JP2001039874A - Prophylactic and therapeutic agent for pulmonary hypeptension - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject prophylactic and therapeutic agent applicable for pulmonary hypertension by including a known compound having antagonism for angiotensin II receptor and applicable for hypertension or the like. SOLUTION: This agent is obtained by including a quinoline compound of the formula (R1 is a lower alkyl or the like; R2 and R3 are each H, a halogen, a lower alkyl or the like; R4 is H, a halogen or the like; R5 is H, a haloyen, COOH or the like; R6 is COOH or the like; R7 and R8 are each H, a halogen, a lower alkyl or the like; X and Y are each C, H or N) or pharmaceutically acceptable salt of the compound as the effective component. The quinoline compound of the formula is preferably N- 2- 6-[(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b]-pyridin-3-yl)methyl]quinolin-2-yl}phenyl)trifluoromethane sulfonamide. The average single dosage of the compound of the formula as active ingradient is 0.05-300 mg/dose for prophylaxis or therapeutics of pulmonary hypertension.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a prophylactic / therapeutic agent for pulmonary hypertension containing a specific quinoline compound as an active ingredient.

[0002]

2. Description of the Related Art Pulmonary hypertension is a generic name of cases in which pulmonary arterial pressure exhibits an abnormally high value (average pressure of 25 mmHg or more), and most of them are secondary to various cardiopulmonary diseases. The increase in pulmonary artery pressure is caused by an increase in resistance of the pulmonary vascular bed to blood flow, and it has been reported that the causes include organic factors and functional factors.

[0003] The applicant has previously reported that the quinoline compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof used in the present invention has an angiotensin II receptor antagonistic effect and is useful for hypertension and the like. It is reported that it can be applied (JP-A-6-80664, JP-A-8-73458). However, hypertension and pulmonary hypertension have different onset mechanisms,
It is the current clinical situation that drugs applicable to hypertension are not necessarily useful for pulmonary hypertension as well.

The above quinoline compounds have been applied to muscle tissue degeneration / cardiomyopathy (WO 98/085).
No. 14), but there is no suggestion of any relationship between these uses and pulmonary hypertension.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide an agent for preventing and treating pulmonary hypertension.

[0006]

Means for Solving the Problems The present inventors have further studied in view of the above circumstances, and as a result, have found that a specific quinoline compound or a pharmaceutically acceptable salt thereof can be applied to pulmonary hypertension. We have completed the present invention. That is, the present invention is as follows. (1) General formula (I):

[0007]

Embedded image

[In the general formula (I), R¹~ R⁸Is also
Is shown. R¹: Lower alkyl group, halo lower alkyl group, lower cycle
Loalkyl group, alkenyl group, alkoxyl group, alcohol
A xy lower alkyl group or an alkylthio group. R^Two, R^Three: Both may be the same or different, it
Each independently a hydrogen atom, a halogen atom, a lower alkyl
Group, halo-lower alkyl group, lower cycloalkyl group,
Kenyl group, alkoxyl group, -C_mF_{2m + 1},-(C
H_Two)_nR⁹, Or-(CH_Two)_PCOR^Ten. R^Four: Hydrogen atom, halogen atom, lower alkyl group, al
Coxyl group, or -C _mF_{2m + 1}. R^Five: Hydrogen atom, halogen atom, -COOH, -COO
R¹¹, -CONH_TwoOr -CN. R⁶: -COOH, -COOR¹², -CONH_Two, -C
N, -NHSO_TwoCF_ThreeOr a C-bonded tetrazolyl group. R⁷, R⁸: Both may be the same or different, it
Each independently a hydrogen atom, a halogen atom, a lower alkyl
Group, alkoxyl group, or -C_mF_{2m + 1}. X, Y: Both may be the same or different,
Independently, a CH or nitrogen atom. However, the above R⁹~ R¹², And m, n, p are
Show things. R⁹: Hydroxyl group or alkoxyl group. R^Ten: Hydrogen atom, hydroxyl group, lower alkyl group,
Or an alkoxyl group. R¹¹, R¹²: Both may be the same or different, it
Each independently represents a lower alkyl group, an alkenyl group, a lower
Chloroalkyl, aryl, or aralkyl groups. m: an integer from 1 to 6. n: an integer from 1 to 4. p: integer of 0 to 4
number. Or a pharmaceutically acceptable compound thereof.
For preventing and treating pulmonary hypertension containing salt as active ingredient
Agent. (2) The quinoline compound represented by the general formula (I) is N-
{2-} 6-[(2-ethyl-5,7-dimethyl-3H
-Imidazo [4,5-b] pyridin-3-yl) methyl
Ru] quinolin-2-yl {phenyl} trifluorometa
And pulmonary hypertension according to (1),
Remedies.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The general formula (I) used in the present invention
As a pharmaceutically acceptable salt of the quinoline compound represented by the formula, there is an acid addition salt derived from the quinoline compound and an inorganic acid or an organic acid. Such salts include, for example, hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, oxalate, tartrate, citrate, maleic acid Salts, fumarate, succinate, lactate, glutarate, acetate, trifluoroacetate, salts of various amino acids and the like.

The pharmaceutically acceptable salt of the quinoline compound represented by the general formula (I) includes a salt formed from the quinoline compound and a base. Such salts include, for example, those formed from alkali metals (eg, sodium, potassium), alkaline earth metals (eg, calcium, magnesium), ammonium and substituted ammonium (eg, dimethylammonium, triethylammonium), and the like.

In the above description and the following description of the present invention, the term "lower" refers to a group having 1 carbon atom unless otherwise specified.
Means six. The “lower alkyl group” may be linear or branched, and suitable examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, Hexyl group and the like. “Halo lower alkyl group” is a lower alkyl group substituted with halogen, and suitable examples thereof include a chloromethyl group, a 2-chloroethyl group, a bromomethyl group, a 2-bromoethyl group, and a 1,2-dichloroethyl group. , 1,2-dibromoethyl group, trifluoromethyl group, 3-trifluoropropyl group and the like. "Lower cycloalkyl group" refers to a cycloalkyl group having 3 to 6 carbon atoms constituting a ring, and suitable examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like. .

The "alkenyl group" is preferably a lower alkenyl group having 2 to 6 carbon atoms, more preferably a linear or branched alkenyl group having 2 to 4 carbon atoms. Is a vinyl group, an allyl group,
Examples thereof include a 1-propenyl group, an isopropenyl group, and a 1-butenyl group. As the “alkoxyl group”, a lower alkoxyl group is preferred, and more preferably a lower alkoxyl group.
4 to 4 linear or branched alkoxyl groups;
Suitable examples include methoxy, ethoxy, propoxy, butoxy and the like. As the "alkoxy lower alkyl group", those in which the alkoxyl group portion is a lower alkoxyl group are preferable, more preferably a straight-chain or branched alkoxyl group having 1 to 4 carbon atoms. Methoxyethyl group, 3-methoxypropyl group, 2-ethoxyethyl group and the like. As the “alkylthio group”, a lower alkylthio group is preferred, and more preferably a C 1 -C 1 alkylthio group.
4 is a linear or branched alkylthio group, and suitable examples thereof include a methylthio group, an ethylthio group, a propylthio group, and a butylthio group.

Further, in the above description and the following description of the present invention, “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The “aryl group” refers to a monovalent aromatic hydrocarbon group, which may have a substituent (for example, a lower alkyl group, a halogen atom, a lower alkoxyl group, a lower alkylamino group, and the like), preferably A phenyl group or a derivative thereof, for example, a phenyl group, a tolyl group, a p-halophenyl group (eg, a p-chlorophenyl group, a p-bromophenyl group, etc.), an alkoxyphenyl group (eg, a methoxyphenyl group, an ethoxyphenyl group, etc.) ), A dialkylaminophenyl group (eg, a dimethylaminophenyl group, a diethylaminophenyl group, and the like). Also,
The “aralkyl group” refers to an aryl group-substituted alkyl group, and examples of the aryl group as the substituent include those described above. The alkyl group preferably has 1 to 4 carbon atoms. Suitable examples thereof include a benzyl group, a benzhydryl group, a trityl group, a phenethyl group and the like.

The quinoline compound represented by the general formula (I)
Among them, preferred is R¹Is a lower alkyl group or
A phenyl group;^TwoAnd R^ThreeAre the same or different
Well, each independently, hydrogen atom, halogen atom, low
Lower alkyl group,-(CH_Two) _nR⁹, Or-(C
H_Two)_PCOR^Ten(Where R⁹Is hydroxyl
Group or alkoxyl group, R^TenIs a hydrogen atom, hydroxy
Or an alkoxyl group, n is an integer of 1 to 4, p is
An integer from 0 to 4);^FourIs a hydrogen atom,
R^FiveIs a hydrogen atom, a halogen atom, -COOH, or-
COOR¹¹(R¹¹Is lower alkyl, alkenyl, lower
Primary cycloalkyl, aryl, or aralkyl
Is a group) and R⁶Is -COOH, -COOR
¹²(R¹²Is lower alkyl, alkenyl, lower cyclo
An alkyl, aryl, or aralkyl group
), -NHSO_TwoCF_ThreeOr C-bonded tetrazolyl
And R is ⁷And R⁸May be the same or different,
Each independently represents a hydrogen atom, a fluorine atom, a chlorine atom,
X is a lower alkyl group or an alkoxyl group;
It is a compound which is an element atom and Y is CH.

More preferably, among the quinoline compounds represented by the general formula (I), R ¹ is a lower alkyl group, and R ² and R ³ may be the same or different. hydrogen atom, a lower alkyl group, - (CH _2)
n R ⁹ , or — (CH ₂ ) _P COR ¹⁰ (where R ⁹ is a hydroxyl group, R ¹⁰ is a hydrogen atom, a hydroxyl group, or an alkoxyl group, n is 1, p is 0 or 1) , R ⁴ is a hydrogen atom, an R ⁵ is a hydrogen atom or a chlorine atom,, R ⁶ is -COOH, -C
OOR ¹² (where R ¹² is a lower alkyl group, an alkenyl group, a lower cycloalkyl group, an aryl group, or an aralkyl group), —NHSO ₂ CF ₃ , or C
The bonding tetrazolyl group, R ⁷ and R ⁸ may be the same or different and are each independently a hydrogen atom, a fluorine atom, a chlorine atom, or a lower alkyl group, X is a nitrogen atom, and Y is CH A certain compound.

The most preferred quinoline compound in terms of the effect of preventing and treating pulmonary hypertension is a compound represented by the following formula (II): N- {2-} 6-[(2-ethyl-
5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl {phenyl} trifluoromethanesulfonamide and its pharmaceutically acceptable salts.

[0017]

Embedded image

The quinoline compound represented by the general formula (I) used in the present invention is a known compound,
For example, it can be manufactured by the method described in JP-A-6-80664.

The prophylactic / therapeutic agent for pulmonary hypertension of the present invention contains a quinoline compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. The quinoline compound represented by the general formula (I) used in the present invention can be advantageously used for the prevention and treatment of pulmonary hypertension and various diseases accompanying it, as is apparent from the experimental examples described later. Moreover, the quinoline compound is effective as a medicament because it has low toxicity and further excellent properties such as absorption, stability, and sustainability.

The prophylactic / therapeutic agent for pulmonary hypertension of the present invention can be prepared in the form of tablets, granules, capsules,
It is formulated into a solid form such as a powder or a liquid form such as a liquid, suspension, syrup, emulsion, lemonade or the like into a form suitable for oral administration, parenteral administration or external use, and used as a pharmaceutical preparation. If necessary, auxiliaries, stabilizers, wetting agents and other conventional additives can be added to the above-mentioned preparations, such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, clay, sucrose, corn starch, talc, gelatin, agar. Pectin, peanut oil, olive oil, cocoa oil, ethylene glycol and the like.

The above-mentioned preparation contains an effective amount of a quinoline compound represented by the formula (I) for prevention and treatment of pulmonary hypertension. The dose varies depending on the route of administration, the type of disease, the condition of the patient, the weight or age, and also varies depending on the type of drug to be applied.
Generally, an amount of about 0.01 mg to 500 mg per day or more may be administered per patient. The average amount of the compound contained as an active ingredient is
A dose of about 0.05 to 300 mg may be used for prevention and treatment of pulmonary hypertension.

Hereinafter, the present invention will be described more specifically with reference to examples and experimental examples, but the present invention is not limited to these examples.

[0023]

EXAMPLES Reference Example N- {2-} 6-[(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b]
Preparation of pyridin-3-yl) methyl] quinolin-2-yl {phenyl} trifluoromethanesulfonamide 2- {6-[(2-ethyl-5,7-dimethyl-3H-
Imidazo [4,5-b] pyridin-3-yl) methyl
Quinolin-2-yl dianiline (8.73 g, 21.4
mmol), triethylamine (6.0 ml, 42.8).
mmol) and chloroform (87 ml) were mixed and stirred, and a solution of trifluoromethanesulfonic anhydride (3.6 ml, 21.4 mmol) in chloroform (36 ml) was added dropwise over 50 minutes while cooling in an ice bath. After stirring for 10 minutes, 2M acetic acid (123 ml) was added dropwise under ice cooling. Separate the mixture, and separate the organic layer with ion-exchanged water (123 ml).
The mixture was washed once with 2% aqueous sodium bicarbonate (123 ml) and once with ion-exchanged water (123 ml) to obtain crude N- {2-} 6.
A chloroform solution of-[(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl {phenyl} trifluoromethanesulfonamide was obtained. 60 ml of ethanol was added to this solution, and the solution was heated to a bath temperature of 90 to 115 ° C.
ml were distilled off. The mixture was allowed to stand at 0 ° C. overnight, and the precipitated crystals were collected by filtration. After washing three times with ethanol (10 ml), it was dried under reduced pressure. 8.3 out of 8.48 g of the obtained crystals
6 g was taken, ethyl acetate (425 ml) and ethanol (175 ml) were added and heated, and 325 ml was distilled off. The mixture was allowed to stand at room temperature, and the precipitated crystals were collected by filtration. After washing three times with ethanol (10 ml), the crystals were dried under reduced pressure to obtain 6.36 g of crystals. Repeat this recrystallization operation,
N- {2-} 6-[(2-ethyl-5,7-dimethyl-
5.52 g of yellow crystals of 3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl {phenyl} trifluoromethanesulfonamide were obtained. Melting point 252.0 ° C.

¹ H-NMR (400 MHz, CDC
l ₃ ) δ (ppm): 8.22 (d, J = 9.2H)
z, 1H); 7.99-8.05 (m, 3H); 7.8
4 (d, J = 8.0 Hz, 1H); 7.69 (dd, J
= 8.6, 1.4 Hz, 1H); 7.48 (t, J =
7.2Hz, 1H); 7.43 (s, 1H); 7.29
(T, J = 8.0 Hz, 1H); 6.94 (s, 1
H); 5.67 (s, 2H); 2.82 (q, J = 7.
2.67 (s, 3H); 2.60
(S, 3H); 1.34 (t, J = 7.6 Hz, 3
H). ¹⁹ F-NMR (400 MHz, CDCl ₃ ) δ (pp
m): -77.183

In the following description, N- {2-} 6-
[(2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridin-3-yl) methyl] quinolin-2-yl {phenyl} trifluoromethanesulfonamide is abbreviated as Compound A.

EXPERIMENTAL EXAMPLE 1 Effect of Monocrotaline on Pulmonary Hypertension Model Preparation of Sample: Monocrotaline was 360 mg in 1 M hydrochloric acid
/3.6 ml, and then neutralized with 1 M sodium hydroxide and further diluted to 10 mg / ml with distilled water. Only a solvent containing no monocrotaline is referred to as a solvent a. After dissolving 3 mg of Compound A in 100 μl of 99.5% ethanol and 100 μl of 2M sodium carbonate, the total volume is made up to 30 ml with distilled water, and then 1 ml with distilled water.
Diluted 0-fold. Solvent b containing only a solvent not containing compound A
And SD male rats (weight: 214-234g)
, Monocrotaline (60 mg / kg body weight) was administered subcutaneously in the posterior neck. From the day after monocrotaline administration, Compound A was orally administered once daily at a dose of 0.1 mg / kg body weight for 20 days. The day after the final administration of Compound A, the rat was fixed in a dorsal position under anesthesia by intraperitoneal administration of Nembutal, and a blood pressure was measured by inserting a catheter into the left femoral artery. Thereafter, a pressure transducer was connected.
A 23G needle was punctured from the right chest into the right ventricle and right ventricular systolic pressure was measured. After sacrifice of the animals, the hearts were removed and the right ventricle weight and right ventricle / (left ventricle + septum) weight ratio were measured. In addition, rats to which monocrotaline was administered were treated with only solvent b at 10 ml / kg body weight according to the same administration schedule as above, and were referred to as “solvent administration group (= pathological group)”. A rat treated with only solvent a at 6 ml / kg body weight and a solvent b alone with 10 ml / kg body weight in the same administration schedule as above was designated as “monocrotaline-untreated rat (= normal rat)”. . Table 1 shows the results
Shown in

[0027]

[Table 1]

Right ventricular systolic pressure and right ventricle / (left ventricle +
The septum) weight ratio was subjected to student's t-test.
A significant difference was shown at P <0.05. In addition, when a student's t-test was performed on the right ventricle weight, the compound A administration group showed a significant difference at P <0.01 from the solvent administration group. From these results, Compound A was effective against pulmonary hypertension in a monocrotaline-pulmonary hypertension model because it suppressed the increase in right ventricular pressure and hypertrophy of the right ventricular myocardium without affecting blood pressure. Yes,
In particular, it was confirmed that a preventive effect was observed.

Experimental Example 2 Prognostic improvement effect Preparation of sample: Compound A (3 mg) was dissolved in 99.5% ethanol (100 μl) and 2 M sodium carbonate (100 μl), and the total volume was made up to 10 ml with distilled water. Further, a solution obtained by diluting this solution 10 times with distilled water was used for 0.3 mg / kg body weight administration. The diluted solution was further added to a solvent (99.5%
300 μl of ethanol and 300 of 2M sodium carbonate
μl was made up to 300 ml with distilled water. Hereinafter, it is referred to as a solvent c. ) Was diluted 3-fold with 0.1 mg /
It was used for kg body weight administration. Similarly, a dilution of the above diluent 10-fold with solvent c was used for administration of 0.03 mg / kg body weight. SD male rats (body weight 208-252g)
Monocrotaline (60 mg / kg body weight) was subcutaneously administered to the back of the mouse and left for 14 days to prepare a pulmonary hypertension model. These model rats were divided into four groups of 10 rats each, one group containing only solvent c at a dose of 10 ml / kg body weight, and the remaining three groups containing compound A (containing prepared sample).
Are 0.03 mg / kg body weight and 0.1 mg / k, respectively.
Oral administration was repeated once daily for 4 weeks at a dose of 0.3 mg / kg body weight. The survival status of the rats in each group immediately after the final administration of compound A or the solvent was observed. Table 2 shows the results.

[0030]

[Table 2]

The survival rate was measured by a generalized Wilcoxon test in which the multiplicity was adjusted by the Hommel method.
In the group administered with / kg body weight and the group administered with 0.1 mg / kg body weight, the risk was significantly increased at less than 5% (p <0.05). Similarly, the group administered with 0.3 mg / kg body weight significantly increased with a risk factor of less than 1% (p <0.01).
In the monocrotaline pulmonary hypertension model, the effect of improving the prognosis by administration of Compound A was observed.
Was confirmed to be effective for pulmonary hypertension.

EXPERIMENTAL EXAMPLE 3 Toxicity No toxicity was observed in male SD rats when compound A was repeatedly orally administered at a dose of 0.3 mg / kg body weight for 4 weeks.

Formulation Example 1 Tablets 1) Compound A 10.0 mg 2) Fine granules No. 209 (manufactured by Fuji Chemical Co., Ltd.) 46.6 mg sodium aluminate metasilicate 20 wt% corn starch 30 wt% lactose 50 wt% 3) crystalline cellulose 24.0 mg 4) carboxymethyl cellulose calcium 4.0 mg 5) magnesium stearate 0.4 mg 1) Each of 3) and 4) is passed through a 100 mesh sieve in advance. After drying 1), 3), 4) and 2) to reduce the water content to a certain level, they are mixed at the above weight ratio using a mixer. 5) is added to the mixed powder having uniform quality and mixed for a short time (30 seconds). The mixed powder is tableted (punch: 6.3 mmφ, 6.0 mmR), and one tablet is obtained.
5 mg tablets were obtained.

The tablet may be coated with a commonly used gastrosoluble film coating agent (for example, polyvinyl acetal diethylaminoacetate) or an edible coloring agent, if necessary.

Formulation Formulation Example 2 Capsules 1) Compound A 50 g 2) Lactose 935 g 3) Magnesium stearate 15 g After weighing each of the above components, they were mixed uniformly, and 200 mg of the mixed powder was filled into hard gelatin capsules.

Formulation Example 3 Injection 1) Compound A 5 mg 2) Sucrose 100 mg 3) Physiological saline 10 ml After filtering the above mixture through a membrane filter, sterilization filtration is performed again, and the filtrate is aseptically vialed. After filling with nitrogen gas, the solution was sealed to give an intravenous injection.

[0037]

According to the present invention, it is possible to provide a medicine having an excellent preventive and therapeutic effect on pulmonary hypertension and low toxicity in a medical setting.

Continued on the front page (72) Inventor Kazutaka Hayashi 2- 25-1, Shodai Otani, Hirakata City, Osaka Yoshitomi Pharmaceutical Co., Ltd. Inside the Drug Discovery Research Laboratory (72) Inventor Hideaki Kido 955 Komatsuri, Yoshitomi-cho, Chikugami-gun, Fukuoka Prefecture Yoshitomi Pharmaceutical Co., Ltd. Development Laboratory (72) Inventor Hiroshi Shinyama 2- 25-1, Shodai Otani, Hirakata City, Osaka Prefecture Yoshitomi Pharmaceutical Co., Ltd. Drug Discovery Laboratory F-term (reference) 4C065 AA04 BB06 CC01 DD03 EE02 HH02 JJ01 KK02 LL01 PP12 4C086 AA01 AA02 CB05 MA01 MA04 NA14 ZA42 ZA59 ZC42

Claims (2)

[Claims] 1. A compound of the general formula (I):[In the general formula (I), R¹~ R⁸Indicates the following. R¹: Lower alkyl group, halo lower alkyl group, lower cycle
Loalkyl group, alkenyl group, alkoxyl group, alcohol
A xy lower alkyl group or an alkylthio group. R^Two, R^Three: Both may be the same or different, it
Each independently a hydrogen atom, a halogen atom, a lower alkyl
Group, halo-lower alkyl group, lower cycloalkyl group,
Kenyl group, alkoxyl group, -C_mF_{2m + 1},-(C
H_Two)_nR⁹, Or-(CH_Two)_PCOR^Ten. R^Four: Hydrogen atom, halogen atom, lower alkyl group, al
Coxyl group, or -C _mF_{2m + 1}. R^Five: Hydrogen atom, halogen atom, -COOH, -COO
R¹¹, -CONH_TwoOr -CN. R⁶: -COOH, -COOR¹², -CONH_Two, -C
N, -NHSO_TwoCF_ThreeOr a C-bonded tetrazolyl group. R⁷, R⁸: Both may be the same or different, it
Each independently a hydrogen atom, a halogen atom, a lower alkyl
Group, alkoxyl group, or -C_mF_{2m + 1}. X, Y: Both may be the same or different,
Independently, a CH or nitrogen atom. However, the above R⁹~ R¹², And m, n, p are
Show things. R⁹: Hydroxyl group or alkoxyl group. R^Ten: Hydrogen atom, hydroxyl group, lower alkyl group,
Or an alkoxyl group. R¹¹, R¹²: Both may be the same or different, it
Each independently represents a lower alkyl group, an alkenyl group, a lower
Chloroalkyl, aryl, or aralkyl groups. m: an integer from 1 to 6. n: an integer from 1 to 4. p: integer of 0 to 4
number. Or a pharmaceutically acceptable compound thereof.
For preventing and treating pulmonary hypertension containing salt as active ingredient
Agent. 2. The quinoline compound represented by the general formula (I) is N- {2-} 6-[(2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine-3. -Ill)
2. The preventive and therapeutic agent for pulmonary hypertension according to claim 1, which is [methyl] quinolin-2-yl {phenyl} trifluoromethanesulfonamide.