 (s, 1H)

Example 9. 2- (1-ethyl-2,3-dimethyl-1 H -Pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride

2- (2,3-Dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoisode prepared in Step 1 of Example 4 The pale yellow title compound (2.6 mg) was prepared in the same manner as Step 2 of Example 4 using quinoline (15 mg, 0.053 mmol) and iodoethane (4.2 ul, 0.053 mmol).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.70 (t, 3H), 2.23 (s, 3H), 2.76 (s, 3H), 3.17 (t, 2H), 4.23 (t, 2H), 4.55 (q, 2H), 5.10 (s, 2H), 7.21 (m, 4H), 8.83 (s, 1H)

Example 10. 2- (2,3-dimethyl-1 H -Pyrrolo [2,3-d] pyridazin-7-yl) -7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride

7-chloro-2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazine (30 mg, 0.165 mmol) and 7-methyl-1,2,3,4-tetrahydroisoquinoline ( 0.3 ml) was used to prepare the title compound (1.8 mg) as a pale yellow solid in the same manner as in Example 1.

¹ H-NMR (400 MHz, MeOD) δ 2.35 (s, 3H), 2.56 (s, 3H), 3.13 (t, 2H), 4.03 (t, 2H), 4.93 (s, 2H), 7.24 (m, 3H ), 9.15 (s, 1 H)

Test Example 1. Proton Pump (H ⁺ / K ⁺ -ATPase) inhibitory effect

1-1. Preparation of Proton Pump Enzyme Sources

After killing pigs, the stomachs were removed, gastric lining cells were taken using a glass plate, and the cells were homogenized with a homogenizer on 0.25M sucrose buffer. The homogenate was centrifuged at 8,000 rpm for 35 minutes, and the supernatant was again centrifuged at 25,000 rpm for 1 hour and 15 minutes at high speed, and the pellet obtained was homogenized again in sucrose buffer. After placing on a% Picol solution tube, ultra-high centrifugation was again performed for 3 hours and 15 minutes. After centrifugation, only the intermediate layer containing the proton pump was taken and ultrafast centrifugation was carried out for 40 minutes to obtain a precipitate, which was suspended in 5 mM hippies-tris buffer solution at pH 6.1, and then aliquoted into tubes by 1 ml and freeze-dried. (-70 ° C) was stored. This microsome was used as an enzyme source for performing an in vitro enzyme reaction assay of a proton pump.

1-2. Determination of Proton Pump

The inhibitory effect of proton pump activity on the compounds of the present invention was determined by enzymatic reaction on 96 well plates. That is the magnesium ion-stimulated activity as (Mg ⁺⁺⁾ in the activity of the negative control group, magnesium (Mg ⁺⁺⁾ and proton pump with the difference between them to the activity of the positive stimulating activity as a potassium ion (K ⁺⁾ control group It was used as the activity of. On 96-well plates, 1% dimethyl sulfoxide soluble compound was added to the negative control group (Group 1) and positive control group (Group 2), and the compound prepared at 5 concentrations in the test substance administration group (Group 3). Was treated to measure the activity inhibitory power.

Enzyme reaction was conducted by calculating all concentrations in the final volume of 100 μl. The enzyme was stored on ice until use and the reaction was performed at room temperature. The third group was treated with 10 [mu] l each so that the final concentration of dimethyl sulfoxide was 1% at 5 concentrations, and 10 [mu] l of buffer containing 10% dimethylsulfoxide was treated for the first and second groups. It was. Enzyme stored on ice was treated to enter 5 μg of each reaction in a volume of 30 μl in all wells, followed by mixing at 1000 rpm for 1 minute using a plate shaker, and then reacting at room temperature for 5 minutes. The group 1 buffer was then treated with 30 μl volume into the negative control on 96 wells and all wells were treated with 30 μl of group 2 buffer. Treatment of ATP as a substrate was treated with 30 μl so that the final concentration was 0.5 mM, mixed using a shaker, and the reaction was performed at 37 ° C. for 30 minutes. After completion of the reaction, all wells were treated with 100 μl of the coloring reagent, and then mixed using a shaker, and then absorbance was measured at a wavelength of 620 nm to measure proton pump activity in each test group.

The difference between the measured values of the first group and the second group was taken as the activity of the K ⁺ specific proton pump, and based on this value, the inhibition of the proton pump activity at each compound concentration of the third group was calculated as a% value. . The percent inhibition value of each of the five concentrations in Group 3 with respect to activity was tested using the Litchfield-Wilcoxon assay ( J. Pharmacol. Exp. Ther . (1949) 96, 99). The IC ₅₀ value of the material was calculated. The results are shown in Table 1.

Example IC ₅₀ (uM) One 1.02 2 1.41 3 1.47 4 1.0 5 3.6 6 2.51 7 2.32 10 0.84

From the results of Table 1, the compound of Chemical Formula 1 according to the present invention was confirmed to have an excellent inhibitory effect on the proton pump.

Test Example 2 Inhibition Effect of Basic Gastric Acid Secretion

The inhibitory effect of basal gastric acid secretion was tested according to Shay's rat model (Shay, H., et al., (1945) Gastroenterology 5, 43-61). 200 ± 10 g of Sprague-Dawley male rats were divided into three groups (n = 5) and fasted with water for 24 hours.The first group was treated with 0.5% aqueous methylcellulose solution as a control. It was administered orally at 1.0 mL / 200 g. In the second group, the compound of Formula 1 of the present invention was diluted with 0.5% aqueous solution of methyl cellulose to a concentration of 10 mg / kg, and then orally administered to rats.

One hour after compound administration, rats were anesthetized with ether and the abdominal cavity was dissected to ligation the pyloric region. Immediately after the ligation, the abdominal cavity was sutured again, and after 5 hours, it was lethal by cervical dislocation and the stomach was extracted to receive gastric juice. The obtained gastric juice was centrifuged at 1,000 × g for 10 minutes to remove the precipitate, and then the amount of gastric juice (ml) and the volume of 0.01N-NaOH (ueq / ml) required for titration of the gastric juice to pH 7.0 were measured. From the results, the total amount of gastric acid secreted for 5 hours (ueq / 5hr, volume of gastric juice x volume of 0.01N-NaOH spent for titration) was calculated. Gastric acid secretion inhibition (%) was calculated by the following formula, and as a result, the compound of Example 5 exhibited 49.5% inhibition.

[expression]

Gastric acid secretion inhibitory power of test compound

= (Total Gastric Acid of Group 1-Total Gastric Acid of Group 2) / (Total Gastric Acid of Group 1) × 100

Test Example 3 Reversibility Test

3-1. Preparation of gastric vesicles

Gastrointestinal vesicles can be obtained by Saccomani et al. (Saccomani G, Stewart HB, Shqw D, Lewin M and Sachs G, Characterization of gastric mucosal membranes.IX. .... zonal centrifugation and free -flow electrophoresis technique Biochem Biophy Acta (BBA) - separated from the top of a pig was prepared in accordance with the Biomembranes 465, 311-330, 1977.). The prepared gastrointestinal vesicles were stored at −70 ° C. in lyophilized vesicles. The prepared vesicle protein was quantified according to the Bradford method using bovine serum albumin as a comparative reference (Bradford MM, A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein- dye binding.Anal Biochem . 72, 248-254, 1976)

3-2. Reversible Suppression Test

Chan et al. (Chan KM, Delfert D, and and Chan), which can measure the amount of free inorganic phosphoric acid using lyophilized vesicles prepared and separated in the concentration of a compound having a 50% inhibitory power in a proton pump. Junger KD, A direct colorimetric assay for Ca ²⁺ -stimulated ATPase activity.Anal Biochem , 157, 375-380, 1986). The inhibitory mechanism for the proton pump of the compound of Formula 1 of the present invention is washout method such as Beil (Beil W, Staar U, and Sewing KF, Substituted thieno [3,4-d] imidazoles, a novel group of H + / K (+)-ATPase inhibitors.Differentiation of their inhibition characteristics from those of omeprazole.Eur . J. Pharmacol., 187, 455-67, 1990). After separating the compound treated group and the compound untreated group at about 50% proton pump inhibition concentration, both were prereacted for 5 minutes at room temperature in 5 mM Pipes / Tris buffer, followed by 2 mM MgCl ₂ , 50 mM KCl, 2.5 uM Valinomycin and The reaction was performed at 37 ° C. for 30 minutes by treatment with 0.5 mM ATP. The activity of the proton pump was measured according to the color search method, and ultrafast centrifugation was performed at 100,000 × g. After 1 hour, the supernatant of the pelleted vesicles was washed with new compound without addition of the compound (washout), pre-reacted for 5 minutes at room temperature, and reacted for 30 minutes at 37 ° C under the same conditions. The activity of the proton pump was evaluated. As a result, the proton pump showed about 50% of the activity by the test substance before the washout, but after the washout, the compound was restored to the untreated group level, and thus, the compound of formula 1 of the present invention showed a reversible inhibitory mechanism.

The pyrrolo [2,3-d] pyridazine derivatives of the general formula (1) of the present invention have an excellent proton pump inhibitory effect, an excellent gastric acid secretion inhibitory effect, and a reversible proton pump inhibitory effect.

Claims (5)

Pyrrolo [2,3-d] pyridazine derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof: Formula 1

From above R ₁ is hydrogen, C _1-5 alkyl, C _2-6 alkenyl, — (CH ₂ ) n C _3-6 cycloalkyl or — (CH ₂ ) n-phenyl (where n is an integer from 0 to 3, Alkyl and phenyl as R ₁ may be substituted with one or more halogens); R ₂ is hydrogen, C _1-5 alkyl or C _3-6 cycloalkyl; And R ₃ is hydrogen or halogen. The method of claim 1, R ₁ is hydrogen, C _1-5 alkyl, C _2-6 alkenyl; -(CH ₂ ) -C _3-6 cycloalkyl or-(CH ₂ ) -phenyl, wherein alkyl and phenyl as R ₁ may be substituted with one or more halogens; R ₂ is hydrogen, methyl or cyclopropyl; And R ₃ is hydrogen or halogen, a pyrrolo [2,3-d] pyridazine derivative represented by formula (1) or a pharmaceutically acceptable salt thereof. The method of claim 1, 1-cyclopropyl-2- (2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride; 1,4-dimethyl-2- (2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride ; 3-methyl-2- (2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride; 2- (1-allyl-2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride; 2- (1-cyclopropylmethyl-2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride; 2- (2,3-dimethyl-1- H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydro isoquinoline hydrochloride; 1-methyl-2- (2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride; 2- [1- (3-fluorobenzyl) -2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl] -1,2,3,4-tetrahydro Isoquinoline hydrochloride; 2- (1-ethyl-2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -1,2,3,4-tetrahydroisoquinoline hydrochloride; 2- (2,3-dimethyl-1 H -pyrrolo [2,3-d] pyridazin-7-yl) -7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride A pyrrolo [2,3-d] pyridazine derivative represented by formula (1) selected from the group consisting of or a pharmaceutically acceptable salt thereof. A method of preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof by reacting a compound of Formula 2 with a compound of Formula 3 and then reacting a compound of Formula 1a with R ₁ -X:

From above R ₁ , R ₂ and R ₃ are the same as defined in claim 1 above, X represents halogen.  Gastric acid secretion inhibitor composition comprising a pyrrolo [2,3-d] pyridazine derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:

From above R ₁ , R ₂ and R ₃ are the same as defined in claim 1.