JPH01500270A - 5-hetero- or aryl-substituted-imidazo[2,1-a]isoquinolines - Google Patents

Abstract

Compounds of formula I <CHEM> wherein each R independently is hydrogen or methyl R1 is in 8- or 9-position and represents hydrogen, chloro, fluoro or C 1-3alkyl and R2 represents thienyl, furyl or <CHEM> wherein each Ro represents independently hydrogen, fluoro, chloro, C 1-10alkyl, C 1-10alkoxy or C 1-10alkylthio or one Ro is hydrogen and the other represents tri-(C 1-3alkyl)silyl, trifluoromethyl, phenyl, monochlorophenyl, monofluorophenyl, <CHEM> wherein X, Y, R3, R3' or R4 are as defined herein or two Ro's on adjacent carbon atoms form methylenedioxy. The compounds are indicated for use in treating PAF-mediated bronchocontriction and extravasation

Description

[Detailed description of the invention] 5-hetero-malco is an aryl-substituted imidazo[2,1-a]yne quinolines The present invention provides certain 5-hetero- or aryl-substituted-imidazo[2, 1-a] Inquinolines and platelet activating factor (PAF) receptor antagonists (re concerning their use as ceptor antagonists) be. The present invention also relates to pharmaceutical compositions containing the above compounds as active ingredients. and PAF-mediated bronchial stenosis (PAF mediated br onchoconstri, ction) and extravasati The present invention also relates to a method of using the composition for inhibiting the use of the present invention. Furthermore, the book The invention also relates to the use of a selected group of said compounds as anti-tumor agents. Ru.

U.S. Patent No. 3,887.566 provides analgesic, anti-inflammatory, and anti-bacteriological properties. , certain 2゜3-dihydroimidas exhibiting anti-viral and cardiovascular properties. Discloses zo-isoquinolines. U.S. Patent 4°too, 165, 5-position Certain 5-hydrocarbons containing a pyridyl, chenyl, or furyl ring xy-2,3,5,6-titrahydrofuran-imidazo[2,1-a]isoxy discloses the Norrins, which compounds are useful as anorectic agents and antilayer agents. Ru. U.S. Pat. No. 4,101,553 discloses that the Certain 5-hydroxy-2,3,5,6-titrahydrides containing a lyl group discloses lofuran-imidazo[2,1-a]isoquinolines, and the compounds is useful as an anorectic and an anticoagulant.

The essence of the invention is that certain 5-hetero- or aryl-substituted-imidazo [2,1-a] Inquinolines are useful as PAF receptor antagonists. the discovery that a selected group of them are useful as anti-tumor agents.

Accordingly, in one aspect, the present invention provides methods for inhibiting PAF-mediated bronchial stenosis and extravasation. ■ For use with [In the formula, each R is independently hydrogen or methyl, and R3 is in the 8- or 9-position. Hydrogen, chloro, fluoro or CI-1 alkyl R2 is chenyl, furyl or group R.

, where Each R. are independently hydrogen, fluoro, chloro, CI-+oalkyl, C1-, , alkoxy or C, -,. represents alkylthio or one R.

or hydrogen and the other a) Tri(C+-3alkyl)silyl, trifluoromethyl, phenyl, molybdenum nochlorophenyl or monofluorophenyl, b) group (wherein each R, is independently hydrogen, chloro, fluoro, CI□alkyl or C 1-, alkoxy, and X is -CH20-, -OCI(,-,CH,S -, -SCH, -, -CH. -, -CHzCHt-, -CH20CH2-, - 0-tf knee represents -S-), C) group (Here, each Rs' independently represents C1-, alcoquine, and Ylt=O (CH2)+-s-, -SCH,-, (CH2)ra- or -CH20CH 2-), or d) group 1CH,N R.

(Here, each R4 independently represents CI-4 argino-C, -7 cycloalkyl, ali Fluoro, chloro or CI-S alkoxy represents benzyl substituted by or two R. but they are combined pyrrolidinyl, piperidyl, hexamethyleneimino, morpholinyl, thiomorpholinyl or 4-methylpiperazinyl) represent or Two R8s on adjacent carbon atoms form methylenedioxy, with the proviso that R When O is other than chloro, fluoro, methyl, methoxy or methylthio, This is possible only in meta or bara position1 and their pharmaceutically acceptable acid addition salts which may exist. It is something.

Preferred compounds of formula 1 are such that each R is hydrogen and R1 is as defined above. and one R8 is hydrogen and the other is in the meta or bara position. may be as defined in b) or c) above, and may exist. Pharmaceutically acceptable acid addition salts thereof (Compound 1').

Another aspect of the invention is the novel compounds of formula I, namely formula Ia [wherein R and R1 are as defined above and R7' is chenyl, fluorine, reel or base R0' , where Each Ro- is independently C6-10 alkyl, C3, □10 alkyl, C 6-2゜alkylthio, or one R6゛ is hydrogen and the other is tri(C+-s alkyl)-silyl, phenyl, monochlorophenyl, mono represents fluorophenyl or as defined in b), c) or d) above Therefore, the R6' substituent is only possible at the meta or bara position. 1, and their possible pharmaceutically acceptable acid addition salts. Regarding.

Preferred compounds of formula 1a are those in which each R is hydrogen and R1 is in the 8-position and that The others are as defined above, provided that R2 is chenyl, furyl or base , where R0~ is in the rose position and the tree CC+-3 alkyl)-silyl or as defined in b) or c) above. and their pharmaceutically acceptable acid addition salts which may exist. (Compound 1a').

Another aspect of the invention provides formula Ib [wherein R and R1 are as defined above and R1# is chenyl, fluorine, reel or base , where Ro“1 independently represents chloro, fluoro, C31 alkyl. or one Ro” is hydrogen and the other is tri(Ci-s alkyl) )-silyl, phenyl, or as defined in b) or C) above or d)' group R4゛ and here Each R4' is allyl or two R4's are the nitrogens to which they are attached. Together with atoms, pyrrolidinyl, piperidyl, hegisamethyleneimino, morpho represents linyl, thiomorpholinyl or 4-methylpiperazinyl, However, as a condition, when R0゛ is other than chloro, fluoro or methyl, is possible only in the meta or bara position] and those that can exist The present invention relates to pharmaceutically acceptable acid addition salts of.

Suitable compounds of formula 1b are those in which R1 is as defined above and R 2-represents chenyl, furyl or a group, where Roo is in the meta or bara position and C2-6 alkyl, tri(CI-3 alkyl)-silyl, fe is as defined in b) or c) above, or R4# (where each R,′ is allyl or two R4′ are linked together) pyrrolidinyl, piperidyl or hahexamethyleneimide together with the nitrogen atom ), and their pharmaceutically acceptable acid additions that may exist. It is a salt compound (compound 1b').

The alkyl moiety may be straight or branched.

A special group of compounds are R1 is as defined above and R3 is chenyl, furyl or a group , where each R8 is independently hydrogen, fluoro, chloro, C, . alkyl, C ,,. represents alkoxy or alkylthio, or one hydrogen is likely and the other is as defined in a) or d) above, or 'R3p (where each Rsp is independently hydrogen, chloro, fluoro or C,-, alkoxy (where each R s'p represents C1-3 alkoxy, and Y is -OCH, -3CR2-1 CH2-l-CH2CH2- or CH, ○CH2) those of formula 1 (and likewise Ia and Ib) and their possible pharmaceutical Includes acceptable acid addition salts.

In other groups of compounds of formula I (and likewise Ia and Ib), R, is 8- or 9 - position and is hydrogen, fluoro or C+-S alkyl, and R2 is chenyl, furyl or group ,R.

R.

, where each R0 is independently hydrogen, fluoro, chloro% Cl-+. Archi or C3-3゜alkoxy, or one R, is hydrogen; and the other a)) Li(Cr-3alkyl)silyl, trifluoromethyl or phenyl le, b) group S (wherein each R1 is independently hydrogen, chloro, fluoro or Cl-8 alkoxy and X is 0CH2, O, CH2O or CH, CH, f), or Taha C) group 7R3' R3/ (where each R3' independently represents C,-, alkoxy, and Y is OCH! , CH20CH,, CH,, CH2CH2 or CH2CH2CH2) ,or d) group -CH,N (Here, each R4 can be independently C1□alkyl, C, cycloalkyl, allyl, or benzyl, or two R4 are identical to the nitrogen atoms to which they are bonded. Together with pyrrolidinyl, piperidyl, morpholinyl or thiomorpholinyl ) or Two Ro on adjacent carbon atoms represent methylenedioxy, provided that Ro is chloro, fluoro, methyl or other than methoxy, it is meta or is possible only in the rose position.

Compounds of the invention have the formula V [In the formula, R1 and R2 are as defined above] and obtained recovered compounds in free form or in the form of possible pharmaceutically acceptable acid addition salts. It can be manufactured by

The reaction is carried out in an inert organic solvent in the presence of an acid catalyst at a temperature of about 35"-200°C. In particular, it is carried out at temperatures between 75° and 120°C.

Examples of suitable solvents are aliphatic hydrocarbons, such as hexane, heptane, aromatic group hydrocarbons, such as benzene, toluene, etc., chlorinated hydrocarbons, e.g. aliphatic ethers such as chloroform, methylene chloride, etc., such as diethyl ether. cyclic ethers, such as tetrahydrofuran, or an excess of acid catalysts, such as Acetic acid. Examples of suitable acid catalysts are mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. or organic acids such as aryl carboxylic acids such as benzoic acid, alkyl sulfonate, etc. acids such as methanesulfonic acid, arylsulfonic acids such as p-)luene The sulfonic acid is preferably an alkylcarboxylic acid, especially acetic acid. Main departure The present invention also relates to methods for preparing compounds of formula Ia.

Compounds of formula ■ are The compound with the formula ■ 0-c y OR.

[In the formula, R1 and R2 are as defined above and R4 is C1□alkyl ] The adduct thus produced is then hydrolyzed and its The compound obtained in free form or in possible pharmaceutically acceptable acid addition salt form. It can be manufactured by collecting it.

The reaction is carried out under a nitrogen atmosphere in an inert solvent such as an aliphatic hydrocarbon such as hexane. aliphatic ethers, such as diethyl ether, or cyclic ethers, such as preferably at a temperature of 30° to 50°C, e.g. It is practiced at temperatures between -20' and oC.

Hydrolysis is a common method, for example using water, dilute mineral acids, or ammonium chloride solution. It is carried out using

Compounds of 2m are of the formula H JLi (wherein R1 and R6 are as defined above) ) can be produced by reacting with

The reaction is carried out under a nitrogen atmosphere with the same reaction as described above for the reaction of ■ and ■. in an active solvent at a temperature of e.g. 25° to 75°C, preferably 30' to 40°C. It will be carried out in

Certain compounds of formula V are new and are part of this invention.

Therefore, the present invention provides the formula Va (8- or 9-) Samurai → -R [In the formula, R, R, and each R0'' are as defined above; and It also relates to their pharmaceutically acceptable acid addition salts.

The starting materials of formulas ■ and ■ are known and/or can be prepared analogously to known methods. can be obtained by conventional methods.

Final products and intermediate products can be isolated and purified using conventional methods. As appropriate, It is also possible to use the intermediates directly in the next step without purification.

As will be clear to those skilled in the art, compounds of formulas I and V may be present in racemic or They can exist in nanomeric forms and the invention encompasses all forms.

Enantiomers can be determined in common ways, e.g. by separating final or intermediate products. or by using optically active starting materials.

Examples of pharmaceutically acceptable acid addition salts include mineral acids that can be prepared by conventional methods, e.g. such as hydrochloric acid, hydrobromic acid, phosphonic acid and sulfuric acid, and organic acids such as tartaric acid, acetic acid, citric acid, malic acid, maleic acid, methanesulfonic acid and gluconic acid, Includes the following.

Compounds of formula 1 were tested in the human platelet PAF receptor potency test (Test A) as follows: Due to their ability to suppress the intrinsic binding of ['H]-PAF to platelets according to Indicated for use as a platelet activating factor receptor antagonist as indicated by: Human blood was obtained by venipuncture of a healthy human donor, and it was diluted with 3°15% Trisodium citrate and 20 μg/ml prostaglandin I! (PCI The blood anticoagulant mixture was added in a ratio of 9=1 blood anticoagulant to the anticoagulant mixture containing the anticoagulant.

This blood was centrifuged (250 x g) for 20 minutes at room temperature to remove platelets. Plasma enriched with PRP' (PRP') was produced.

The PRP was then centrifuged (900xg) for 10 minutes at room temperature, and the blood The platelets were treated with 0.25% bovine serum albumin (BSA) having a pH of 7.4. PCI was added at a final concentration of 0.3 μg/rnI. Washed twice with resutiroad (TT) solution. Platelets, 1. 4mM CaC T containing l2-2H20 and 0.7mM MgClg, 6Hto Resuspend in 350.000 μl in T/BSA. Do all tests twice and each of the test compounds at a concentration of 100.50, 1 and 0.1 μM. It was evaluated by

For each measurement, the following solutions were mixed: 500 μl of the above platelets; [3H]-PAF of 10/Jl (1.5g at 40,000 cycles per minute (cpm) up to the final concentration of M); and 10 μl of test compound at 50 times the desired final concentration, 10 μl of excipient (all concentrated). (combined) or 10 μm 1.85Xlo-’M cold PAF (solid (not bound) Either.

Each mixture was incubated for 1 hour at room temperature, after which time it was incubated with 500 μm ice-cold TT/BSA. The reaction was terminated by addition of make it complete. The resulting supernatant was aspirated into a scintillation bottle and the pellets were collected at 25 Wash with 0 ml water-cold TT/BSA, rinse and centrifuge at 4°C for 10 min (90 ml). 0xg). The supernatant was then aspirated into the same scintillation bottle as before and lo Add l of Scintiverse It (Liquid Scintillation Cocktail) and Mix. Resuspend the globules in 500 μl of scintillation and mix well. do. Next, add another 2 ml of Cinchverse ■ to the bottle, and after mixing, remove the bottle from the liquid. Count for 1 minute in a scintillation spectrometer. The amount of unique connections are all combined [ Difference between [3H]-PAF and non-intrinsically bound [”H]-PAF (cpm) It is calculated as The percentage inhibition of specific binding is the percentage of inhibition of specific binding in the presence of the test compound. Divide the resulting cpm by the uniquely combined cpm, multiply by 100, and then It is determined by subtracting from 100. I.C.

(50% inhibitory concentration) value is determined by evaluating the test compound over the entire concentration range. can get.

Furthermore, with respect to their ability as PAF receptor antagonists, the compounds of formula I - It is indicated for use as an inhibitor of bronchial stenosis mediated by As assessed by the PAF-induced gonadal inflation pressure (PIF) increase test (Test B) as described below. Valued: Male guinea pigs weighing between 300 and 400 g were anesthetized, and after a period of time the trachea was injected. , insert carotid artery and jugular vein catheters. Test animals are then given small animal herbs. Force evacuation using an ard suction device, then use a pressure transducer and recorder. and measure the resistance to lung inflation (PIF). Introduction of test compound into PAF orally for 30 minutes during the 4 hours before induction or for 4 minutes during the 4 hours before induction. or parenterally, such as intravenously (into the jugular vein). PAF(C1, - Zand, Hannover) dissolved in Trisuchiroad bovine serum albumin buffer. and administered intravenously (intrajugular vein) at 1100 n/kg. Blood pressure obtained Measurements are recorded from a transducer connected to the carotid catheter. After administration of PAF Two types of responses are noted in the PIF recordings: ], ) Test movements treated with PAF alone For objects, the response immediately after the average value deviates from the reference line PIP value by 70% to 80% (this The initial response of is also the largest response and is therefore called the maximum PIP); and and 2) long-term (at least 30 minutes) PIF that slowly decreases to baseline. response. The reading 15 minutes after administration of PAF is referred to as the final point PIF. For PIF response The effect of a test compound on PA compared to test animals receiving PAF alone F and the maximum PIF above baseline for test animals receiving test compound. determined by the difference between the percentage increase in .

In addition, compounds of formula I can be used in blood according to the PAF-induced extravasation test (Test C) as described below. PAF-mediated extravasation (from the vessel lumen to the vessel wall and Also indicated for use as an inhibitor of plasma protrusion into surrounding tissues: Male guinea pigs weighing between 300 and 400 g were anesthetized, and after some time the thigh was Insert the catheter. test compound for a period of 4 hours before introduction of PAF. Administer orally or parenterally. PAF (C, - Zand, Hannover) Trisutiload bovine serum albumin buffer and l00 days Administer intravenously (intrajugular vein) at g/kg.

used to indicate hemoconcentration and to separate plasma from cellular components. The hemetocrine value is defined as the percentage of packed red blood cells in the collected blood sample. For the measurement, the blood sample was placed in a 50 μl henolytic hemetocrite tube. to collect. These samples were taken immediately before the PAF injection and also within 1 minute after the PAF injection. Thereafter, samples are collected every 2 minutes until 15 minutes after the PAF injection. The tube is then centrifuged and and measure the percentage of packed red blood cells (hemetocrit) (PAF is the volume of PAF). 5-7 minutes after injection produces the maximum increase in hemetochryso). Pre-injection value of PAF Calculate the percentage increase in hemetcrit. obtained using the test compound Compare the hemetocrit value with the hemoconcentration value obtained using PAF alone and Expressed as percentage inhibition of percentage increase in metocrit.

Additionally, compounds of formula I may be used to treat PAF-mediated endotoxin-induced lung disease, as well as and similar endotoxin-induced lungworm shock and adult respiratory distress syndrome. It is also indicated for use as a suppressant. Endotoxin-induced lung disease, also known as The term is commonly used with respect to all three types of instructions. Compounds of formula I are PA The ability of F to suppress endotoxin-induced lung disease was demonstrated by S, Zhang (C hang) in Gatlinburg, Tenn., on October 2619, 1986. Part 2 on "Platelet activating factors and structurally related alkyl ether lipids" It can be measured according to the test presented at the 2017 International Conference.

Tissue and blood PAF increased in endotoxin-treated mice. Based on previous reports, no distortion occurred 90 minutes after endotoxin treatment in vitro. From extravascular accumulation of water rts1-albumin in perfused lungs isolated from 2 mg/kg of endotoxin (S, enterigoodis) was evaluated. It was determined that intraperitoneal administration of C. itidis) caused acute lung disease. Therefore, The wet lung/body weight ratio (an index of water content in the lungs) ranges from 5°35±0.48 to 826±0. 36, and the albumin leakage index increased from 0.46±0.09 to 1.01± Increases to 0.07. Efficacy of compounds as endotoxin-induced lung disease inhibitors To measure the effects, test compounds were administered intraperitoneally prior to in vivo endotoxin treatment. give

Compounds of formula I inhibit PAF-mediated endotoxin-induced lungworm disease shock. The ability to suppress Presented at the American Annual Meeting on Clinical Research in New Orleans, Georgia. It can be measured according to the test.

All samples were tested using chronic sheep lung lymph specimens, which are well discussed in the literature. Either prepare a new sheep or make sure that the test animal has chronic emaciation and multiple The modification is that a pressure catheter is inserted during the initial surgery. all categories The test animal is exposed through the puncture wound in the skin, the chest is closed, and the test animal is ．． Allow them to recover for 6 days until they appear healthy, then experiment. Remove blood from lung lymph before starting.

Inhibitor of certain important hemodynamic effects of endotoxin on lungworm shock To determine the effect of the compound as a or saline was administered intravenously to test animal groups over 30 minutes, and 20 mg/kg of test compound or saline is administered intravenously over 5 hours. Pulmonary artery pressure (PAP) ), 4 = Visceral blood pumping 1 (Co) and oxygen partial pressure (PO2) continuously for 5 hours to supervise.

To inhibit PAF-mediated endo)4-syn-induced respiratory distress syndrome in adults. The ability of the compounds of formula I to be et al., Annual General Meeting of the American Thoracic Society and American Lung Association, May 10-13, 1987. It can be measured by a test published in 8.

Certain important hemodynamic effects of endotoxin on respiratory distress syndrome in adults. To determine the effectiveness of the compounds as inhibitors, 0.5 μg/kg of E. coli Dotoxin for 20 minutes and test compound at 20 mg/kg/hour for 6 hours. or 0.5 μg/kg E. coli endotoxin for 1 hour. and then 20 mg/kg/hr of test compound was administered to the test animal group for 6 hours. Administer intravenously. Pulmonary artery pressure (PAP), pulmonary kinetic response (DC) and pulmonary lymph flow ( LL F) is monitored continuously for 5 hours.

Therefore, the compounds may be used to treat PAF-mediated bronchial stenosis and hyperemia as well as PAF-mediated bronchial stenosis and hemorrhage. It is also indicated for use in the treatment of existing endotoxin-induced lung diseases, and The dosage indicated for use is about 10-2003 mg, preferably lOlo- 35Q, which is divided into, for example, up to 4 times a day and is 0.25-25-5 00, especially administered in a dosage of 0.25-25-35O or in modified release form. given. A typical oral dosage is 50 or is 100mg. A typical oral unit dose is 2.5 500+ ag. Preferably it can contain 5 to 200 mg of active substance, especially I (1-100 mg). .

Compounds of formula ■ are also indicated for use in the same indications and may be used in similar dosages. Wear.

Compounds of formula Ib are effective against various lymphomas, sarcomas, as shown in the studies below. As evidenced by their ability to suppress myeloma and leukemia lining cells, Use as an anti-tumor agent is also indicated.

Test D) Tumor Cytotoxicity Test (TCCT) Flat Bottom Microscopic Titration Plate (Nunc Roskiei) Abelson 8.1 in DMEM + 10% fetal calf serum (De, Denmark) Tumor cells were placed and the plate containing the tumor cells was loaded with 1.3 and 5 μg Incubation with test compound for 6-72 hours. Number of viable tumor cells present was measured by measuring alkaline phosphotase using the method described below.

Tumor cell plates were centrifuged for 10 minutes at 500×g) and the supernatant was flicked off. . Without further washing, 20 μM jetanolamine, 20 μM MgCl2. 6H20, 2, 5 μM p-nitrophenylphosphate-1 and lomg 100 pl of buffer containing Riton X-100 was added. Sample at room temperature Incubate for 0 min and terminate the enzyme reaction by adding 100 μl of 0.5N NaOH. I finished it. Then at 405 nM using a Titeltec Multiscan instrument. Absorption was measured.

Test E) Effect test on cytotoxicity of ET-18-OCH3 (IC-ET test) flat bottom microscope [BALB/CX57/BL&]Fl obtained from Mus musculus in a mirror titration plate. IOμg of 1-octatene was added to bone marrow macrophages (10’/well). 2-methoxy-3-phosphorylcholine (ET-18-OCHs) for 24 hours. After that time, they were centrifuged and washed once. Abern 8.1 tumor cells and 113 and 5 in fetal serum of M+10% calf μg of test compound was then added to the plate. ET 18 0CH3 (I Oμg) only Measured by alkaline phosphotase potency assay with cytotoxicity set at 100%. The suppression or enhancement of the cytotoxic effect was determined by testing L3 and 5 μg. Values for compounds were recorded after 72 hours.

Test F) Old (Old) Other processes (L, J, Old, E, A, Voice (B) oyse), D, A, C1arke and E, Carswell ( Carswell) Ann, N, Y, Acad, Sci, earthy smell↓ , 80 (1962)) by administering methylcholanthrene. Fibrosarcoma cells were induced in BALB/C cells. These tumor cells The abdominal cavity was harvested 10-12 days after administration of methylcholanthrene. 10-12 years old 7.3XlO' meta-A sarcoma cells were added to each of the weekly CBF and Mentha sarcoma cells. It was transplanted and used as a control. Second group of 10 CBFs.

7.3XlO' meta-A sarcoma cells were transplanted into each peppermint, and One day after transplantation, each honeyweed was given a total of 5-50 μg of test compound per day. They were treated orally for 20 or 27 days. From tumor transplant 7.14.21 and 28 Days later, tumor growth and survival numbers were assessed. Under these conditions, the control group However, 5011 g of the compound of Example 3N) per day was administered. All given animals showed not only survival but also evidence of the presence of tumors. There wasn't.

The compounds are also indicated for use in tumor suppression and are The recommended dosage is about 500-2000 mg, preferably 1000 mg. 1500mg, which can be divided into 4 doses per day for example 125 75 Administered in a dosage of 0 mg or in modified release form. typical oral Dosage is 400 mg administered 2 or 3 times a day or over 24 hours. The dose is 20 mg/kg body weight administered intravenously. Typical oral unit dose is 300-600 mg, preferably 300-500 mg, especially 350-450 mg. mg of active substance.

The appropriate daily dosage depends on a number of factors, such as the relative potency of the compound's activity. Will. A preferred compound according to the invention, 5-[4'-(3,4,5-trimethane) toxyphenylethyl)phenyl]-2,3-dihydroimidazo[2,1-a] Inquinoline hydrochloride gave, for example, the following results in Tests A-C. Exam, Hee I C6゜006μM1 test B-EDso 5. Omg/kg orally, test CE Dso 4-2 mg/kg orally.

Compound 5-(4'-diallylaminomethylphenyl)-2,3-dihydroimida Zo[2,1-a]inquinoline hydrochloride gave, for example, the following results in tests D-E. Ta. Test D-99% inhibition at 5μg, Test E-97% inhibition at 5μg. Regulation.

Accordingly, the present invention provides a compound of formula I or a pharmaceutically acceptable compound thereof for patients in need of treatment. bronchial stenosis or A method for treating endotokin-induced lung disease mediated by blood and extravasation and PAF , and e.g. PAF-mediated bronchial stenosis and hemorrhage and PAF-mediated Said compound for use as a drug in the treatment of endotokin-induced lung disease objects, and PAF-mediated bronchial stenosis and hemorrhage, as well as PAF-mediated It also relates to the manufacture of drugs for the treatment of endotoxin-induced lung diseases. .

The present invention further provides a method for administering compound No. 1b or its pharmaceutical composition to a patient in need of treatment. A method of treating tumors, including leukemia, comprising administering an acceptable acid addition salt, and Also related to the production of such compounds and antitumor agents for use as anti-tumor agents. It is.

The compounds can be used in free form or in the form of pharmaceutically acceptable acid addition salts. Ru.

Compounds of the invention, in free form or in pharmaceutically acceptable acid addition salt form, may be added to one or more drugs. together with a pharmaceutically acceptable carrier and optionally one or more common pharmaceutical adjuvants; and in the form of tablets, dispersible powders, granules, capsules, elixirs, suspensions, etc. It can be administered orally or parenterally in the form of a sterile injection or suspension solution. set The composition can be manufactured by conventional methods.

Examples of compositions are as follows: Compound of formula I 50-50- (The example is from Example 7E) Compound of formula 1b -400-400 (The example is from Example 3N) Tragacan l-1010 Lactose (spray dried) 212.5 197.5 100 250 Corn Star 1525 Talcum 1015 Magnesium stearate 2.52.5 total 300.0 650.0 +5 0.0 650.0 liquid type (Weight (mg)) ffle Sterile injection oral liquid −μj member−−Shuiro Δ− Carpenter's compound 53 (For example, Example 7E) Sodium carboxy 18 Methylcellulose, U, S, P.

Methylcellulose 0.3 Polyvinylpyrrolidone 2.7 Lecithin 1.5 Benzyl alcohol 001 Magnesium aluminum silicate - 25 fragrance sufficient amount Colorant Sufficient amount Methylparaben, U, S, P, 3 Propylparaben, U, S, P, 0.7 polysorbate 805 (For example, Tween 80), U, S, P.

Sorbitol solution, 70%, l], s, P, -1450 for desired stability. For injection, sufficient amount B buffer to adjust r+H Sufficient amount Make the water 1ml or 5ml sufficient amount for sufficient amount for Pharmaceutical compositions suitable from the standpoint of ease of formulation and administration include those for PAF inhibition applications. About 10-10Qmg of active ingredient and about 350-4Qmg of tumor suppression Solid compositions containing 50 mg of active ingredient, especially liquid or hard-filled containers. capsules and tablets.

Such compositions also form part of the present invention.

The following examples illustrate the invention, in which all temperatures are in °C.

Example 1 5-(p-fluorophenyl)-2,3-dihydroimidazo-[2,l-al　 Inquinoline (R, -H, R2 p-fluorophenyl) a) 5-(p-fluorophenyl) lophenyl)-2,3,5,6-titrahydroimidazo[2,1-al ink Norin-5-ol (a compound of formula 1, where RI=H, R2=p-fluorophenyl) thing) Flask with stirrer, condenser and dropping funnel kept under nitrogen in which 6.26 g (0.04 mol) of 2-(o-tolyl)-2(IH)-imida Charged syringe and looml dry tetrahydrofuran. Stir the solution; Treated with 1.6 M n-butyllithium (0.13 mol) in 84 ml hexane and kept at 35°C for about 5 hours. Pour the mixture into 50 ml of dry tetrahydrofurane. 20.7 g (0.16 mol) of ethyl p-fluorobenzoate in a The temperature was then kept at 50°C for about 5 hours. The reaction was then cooled in a water bath and 22.8 ml of saturated ammonium chloride. Separate the tetrahydrofuran layer in a separation funnel. Separated, dried over magnesium sulfate, filtered, and then concentrated in vacuo. Residue The residue is hot with chloride, and I have diarrhea. The desired compound was then produced.

b) 5-(p-fluorophenyl)-2,3-dihydroimidazo-[2゜1-a l Isoquinoline 2.8 g (0.01 mol) of the compound prepared in a) above and 40 ml of ice vinegar The solution containing the acid was refluxed with stirring under a nitrogen atmosphere for about 5 hours. next The acetic acid was removed by π-distillation, the residue was treated with 50 ml of water, and then 35 ml of water was added. The mixture was made alkaline using 2N sodium carbonate. Next, add 100ml of the mixture. After that time, the organic layer was separated and extracted with anhydrous magnesium sulfate. Dry over sium, filter and remove solvent in vacuo. The crude product obtained was recrystallized using a mixture of methanol and water to yield the title compound. Ta. Melting point 150-15100° Example 2 By essentially repeating the steps of Example 1a) above, ethyl p-fluorobenzoate was prepared. When an appropriate compound of formula ■ is used in place of , the compounds of formula ■ below are obtained respectively. Obtained: A,) 5-[4-diethylamino)methylphenyl]-2,3,5,6-titra Hydroimidazo[2,1-al inquinolin-5-ol B) 5-(p-chloro lophenyl’)-2,3,5,6-titrahydroimidazo[2,1-mycoisox Norin-5-ol C) 5-phenyl-2,3,5,6-titrahydroimidazo [2,1-mycoisoquinolin-5-ol D) 5-(3,4-dimethoxyphenyl')-2,3,5,6-titrahydro imidazo[2,1-a coisoquinolin-5-ol E) 5-(4-Metkinf phenyl)-2,3,5,6-titrahydroimidazo[2,1-al isoquinol 5-(3,4-methylenedioxyphenyl)-2,3,5 ,6-titrahydroimidazo[2,1,-al　inquinolin-5-ol G) 5-(3,.1-dichlorophenyl)-2,3,5,6-titrahydroimida Zo[2,1-mycoisoquinolin-5-ol H)5-(2,4-dichlorophene 2,3,5,6-titrahydroimidazo[2,1-mycoisoquinoline- 5-ol I) 5-(3-trifluoromethylphenyl)i,3,5.6-thi Trahydroimidazo[2,1-al Isoquinolin-5-ol J) 5-(2- chlorophenyl)-2,3,5,6-titrahydroimidazo[2,1-mycoiso Quinolin-5-ol K) 5-(4-methylphenyl')-2,3,5,6- titrahydroimidazo[2,1-al isoquinolin-5-ol L) 5-( 3-chlorophenyl)-2,3,5,6-titrahydroimidazo[2,1-myco Isoquinolin-5-ol M) 5-(2-fluorophenyl)-2,3,5,6 -Titrahydroimidazo[2,1-a,]]inquinolin-5-ol N5- (4-piperidinomethylphenyl)-2,3,5,6-titrahydroimidazo[ 2,1-al Isoquinolin-5-ol 0) 5-(4-pyrrolidinomethylphenyl phenyl)-2,3,5,6-titrahydroimidazo[2,1,-a,]]in Quinolin-5-ol P5-(4-morpholinomethylphenyl)-2,3,5 ,6-titrahydroimidazo[2,1-al　inquinolin-5-ol Q)5 -(2-chenyl)-2,3,5,6-titrahydroimidazo[2,1-al　 inquinolin-5-ol R) 5-[4'-(2-10ro 4-fluoroben zyloxy)phenyl]-2,3,5,6-titrahydroimidazo[2,1-a l Inquinolin-5-ol 5) 5-r4'-(2,6-dichloropenzyloxy)phenyl]-2゜3 ．． 5.6-tetrahydroimidazo[2,1-al　quinolin-5-ol T) 5-(4-t-butylphenyl)-2,3,5,6-tetrahydroimida zo[2,1-alisoquinolin-5-oltJ)5-(4-phenylphenyl )-2,3,5,6-tetrahydroimidazo(2,1-al isoquinoline-5 -ol V) 5-(4-dibenzylaminomethylphenyl")-2,3,5, 6-tetrahydroimidazo[2,1-al isoquinolin-5-ol W) 5- (4'-dicyclohexylaminomethylphenyl)-2,3゜5.6-titrahy Doloimidazo[2,1-23isoquinoline-5-oX)5-(4'-diimp (ropylamine methylphenyl)-2,3,5゜6-tetrahydroimidazo[2, 1-alisoquinolin-5-ol Y)5-(4'-ethylphenyl)-2, 3,5,6-tetrahydroimidazo[2,1-al isoquinolin-5-ol Z )5-(4'-)limethylsilylphenyl)-2,3,5,6-tetrahydroy midazo[2,1-al isoquinolin-5-ol AA) 5-(4'-7 dino xyphenyl)-2,3,5,5-tetrahydroimidazo[2,1-al] Quinolin-5-ol BB) 5-(4'-diallylaminomethylphenyl) -2,3,5,6-tetrahydroimidazo[2,1-al　inquinoline-5- all cc) 5-(4'-benzyloxyphenyl)-2,3,5,6-tet lahydroimidazo[2,1-al inquinolin-5-ol DD) 5-(2 '-Freel)-2,3,5,6-tetrahydroimidazo[2,1-a] ink Norin-5-ol EE) 5-(4'-thiomorpholinomethylphenyl)-2, 3,5,6=tetrahydroimidazo[2,1-al isoquinolin-5-ol FF) 5-(3'-t-butylphenyl)-2,3,5,6-tetrahydroyl midazo[2,1-a]isoquinolin-5-ol GG)5-[4’-(2, 6-cyclophenyloxymethyl)phenyl]-2,3,5,6-titrahydride loimidazo[2,1-al inquinolin-5-ol )IH) 5-[4'-(3,4,5-trimethoxybenzyloxy)phenyl ]-2.3,5.6-titrahydroimidazo[2,1-alinquinoline-5- oar z) 5-[4'-(2-fluorobenzyloxy)phenyl]-2°3.5. 6-tetrahydroimidazo[2,1-al isoquinolin-5-ol J J) 5-[4'-(4-fluorobenzyloxy)phenyl]-2゜3. 5.6-Tetrahydroimidazo[2,1-a]isoquinolin-5-ol Kl()5-[4'-(2-chlorobenzyloxy)phenyl]-2,3゜5 ．． 6-tetrahydroimidazo[2,1-al isoquinoline-5-oh LL)5 -[4'-(2-chloro-6-fluorobenzyloxy)phenyl]-2.3 , 5,6-titrahydroimidazo[2,1-al isoquinolin-5-ol MM) 5-[4'-(?,4-dichlorobenzyloxy)phenylco-2,3 ,5,6-tetrahydroimidazo[2,1-8,]]inquinoline-5-o NN) 5-[4'-(4-L-butylbenzyloxy)phenylj-2゜3. 5.6-tetrahydroimidazo[2,1-al　quinolin-5-ol 00) 5-[4″-(3,4,5-trimethoxyphenylpropyloxy)ph henyl]-2,3,5,6-titrahydroimidazo[2,1-a]inquinoline -5-ol pp) 5-[4'-(3,4,5-trimethoxyphenylhexyl)7enyl ]-2,3,5,6-tetrahydroimidazo[2,1-al　inquinoline-5 -all, and QQ) 5-[4'-(3,4,5-1-rimethoxyphenylethyloxyphenol) i, 3,5,6-tetrahydroimidazo[2,l-al] -5-ol.

Example 3 Essentially repeating the steps of Example 1b) above and substituting the compound of Example 1a). Using appropriate amounts of the compounds of Examples 2A) to 28N) in each case, The following were obtained: A) 5-[4'-(diethylamino)methylene ruphenyl]-2,3-dihydroimidazo[2,1-al isoquinoline dihydrochloric acid Salt, melting point 292-294°C B) 5-(p-chlorophenyl)-2,3-dihydroimidazo[2,l-al] inquinoline, melting point 250°C) 5-phenyl-2,3-dihydroimidazo[ 2,1-al Isoquinoline, melting point 143-145℃ D) 5-(3',4'-dimethoxyphenyl)-2,3-dihydroimidazo[2 , 1-a coisoquinoline, melting point 158-160°CE) 5-(4'-methoxy phenyl)-2,3-dihydroimidazo[2゜1-al　inquinoline, melting point 1 26-128°CF) 5-(3',4'-methylenedioxyphenyl)i,3- Dihydroimidazo[2,1-al isoquinoline, melting point 128-130℃G)5 -(3',4'-dichlorophenyl)-2,3-dihydroimidazo[2,1 -a] Isoquinoline, melting point 158-160°CH) 5-(2',4'-dic lorophenyl)-2,3-dihydroimidazo[2,1-a]inquinoline, melting point 150-152℃1) 5-(3'i-lifluoromethylphenyl)-2,3-di Hydroimidazo[2,1-al Isoquinoline, 〉250℃J)5-(2'- chlorophenyl)-2,3-dihydroimidazo[2゜1-al　isoquinoline, Melting point 134-136℃K) 5-(p-methylphenyl)-2,3-dihydroimine Dazo[2,l-al Isoquinoline, melting point> 250″CL) 5-(3’-chloro phenyl)-2,3-dihydroimidazo[2゜l-al　isoquinoline, melting point〉 250℃M) 5-(2'--fluorophenyl)-2,3-dihydroimidazo 12゜1-81 isoginoline, melting point >250'CN) 5-(4'--piperidino methylphenyl)-2,3-dihydroimidazo(2,1-al isoquinoline disalt Acid acid, melting point 317-320°C0) 5-(4'-pyrrolidinomethylphenyl) -2,3-dihydroimidashi[2,1-al　inquinoline, melting point 106-10 8°CP) 5-(4'-morpholinomethylphenyl)1,3-dihydroimida Zo[2,l-al Isoquinoline, melting point 160-162°CQ)5-(:2- Chenilton-2,3-dihydroimidazo[2,1-a]inquinoline, melting point 9 8-100'c R) 5-[4'-(2--chloro-4-fluorobenzyloki V) phenyl ]-2,3-dihydroimidazo[2,1-al isoquinoline hydrochloride, melting point 2 52-254°C (decomposition) S) 5-[4'-(2,6-dichlorobenzyloxy)phenyl 1-2゜3-di Hydroimidazo[2,ha] isoquinoline hydrochloride, melting point 277-280°C T) 5-(4'-t-butylphenyl)i,3-dihydroimidazo[2,1- al inquinoline, melting point 200℃U) 5-(4'-phenylphenyl) -2,3-dihydroimidazo[2゜1-al　inquinoline, melting point〉200℃V )5-(4'-dibenzylaminomethylphenyl)-2,3-dihydroimida Zo[2,1-al　inquinoline dihydrochloride, melting point 225℃W)5-(4'-disy chlorohexylaminomethylfuconyl)-2,3-dihydroimidazo[2,1- a] Isoquinoline dihydrochloride, melting point 273°C (decomposition) X) 5- (4' -Jiso Provirminomethyl J, Nil) -2, 3 -Jihi Doloimidazo[2,1-al inquinolin dihydrochloride hydrate, melting point 264°C (min. solution) Y) 5-(4'-ethylphenyl)-2,3-dihydroimidazo[2゜1-a Isogynoline hydrochloride, melting point 298-300℃Z) 5-(4'-trimethylsilyl) rutuunyl)-2,3-dihydroimidazo[2,1-al isoquinoline hydrochloride , melting point>270°CAA) 5-(4'-phenoxyphenyl)-2,3-dihyde Loimidazo[2,1-a]isoquinoline hydrochloride, melting point >270'C'BB) 5- (4'-diallylaminomethylphenyl)-,2,3-dihydroimidazo[2 1-al Isoquinoline hydrochloride, melting point 228°C CC) 5-(4'-benzyl xyphenyl)-2,3-dihydroimidazo[2,1-al isoquinoline hydrochloride Salt, mp 213-215°C DD) 5-(2'-furyl)-2,3-dihydro imidazo[2,1-a1 isoquinoline dihydrochloride, melting point> 315°C EE) 5-(4 '-thiomorpholinomethylphenyl)-2,3-dihydroimidazo[2i-al Inquinoline dihydrochloride, melting point 275-278C FF) 5-(3'-t-butylphenyl)-1,3-dihydroimidazo[2 , la] Inquinoline hydrochloride, melting point 290° CGG) 5-[4'-(2,6 -dichlorophenyloxymethyl)phenyl] -2,3-dihydroimidazo[ 2,1-al inquinoline hydrochloride, melting point 242°C 1-iH)5-[4'-(3,4,5-trimethoxybenzyloxy)phenylene ]-2,3-dihydroimidazo[2,1-al inquinoline hydrochloride, melting point 2 05-207°C I I) 5-[4'-(2-fluorobenzyloxy)phenyl]-2゜ 3-dihydroimidazo[2,1-al　inquinoline hydrochloride, melting point 253-25 4℃ (decomposition) J J) 5-[4'-(4-fluorobenzyloxy)phenyl]-2゜3- Dihydroimidazo[2,1-al inquinoline hydrochloride, melting point 257-258° C (decomposition) KK) 5-[4'-(2-chlorobenzylleoxy)phenyl]-2,3 -dihydroimidazo[2,1-al　inquinoline hydrochloride, melting point 272°C (decomposed) ) LL) 5-[4'=(2-chloro-6-fluorobenzyloxy)phenyl] -2,3-dihydroimidazo[2,1-al　inquinoline hydrochloride, melting point〉25 0°C MM) 5-[4'-(2,4-dichlorobenzyloxy)phenyl]-2,3 -dihydroimidazo[2,1-a,] isoquinoline hydrochloride, melting point 254°C ( Disassembly) NN) 5-[4'-(4-t-butylbenzyloxy)phenyl 1-2° 3-dihydroimidazo[2,1-al isoquinoline hydrochloride, melting point 271°C (min. solution) 00) 5-[4'-(3,4,5-trimethoxyphenylpropyloxy)ph henyl]-2,3-dihydroimidazo[2,1-al in quinoline hydrochloride, fused Point 215-217℃ (decomposition) PP) 5-[4'-(3,4,5-1-rimethoxy) Cyphenylhexyl)phenyl]-2,3-dihydroimidazo[2,1-al Isoquinoline hydrochloride, melting point 213-215°C, and QQ) 5-[4'-(3,4,5-1-rimethoxyphenylethyloxy) ) phenyl] i,3-dihydroimidazo[2,1-a,] inquinoline hydrochloride Salt, melting point 242-243°C.

Example 4 Essentially repeating the steps of Example 1a) above and preparing 2-(o-)lyl)-2(I H)-imidacillin and ethyl p-fluorobenzoate as appropriate Using compounds 2 and 3, the following were obtained, respectively: A) 5-(4'-t-butylphenyl)-8-chloro-2,3,5,6-cyto lahydroimidazo[2,1-al inquinolin-5-ol B) 5-(4 '-t-butylphenyl)-9-chloro-2,3,5,6-titrahydroimida zo[2,1-al　inquinolin-5-ol, and C) 5-(4'-t-butylphenyl)-9-methyl-2,3,5,6-thi Trahydroimidazo[2,1-al inquinolin-5-ol D) 8-chloro -5-[4'-(3,4,5-trimethoxyphenylethyl)phenyl]-2, 3,5,6-titrahydroimidazo[2,1-a]isoquinolin-5-ol, E) 2,2-dimethyl-5-[4'-(3,4,5-trimethoxyphenylethyl) thyl)phenyl]-2,3,5,6-titrahydroimidazo[2゜1-a]iso Quinolin-5-ol.

Example 5 Essentially repeating the process of Example 1b and substituting the compound of Example 1a) Using appropriate amounts of the compounds of Example 4A) to Embodiment 4C), each The following was obtained: A) 5-(4'-t-butylphenyl)-8-chloro -2,3-dihydroimidazo[2,la]alquinoline hydrochloride, melting point>250°C B) 5-(4'-t-butylphenyl)-9-chloro-2,3-dihydroy Midazo[2,la]alquinoline hydrochloride, melting point >298°C1 and C) 5-(4'-t-butylphenyl)-9-methyl-2,3-dihydroimida Zo[2,1-al Isoquinoline hydrochloride, melting point>275°CD) 8-chloro-5 -[4'-(3,4,5-trimethoxyphenylethyl)phenyl]-2,3- Dihydroimidazo[2,1-al isoquinoline hydrochloride, melting point 268°C (decomposition ), E) 2,2-dimethyl-5-[4'-(3,4,5-trimethoxyphenyl ethyl)phenyl]-2,3-dihydroimittfso[2,l　-al　isoquino Phosphorus hydrochloride.

Example 6 By essentially repeating the steps of Example 1a) above, ethyl p-fluorobenzoate was prepared. When an appropriate compound of formula (1) was used in place of , the following were obtained, respectively.

A) 5-[4'-(3,4,5-1rimethoxybenzyloxymethyl)phenylene ]-2.3,5.6-titrahydroimidazo[2,1-al　inquinoline- 5-all B) 5-[4'-(3,4-dimethoxybenzyloxy)phenyl]-2,3 ,5,6-titrahydroimidazo[2,1-a]inquinolin-5-ol C') 5-[3'-(3,4,5-trimethoxybenzyloxy)phenyl] -2.3,5.6-titrahydroimidazo[2,1-al isoquinoline-5-o rule D) 5[2'-(3,4,5-trimethoxybenzyloxy)phenyl 1-2 ．． 3,5,6-titrahydroimidazo[2,1-al inquinolin-5-o le E) 5-[4'-(3,,4,5-)rimethoxyphenylethyl)phenyl] -2.3,5.6-titrahydroimidazo[2,1-a]inquinolin-5-o rule F) 5-[3゛-(3,4,5-trimethoxyphenylethyl)phenyl]- 2,3,5,6-titrahydroimidazo[2,1-a,]]isoquinoline-5 -Oh ) 5-(4'-(3,4-dime)xyphenylethyl)phenyl 1-2. 3.5.6-Titrahydroimidazo[2,1-a]isoquinolin-5-ol H) 5-[4'-(2-methoxyphenylethyl)phenyl]-2,3°5. 6-titrahydroimidazo[2,1-8]inquinoline-5-oh 1) 5-[ 4'-(4-methquinbenzyloxy)phenyl]-2,3°5.6-titrahy Doloimidazo[2,1-8] inquinoline-5-oJ)5-[4'-(3 ,4-dimethylbenzyloxy)phenyl]-2゜3.5.6-titrahydroy midazo[2,ha]inquinolin-5-ol K) 5-[4″-(3,4,5-trimethoxyphenylpropyl)phenyl] -2.3,5.6-teI lahydroimidazo[2,1-al isoquinoline-5- oar L) 5-[4'-(2,3,4-trimethoxybenzyloxy)phel]- 2.3,5.6-titrahydroimidazo[2,1-a,]]inquinoline-5 -Oh )5-r4'~(3-methoxy-4-pentoxyphenylethyl)phenyl] -2.3,5.6-titrahydroimidazo[2,1-a]inquinolin-5-o rules, and N) 5-[4'-(3,4,5-1-rime[·xybenzyl)phenyl]-2 ,3,5,6-titrahydroimidazo[2,1-al　inquinolin-5-oh Le.

Example 7 Essentially repeating the process of Example 1b and substituting the compound of Example 1a) Using appropriate amounts of the compounds of Examples 6A) to 6N), each The following was obtained: A) 5-[4'-(3,4,5-trimethoxybenzi (oxymethyl)phenyl]-2,3-dihydroimidazo[2,1-al　yne Quinoline hydrochloride, melting point >240’C (decomposed) B) 5-[4'-(3,4-dimethoxybenzyloxy)phenyl]-2,3 -dihydroimidazo[2,l-al　inquinoline hydrochloride, -hydrate salt, melting point>23 9°C (decomposition) C) 5-r3'-(3,4,5-)rime[・quinobenzyloxi/)phenyl]- 2,3-dihydroimidazo[2,1-al isoquinoline hydrochloride, melting point 238°C D) 5-[2'-(3,4,5-trimethoxybenzyloxy)phenyl]- 2,3-dihydroimidazo[2,1-al　inquinoline hydrochloride, melting point 252° C E) 5-[4'-(3,4,5-+-rimethoxyphenylethyl)phenyl ]-2,3-dihydroimidazo[2,1-al isoquinoline hydrochloride, melting point 24 3-245°C F) 5-[3'-(3,4,5-trimethoxyphenylethyl)phenyl]- 2,3-dihydroimidazo[2,1-al inquinoline hydrochloride, melting point 260- 26100 G) 5-[4'-(3,4-dimethoxyphenylethyl)phenyl] = 2. 3-dihydroimidazo[2,1-8]inquinoline hydrochloride, melting point 263-26 5℃ H) 5-[4'-(2-methoxyphe,-luyutyl)phenyl]-2,3-di Hydroimidazo[2,1-al　inquinoline hydrochloride, melting point〉270℃ 1) 5-[4'-(4-me)-xybenzyloxy)phenyl]-2,3- Dihydroimidazo[2,1-al inquinoline hydrochloride, melting point> 250°C J) 5-[4” (3,4-dimethylbenzyloxy)phenyl 1-2゜3- Dihydroimidazo[2,1-al inquinoline hydrochloride, melting point> 270°C K) 5-[4'-(3,4,5-1-rimethoxy/phenylpropyl)phenyl ]-2,3-dividroimidazo(2,1,-al inquinoline hydrochloride, melting point 2 42-244°C L) 5-[4'-(2,3,4-trimethoxybenzyloxy)phenyl]- 2.3-dihydroimidazo[2,1-al　inquinoline hydrochloride, melting point〉240 °C M) 5-[4'-(3-methoxy-4-pentoxyphenylethyl)phenyl ]-2,3-dihydroimidazo[2,1-al isoquinoline hydrochloride, melting point 26 0°C (decomposition), and N) 5-[4'-(3,4,5-trimethoxybenzyl)phenyl]-2,3 -dihydroimidazo[2,1-a,]inquinoline hydrochloride, melting point 238140 °C0 international search report international search report εP　8700366 SA 17B95

Claims (11)

[Claims] 1. Formula for use in controlling PAF-mediated bronchial stenosis and extravasation I ▲There are mathematical formulas, chemical formulas, tables, etc.▼I [In the formula, R1 is in the 8- or 9-position and is hydrogen, chloro, fluoro or C1-3 represents alkyl and R2 is chenyl, aryl or a group ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ , where Each Ro is independently hydrogen, fluoro, chloro, C1-10 alkyl, C1-10 represents alkoxy or C1-10 alkylthio, or one Ro is water element and the other a) Tri-(C1-3 alkyl)silyl, trifluoromethyl, phenyl, mono chlorophenyl or monofluorophenyl, b) group ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (where each R3 is independently hydrogen, chloro, fluoro, C1-4 alkyl or represents C1-5 alkoxy and X is -CH2O-, -OCH2-, CH2S -, -SCH2-, -CH2-, -CH2CH2-, -CH2OCH2-, -O - or -S-), c) group ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (where each R3' independently represents C1-3 alkoxy and Y is -OCH 2-, -SCH2-, -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2OCH2-), or d) group ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (Here, each R4 is independently C1-4 alkyl, C5-7 cycloalkyl, ali Fluoro, chloro or C1-5 alkoxy in the para, benzyl or para position represents benzyl substituted by pyrrolidinyl, piperidyl, hexamethyleneimino, morpholinyl, thiomorpholinyl or 4-methylbiverazinyl) represent or Two Ro on adjacent carbon atoms form methylenedioxy, with the proviso that R When o is other than chloro, fluoro, methyl, methoxy or methylthio, This is only possible in meta or para positions.] compounds or their pharmaceutically acceptable acid addition salts. 2. In formula I, R1 is as defined above and one Ro is hydrogen and the other is in the meta- or para-position, and claim 1 The use according to claim 1, as defined in b) or c). 3. Formula Ib▲ includes mathematical formulas, chemical formulas, tables, etc. for use in tumor treatment. ▼Ib [in the formula, R1 is as defined above and R2''' is chenyl, aryl. ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ , where Ro′′ is in the meta or para position and C2-6 alkyl , tri-(C1-3alkyl)-silyl, or b) above or c) or d) as defined in ▲There are mathematical formulas, chemical formulas, tables, etc.▼, where each R4' is allyl or or two R4′ together with the nitrogen atoms to which they are bonded form a pyrrolidinium ru, piperidyl, hexamethyleneimino, morpholinyl, thiomorpholinyl represents 4-methylpiperazinyl] or its pharmaceutically acceptable acid addition salts. 4. R1 is as defined in claim 1 and R2''' is frill or base ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ where Ro' is in the meta or para position and C2-6 alkyl, represents tri-(C1-3 alkyl)-silyl, or b) of claim 1; is as defined in c) or d)′′ group ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (where each R4'' is allyl or two R4'' are connected together) Pyrrolidinyl, piperidyl or hexamethylene together with a nitrogen atom 3. The use according to claim 3, which represents imino. 5. Formula Ia ▲There are mathematical formulas, chemical formulas, tables, etc.▼Ia [in the formula, R1 is as defined above and R2' is chenyl, freel or or group ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ , where Each Ro'' is independently C5-10 alkyl, C5-10 alkoxy or C represents 5-10 alkylthio, or one Ro'' is hydrogen and the other Tri-(C1-3 alkyl)-silyl, phenyl, monochlorophenyl, monochlorophenyl represents nofluorophenyl or as defined in b), c) or d) above Therefore, the Ro′′ substituent can only be placed in the meta or bara position. or a pharmaceutically acceptable acid addition salt thereof. 6. R1 is in the 8-position and as defined in claim 1. , and R2 is chenyl, furyl, or group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ , where Ro′′′ is in the meta or para position and tri-(C1- 3alkyl)-silyl or b) or c) in claim 1; or d) as defined in claim 5. 7.5-[4'-(piperidinomethylphenyl]-2,3-dihydroimidazo[ 2,1-a] isoquinoline, 5-[4'-(3,4,5-trimethoxybenzyloxy)phenyl]-2,3 -dihydroimidazo[2,1-a]isoquinoline, 5-[3'-(3,4,5- trimethoxybenzyloxy)phenyl]-2,3-dihydroimidazo[2,1 -a] Isoquinoline, 5-[4'-(3,4,5-trimethoxyphenylethyl ) phenyl]-2,3-dihydroimidazo[2,1-a]isoquinoline, 5-[ 3'-(3,4,5-trimethoxyphenylethyl)phenyl]-2,3-dihydrogen a compound selected from doloimidazo[2,1-a]isoquinoline; Pharmaceutically acceptable acid addition salts. 8. A pharmaceutically acceptable diluent for the compound according to claim 5, 6 or 7. or a pharmaceutical composition containing together with a carrier. 9. Compounds according to claim 5, 6 or 7 for use as medicines . 10. Formula V ▲There are mathematical formulas, chemical formulas, tables, etc.▼The corresponding compound of V is dehydrated and the obtained recovering the compound in free form or pharmaceutically acceptable acid addition salt form; A compound of formula I, Ib or Ia according to claim 1, 3 or 5 or A method for producing a pharmaceutically acceptable acid addition salt thereof. 11. Formula Va (8- or 9-) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Va [in the formula, R1 is as defined in claim 1 and Ro'' is as defined in claim 1; as defined in Range Item 7].