JPS6193191A - Substituted 2-furanyl or 5-oxo-2-furanyl- alkoxyphosphorylalkylcyclimmonium salts - Google Patents

Abstract

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

Description

[Detailed description of the invention]

The present invention describes certain substituted 2-furanyl or 5-oxo-2-7 ranyl-alkoxyphosphorylalkyl cyclimonium salts as platelet-activating factor (PAF) receptor antagonists and for inhibiting PAF-induced platelet aggregation. concerning their use as agents. The invention also provides pharmaceutical compositions containing the above compounds as active ingredients and the inhibition of PAF-mediated bronchial stenosis and hyperemia, PAF-induced hypotension and PAF-complicated ischemic bowel disease. It also relates to methods of using the compositions for use. Platelets, also called thrombocytes, are well recognized as important cellular factors circulating in the blood. Their role is to stop bleeding by forming blood clots in ruptured blood vessels; they are natural corks. However, they are associated with various immunologically mediated forms of tissue damage. Their involvement in these processes activates platelet-interacting factor (PAF) and involves release of platelets that induces aggregation and excretion of granular components. Additional effects of platelet activation include a lethal response consisting of primary hypertension, right-sided heart dilatation, systemic hypotension, substantial increases in renal vascular resistance, decreased mechanical pulmonary compliance, and frequent complete pulmonary apneas. cause Recently, evidence has been obtained that platelets appear to activate factors in the generation of fibromuscular lesions in the arterial walls of the aorta and coronary arteries, thereby contributing to the progression of atherosclerosis. moreover,
A possible role for PAF in ischemic bowel disease, particularly necrotizing small colitis (NEC), has also been recently described, suggesting that PAF may be involved in disease progression that causes intestinal recruitment. ing. In particular, the present invention provides compounds of the formula
Thailand: Cy-. phenylalkyl, spanning O-C, where R.0 is hydrogen or methyl, and X is CH, or -C-, and one other selected heteroatom May contain 5
- or a 6-membered monocyclic ring, or a 10-membered bicyclic ring optionally containing one other nitrogen atom, each of which rings may be unsubstituted or Cl-
Mono-, di- or tri-substituted by 4 alkyl or CF, halo, COOH or ("0
Optionally mono-substituted by OCH8, m is 1 or 2, n is 1 or 2, p is 2-8, and y is 0 and q is O or y is H and q is l. Group Y for R group
The points of attachment of are as follows: Hl-1 The compounds of formula (1) can be divided into three subgroups, viz. Preferred compounds of subgroup ia are: R is n-C, . alkyl, alkenyl or alkynyl, or C11-4°alkoxyalkyl, phenyl, penzyltetyly, roxy, or CF8, halo, C0OH or C00CH,
a monosubstituted thiazolium, pyridinium, pyridazinium, quinolinium or inquinolinium ring, p is 2 to 6, and ROs, ffl, Q,, y, 7. and q are as defined above (compound ①a'). Further preferred compounds of subgroup ia are where R is n-C, . Thiazolinium which is alkyl, alkenyl or alkynyl, or Cl4-1m alkoxyalkyl, phenyl or benzyl, substituted by K, di- or tri-substituted or monosubstituted by CF, halo, C00)J or C00CH3, a pyridinium or quinolinium ring, p is 2 to 4, and Ro, m, n, yXZ and q are as defined above (compounds ia"). Particularly preferred compounds of subgroup 1a The groups are ``018-18 alkyl, alkenyl or alkynyl or Cl4-18 alkoxyalkyl, p is 2, and Ro, m, n, yXZ and q are as defined above (compounds ■a'''). Regarding subgroups Ib and )c, the corresponding preferred groups are (i) R can ''14-t. Alkyl, alkenyl moji or alkynyl or C12-! . alkoxyalkyl, n is 1, and the substituents for the remainder υ are as described for la/ (compounds Ib' and IC'); (ii) R is "-CIll-1°alkyl; , alkenyl or alkynyl or Cl4-18 alkoxyalkyl, n is 1, and the remaining substituents are as described for la" (compound 1b"
and lc"), (+ii) R is n CH@1@7/l/kyl, alk=,!1/or alkynyl or Cl4
-18 alkoxyalkyl, n is 1, and the remaining substituents are as described for 18'' (compounds t b m and ■C1//). Other groups of compounds include: R is n-C12-2゜alkyl, X is CH, or C═O, and R. , m is 1″! ! or 2, n is 1, p is 2 to 4, and q is 0 (compound ip). In accordance with the invention, the compounds are prepared by reacting a compound of formula C with a compound of formula cc, in which RlY, T, m, n, p and y are as defined above; keep things inside (innet)
salt) form or pharmaceutically acceptable acid addition salt form. The reaction is carried out in an inert solvent, e.g. an aromatic hydrocarbon, e.g.
It is suitably carried out in zene or toluene, a lower alkyl nitrile such as acetonitrile, or a polar aprotic solvent such as dimethylformamide at a temperature of 50'-100'. Depending on the nature of cc, it can also be used both as reactant and as solvent (for example in the case of pyridi). The starting material for formula C has the formula CCC RY-(CHt)-T-(CI-1,)-OHcc
It can be prepared by reacting a compound of cm n □ with a compound of formula CCCC. This reaction is carried out in a conventional manner in the presence of an amine base such as pyridine or triethylamine and in an inert solvent such as toluene, benzene or an aromatic hydrocarbon such as xylene, such as methylene chloride, chloroform or carbon tetrachloride. halogenated aliphatic hydrocarbons such as halogenated aromatic hydrocarbons such as chlorobenzene;
Or, for example, in diethyl ether. The reaction can be carried out at temperatures between 20° and 70°. The product thus produced is then subjected to basic hydrolysis, for example by suspending the product in water. Hydrolysis is conveniently carried out at temperatures between 20° and 100°C. The starting material for 2ccc can be prepared according to or analogously to the reaction shown in the reaction scheme below. Description for Reaction Scheme R・I = n'14-23 alkyl, alkenyl or alkynyl, CH, OR, or CH, CHxOR
(=Ra) or ('(”:)T,) -QC(CH,
), OCH3(=R,b) R,2=n -C,, alkyl Bn = benzyl HX' = organic or mineral acid M = alkali or alkaline earth metal J = NGO
, NC8, chlorocarbonate or carboxyl chloride G = alkaryl protecting group, e.g. benzyl B' = (
'I Br I m'=2 or 3 E=C1, Br-+f, :-HaT, phenylsulfonyl, toluenesulfonyl, Cl-4 alkylsulfonyl (
Examples of conditions for the process in the reaction scheme are illustrated in the table below or in the examples below. Abbreviations IO = inert organic) [C = hydrocarbon Ha 1l-IC = halogenated hydrocarbon THF = tetrahydrofuran PA = polar protic DMSO = dimethyl sulfoxide DMA dimethylacetamide DMS = dimethyl sulfide LDA = lithium diisopropylamide Intermediates containing substituents other than those mentioned can be prepared analogously thereto, or are known or can be prepared analogously to known methods. The starting materials mentioned above are known and/or can be obtained in a customary manner analogously to known methods. Final products and intermediate products can be isolated and purified using conventional methods. Intermediate products can be used directly in the next step without appropriate purification. As will be apparent to those skilled in the art, the compounds of formula I can exist in racemic or enantiomeric forms and the invention is meant to encompass all forms. Enantiomeric forms can be obtained in common ways, for example by resolution of final or intermediate products! 11 or by using optically active starting materials. The species also exist in cis/trans-isomeric forms. Examples of anions as Z○ are chloride, bromide, iodide, phosphate, hydrogenphosphate, metaphosphate, sulfate, hydrogensulfate and perchlorate. Compounds of formula (1) have been shown to be highly effective due to their ability to inhibit platelet activating factor (PAF)-induced human platelet aggregation in vitro according to the Platelet Aggregation Inhibitory Efficacy Assay (PAIA test) as described below. As indicated, use as a platelet activating factor inhibitor is indicated. Human patients are given no aspirin for one week and fasted overnight. Platelet-rich plasma (PRP) is produced by centrifugation (200Xg) of freshly drawn blood and has a concentration of 0.38%.
Anticoagulate with sodium citrate (final concentration). Platelet-poor plasma (PPP) obtained by centrifugation of blood samples (700X, +7) was used to adjust the platelet count to 250,000 per 1μ. A portion of PRP (0,38 #Il) is administered into the Couvette and kept at room temperature (22° C.) in the trench used (within 2 hours). P
The R.P-containing Couvette is cultured at 37° C. and stirred at 900 rpm in a Beighton agglomerometer to activate it according to the light reflection pattern before addition of the test compound. (
The test compound (dissolved in a suitable solvent mixture that does not affect platelet aggregation) is then added to the PRP-containing Couvette in an amount sufficient to give a final concentration of 100 μM. 0,01 with 0.25% bovine serum albuminy (pH 7,4) 1-2 minutes after addition of test compound
M) an aggregation-inducing agent (C-16PAF'-Zandohannover:PRP-containing query) dissolved in a buffer consisting of resutiroad buffer solution at a predetermined t to give a constant agglutination response. (0,1μM or 0
．． 01 μM). All aggregation occurred after addition of inducing agent 6
Let it proceed for minutes. The aggregation response is quantified by measuring the area under the curve (AUC). Consider the AU calculated for the inducer alone (' to be 100%. The AUC that occurs in the presence of the compound is divided by the AUC of the inducer alone, and 100%.
Multiply and then subtract from 100 to determine the effective % inhibition of the aggregation response. 50% at 100μM
Compounds showing greater inhibition are evaluated at lower concentrations that yield ICa (50% inhibitory concentration) values. In addition, compounds of formula I may be used in human platelet PA, such as:
As platelet activating factor receptor antagonists, as demonstrated by their ability to inhibit the specific binding of (31-1)-PAF to platelets according to the F receptor potency assay (Test A). The use has also been found to be indicated. Healthy human blood donations were treated with 3.15% trisodium citrate and 20 μg/ν prostaglandin T, (
Human blood is obtained by venipuncture at a 9:1 blood-to-coagulant ratio into a layered anticoagulant mixture containing PGI, ). This blood was centrifuged at room temperature for 20 minutes (250 x g
) to produce platelet-rich plasma (pRp). The PRP is then centrifuged at 900Xl for 10 minutes at room temperature.
), and platelet globules with a pH of 7.4 and 0.25
Wash twice with trisutrode (':TT) solution containing bovine serum albumin (BsA) and to which PGI has been added at a final concentration of 0.3 jJ/y. Blood, platelets were treated with TT containing 1.4mM cac12-2H,0 and 0.7mM MgC1,6H20.
Resuspend 350.000μ in /B8A. All tests are performed in duplicate and each of the test compounds is evaluated at concentrations of 100.50.1 and 0.1 μM. The following solutions are mixed for each measurement: 500 μt of the above platelets 10 μt of [:”t-1:]-PAF (1,5 μM of platelets)
40.000 counts per minute (cpm) to final concentration, and either: 10 μt of test compound at 50 times the desired final concentration, IO μt of excipient (all bound), or 10 μt of 1.
85X10'M cold PAF (non-specific binding). Each mixture was incubated for 1 hour at room temperature, after which time the 5'O
Addition of O μt of ice-cold TT/BSA and 1 at 4°C.
The reaction is terminated by centrifugation (900% g) for 0 min. The resulting supernatant was suctioned into a scintillation bottle, the pellet was washed with 250 d of water-cooled TTBS, and
Then centrifuge for 10 minutes at 4°C (9 ooxl). The supernatant is then aspirated into the same scintillation bottle as before and placed in a 10 d scintillation bottle.
Add and mix with it (liquid'/7f ration cocktail). The pellet is suspended in a 500 μt scintillator and mixed well. another 2
A scintillator of μ' is then added to the bottle and after mixing the bottle is counted in a liquid scintillation spectrometer.Total bound C3H]-PAF and non-specific bound [3
Calculate the amount of specific binding as the difference between H]-PAF, cpm. % inhibition of specific binding is defined as the total specific bound cpm in the presence of the test compound.
Measure by multiplying 1 in pm by 100 and then subtracting from 100. F by evaluating the test feed compounds over the entire concentration range.
) IC,. (50% inhibitory concentration). Furthermore, in view of their ability to act as PAF receptor receptor antibodies, compounds of formula 1a are indicated for use as inhibitors of PAF-mediated bronchial stenosis; Hypertension (PIF) increase test (Test B)
Evaluated by. Male guinea pigs weighing between 300-400 g are anesthetized and then endotracheal tubes, carotid artery and jugular vein catheters are inserted. Harvard re-spirator for small test animals
forced ventilation using the and pulmonary inflation resistance (PIF)
pressure transducer
) and a recorder. Test compounds are administered orally 30 minutes or intravenously (jugular) 5 minutes before addition of PAF. PAF (C+a-Sand, Hannover) was dissolved in trisuti-loaded bovine serum albumin buffer and
Administer intravenously (jugular vein) at 0 ng/kg. Blood pressure measurements taken are recorded from a transducer connected to the carotid catheter. 2 in PIF record after administration of PAF
Species responses were observed. i.e. z) Immediate response with a mean value of 70% to 80% above the baseline PIP value in test animals treated with PAF alone. (this initial response is also the maximum response, and is therefore referred to as a large PIF); and 2) a long (at least 30 minutes) PIF that slowly decreases to baseline.
response. The reading at 15 minutes after administration of PAF is the end point PIF.
It is called. The effect of a test compound on the PIF response is determined by the maximum PIF from baseline for test animals that received PAF and test compound compared to test animals that received PAF alone.
It is measured by the difference between the % increase in In addition, the compound of formula (II) is capable of inhibiting PAF-mediated extravasation (transfer of plasma from the tube embryo of the blood vessel into the vessel wall and surrounding tissues), measured as a function of hemoconcentration according to the PAF-induced extravasation test (Test C) as described below. It is also indicated for use as an inhibitor of protrusion). Male guinea pigs weighing 300-400 g are anesthetized and then a femoral catheter is inserted. PAF addition 1~
Test compound is administered intra-arterially 5 minutes prior. PAF(C,,
- Zand, Hannover) was dissolved in trisuterode bovine serum albumin buffer and 100 n117
Administer intravenously (jugular vein) in kg. To measure the hematocrit value, which is used for the hemoconcentration index and is defined as the percentage of packed red blood cells in a sample of blood that is centrifuged to separate plasma from cellular components, blood samples were injected with 50 μt heparin. Collect in added hematocrit tubes. These samples
Immediately before injection of PAF, 1 minute after injection of PAF, and PA
Samples are taken every 2 minutes thereafter until 15 minutes have elapsed since the injection of F. The tubes are then centrifuged and the percentage of packed red blood cells (hematocrit) is determined (PAF induces a maximum increase in hematocrit 5-7 minutes after injection of PAF). Calculate the percentage increase in hematocrit relative to the pre-injection value of PAF. The hematocrit values obtained with the test compound are compared to the hemoconcentration values obtained with PAF alone and are expressed as the percentage inhibition of the percentage increase in hematocrit. Furthermore, the compound of formula I was tested according to the test below (test D).
Their use as inhibitors of PAF-induced hypertension as measured by their ability to inhibit AF-induced decreases in blood pressure water rates is also indicated. Male Rice p-(Wistar) weighing approximately 300g
Anesthetize the rats and insert a cannula into their carotid artery to allow their diastolic and systolic arterial blood pressure measurements to be recorded. PAFf:100f or 500 nI/kg was then administered intravenously and the blood pressure decreased (within 10 seconds) and pre-
The recovery time required to reach the injectable blood pressure level is determined. At 1100 n/kg, a 30% decrease in blood pressure and recovery time of 3-4 minutes was observed, while at 500 n/kg
A 52% reduction in blood pressure and a recovery time of 10 minutes was observed. To determine the effectiveness of compounds both in reducing blood pressure drop and shortening recovery time,
Test compounds are administered intravenously over a range of 5 to 7 dose levels (1 or 2 test animals per dose) and 1 to 5 minutes before addition of PAF to obtain HD, o. Furthermore, the compound of formula I is also indicated for use as an inhibitor of PAF-induced ischemic bowel disease, the properties of which were determined according to the test described below (Test E). Essentially F, Gonzalez
-Crussi and W, Hsueh
)'s The Journal of American Patology (
J, Amer. Pathol, ), pp. 112.127-135 (198
3: Approximately 260 to 300 according to the steps described in
Sprague-Dawley weighing between J.
- Dawley) Rats are anesthetized, cannulated into their carotid artery and connected to a blood pressure transducer and recorder. Test compounds are added into a cannula inserted into the jugular vein 1° prior to PAF administration. The abdomen is then incised along the midline and 2 JilOPAF or 2Q, uJ of LPs (lipopolysaccharide) and immediately followed by lu, 17 of PAF are injected into the abdominal aorta at the level of the renal arteries. Then cover the abdominal incision with gauze moistened with saline, expose the intestines, and die 2-3
Inspect regularly until the scheduled time. Next 5d 2 into the jugular vein
% Evans Blue is injected to assess intestinal currents. A chunk of intestinal tissue is then taken for microscopic examination to determine the extent of necrosis or to demonstrate the absence of necrosis when inhibited by the test compound. In situ microscopic changes are evaluated by hematoxylin and eosin staining. Test compounds: are evaluated for their ability to reduce or prevent the growth of gross and microscopic lesions and are expressed as the number of animals in which inhibition is observed relative to the control (taken as 100%). The compounds are therefore also indicated for use in inhibiting or antagonizing PAF, and suitable daily doses indicated for this use are about 1-500rn9, preferably 1-500rn9.
rr19, they are suitably 0.25-500
Administered in divided doses, preferably from 0.25 to 5011 Ig, four times a day or in modified release form. A typical oral dose is 59 times a day. The compound further inhibits PAF-mediated bronchial stenosis and hemorrhage;
It is also indicated for use in the treatment of PAF-induced hypotension and ischemic bowel disease, and the indicated daily dosage for this use is about 10-2000rn9, preferably 10-350rn9. and suitably 0.25~5o
oIn9 (particularly 0.25-3 somp) is administered in divided doses of 4 to 18 or in modified release form. Typical oral dosage is 50t or 100g two or three times a day.
It's da. Therefore, the present invention provides a method for inhibiting or antagonizing platelet activating factor, which comprises administering to a patient in need of treatment a compound of formula Methods for the treatment of hypertension and ischemic bowel disease, and in the treatment of, for example, inhibition or antagonism of platelet activating factor and platelet activating factor-mediated bronchial stenosis and extravasation, platelet activating factor-induced hypotension and ischemic bowel disease. It also relates to said compounds for use as medicines. The compounds can be administered alone or mixed with a pharmaceutically acceptable diluent or carrier and optionally other excipients, and can be administered orally, for example in tablets, dispersible powders, granules, elixirs, capsules or It can be administered in the form of a suspension or parenterally, for example in the form of a sterile injection solution or FiS suspension. Preferred pharmaceutical compositions from the standpoint of ease of manufacture and administration are solid compositions, I# tablets and hard-filled or liquid-filled capsules. Such compositions also form part of the invention. The following examples illustrate the invention, in which all temperatures are in °C. Example 1 3-12-1(2-octadecyloxy)ethyl-5-
oxo-tetrahydro7ran-2-yl] methoxyhydroxyphosphinyloxy-ethane J thiazolium hydroxide Uchibori-4-1st el'-1
-----------〇=Thiazoolium; p=O a) Production of 1-benzyloxy-4-year-old tadecyloxy-butan-2-ol Washed until oil-free using petroleum ether 12. in mineral oil (30 mmol). 200 mj in 60% sodium hydride of Og! 32.4 g (0.3 mol) of benzyl alcohol in dry dimethylformamide were added. The suspension was kept at this temperature for 45 minutes, then 1
66.1 g (0,
19 mol) of epoxide (prepared by peracid oxidation of octadecyl-3-butenyl ether) were added and the temperature was maintained at 80° for 15 hours. The solvent is then removed in vacuo,
The residue was then chromatographed on silica gel using a mixture of petroleum ether and diethyl ether in a ratio of 3:2 as eluent to yield a waxy solid. b) Preparation of 1-benzyloxy-4-octadecyloxy-2-butanone from the addition of 10.4 mf of dry trimethyl sulfoxide to 8.9 bi(70 mmol) of oxalyl chloride in 150+n/methylene chloride at -60°C. 27.7 g (62.2 mmol) of the above a
) was added directly. After stirring the mixture for 1 hour under nitrogen atmosphere, 50 mm! of triethylamine in methylene chloride is added and the resulting mixture is warmed to Oo for 30 minutes, after which it is heated to 75+aj! Cooled with water. After the mixture was allowed to warm to room temperature, the organic layer was separated, washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give an oil that solidified on standing. On the silica sol a mixture of petroleum ether and diethyl ether in a ratio of 7:3 was added as eluent and 1. Solid, melting point 33°-34° by flash chromatography using
, occurred. C);)-pencyloxymethyl-3-hydroxy-1
- Preparation of tadecyloxy-hept-6-ene 1.12 g (8 mmol) in 15 ml of dry ether
of 4-promo-1-butene was reacted with 200+eg of magnesium flakes under reflux and nitrogen pressure for 1 hour. The resulting Grignard reagent was cooled to −6()° and then: 2°22 g (5 mmol) in 10 val of ether.
91 was treated with the compound prepared in b) above. -60
After 1 h at °C, the mixture was allowed to warm to room temperature overnight, then washed twice with saturated ammonium acetate, saturated sodium chloride solution and dried over magnesium sulfate, after which the solvent was removed under reduced pressure. Purification of the crude product was carried out on silica gel using a mixture of petroleum ether and diethyl ether as eluent to yield a low melting, alpha solid. d) h-benzyloxymethyl-2-hydroxy-5-
(2-Octadecyloxyethyl)-tetrahydro 7 run f'i, 15 g (12°3 mmol) of the compound prepared in C) above in 100 m/m of methylene chloride - 60
Treated with ozone at °C. After olefin's tl ¥ cost, 25-! dimethyl sulfoxide and the mixture was allowed to warm to room temperature. ? The Il solvent was removed in vacuo and the crude product was purified on silica gel using a 7:3 ratio mixture of oil ether and diethyl ether as eluent to yield a colorless oil. c) S-benzyloxymethyl-5-(2-octadecyloxyethyl)-4,5-dihydro-2(311
)-72 non yl preparation 1, 25 mj of 6 g (7.4 mmol) of pyridinium chlorochromate! In a solution of 25+II in methylene chloride,
j! 3.5 g (6.5 mmol) of the compound prepared in point 11 b) of 1 in methylene chloride were added. After 18 hours at 25°, the solution was diluted with 150 mA of ether, filtered through silica gel, and the filtrate was evaporated to give an oil. The oil was then flash chromatographed on silica sol using a mixture of petroleum ether and 1 diethyl ether in a 7=3 ratio as eluent to yield a colorless oil. 10.2 g (21,83 mmol) of 5-hydroxymethyl-5-(2-year-old 2-tadecyloxyethyl)-4,5-nohydro-2(3I summer)-furanone (C) A mixture containing 5% palladium on carbon (50% water content), 300 ml of ethyl alcohol and water in a ratio of 9:1 was placed in a pressure bottle and 40" The odor was threaded under 50 Bond water system pressure until absorption was complete. The catalyst was then filtered and the furnace liquid was decanted (in vacuo). The residue was recrystallized from methanol to form a solid. g) 2-bromoethyl-(2-octadecyloxyethyltetrahydro-5-oxo-72-2-yl)-methylphosphoric acid diester 6(n+nn) in dry benzene 141?(:(3,9
mmol) of the compound prepared in f) above;
, (/lo, 7 mmol) of 2-bromoethyloxyphosphorodichloridate was added. The resulting solution was cooled in a water-salt bath and treated thoroughly with a solution of 3.5 ml of pyridine in 40 ml of benzene under a nitrogen X atmosphere. water-
After removal of the salt bath, the mixture was allowed to warm to room temperature over a period of 6 hours. The volatiles were removed under reduced pressure and the residue was
of water and heated on a steam bath for 80 minutes. After cooling to room temperature, the mixture was extracted with chloroform. After drying the extract over magnesium sulfate, filtering, and removing the solvent, a white solid was observed. h) Preparation gA of the title compound 2-Bromoethyl-(2-octadecyloxyethyltetrahydro-5-oxo-7ran-2-yl)-methylphosphoric acid diester was placed in a pressure bottle and 20w+j! of thiazole in toluene was added. The resulting mixture was reduced to 65° by 5011. ? After heating in the dark, it was cooled and evaporated in vacuo. Next, remove the remaining liquid to 500 Io.
After adding 10.5 g of silver carbonate, the mixture was stirred for 90 minutes. The solids were then removed by filtration and the filtrate was evaporated under reduced pressure to yield the crude product in the form of a brown residue.
Purify with 1. Continuously methanol in methylene chloride 95% solution, methanol in methylene chloride 1, + 20%
Elution with solution and finally a solution of methylene chloride, methanol and water in the ratio 10:5:1 yielded the title compound as a white solid, molten, -x200°-205° (decomposed). Example 2 3-42-((2-octadecyloxymethyltetrahydrof-2-2-yl-methoxy)-human Uxyphosphinyloxy]-ethane 1-thiazolium 1-4 -Oxide a) of 2-hydroxymethyl-2-octadecyloxyethyltetrahydrofuran! 2.64 g (20 mmol) of 2,2-bishydroxymethyltetofhydro7 in 8 liquids in a 1:1 ratio of dimethyl sulfoxide-tetrahydro7 run of in8 h+β
To a mixture of oran and 2.20 g (6.6 mmol) of octadecyl bromide was added 1.84 g (26.4 mmol) of pulverulent potassium hydroxide and the resulting mixture was stirred at room temperature for 2 hours. . The mixture was then poured into 10 mf of water, diluted with saturated sodium chloride solution and extracted with ether. The ethereal extract was then washed with saturated sodium chloride and dried over sodium sulfate. was removed to yield the crude product as a low melting, alpha solid. The crude product was then purified on silica gel using 3:1 ratio of methyl-1-butyl ether and hexane as solvent M agent and 17 , produced a white waxy solid. b) 2-bromoethyl-1(2-octadecyloxyethyltetrahydrofuran-2-yl)-methylphosphoric acid diester 2,! ;0.244H promoe in mA benzene)
-N cyphosphor dichloridate at 0.322° ((1,
After adding 84 μl of the compound prepared in a) above and cooling the resulting mixture in a water bath, the cooled mixture was treated dropwise with 82 μl of dry pyridine. The water bath was then removed and the mixture was stirred under nitrogen atmosphere for 5 hours. The solvent is then removed in vacuo and the residue is 4+a
1 of water was added. The mixture was then heated on a water bath for 15 min, then cooled to room temperature, diluted with water, and extracted with ether. The ether extract was then washed with water and dried over sodium sulfate. , and after removal of the solvent 7 ohms were obtained. C) Preparation of the title compound 2-bromoethyl-(
2-Year-Old Tadecyloxymethyl Tetrahydro 7ran-2
-yl) methyl phosphoric acid diester was added and the mixture was heated for 6 H after sealing the bottle. The volatiles were then removed in vacuo and the residue was added to ethanol and 0.5 g
of silver carbonate was then added and the mixture was stirred for 1 hour, after which it was filtered through Celite, 1hfJk-, and the filtrate was evaporated to a solid state. Generated remainder, -8 to 1()1111
of methanol and I001nβ of activated charcoal were added and the mixture was heated for 50” to 1111 min. The solids were then removed by filtration and the filtrate was evaporated under reduced pressure to yield the crude product. 111 product to silica gel.
L''c'A Purification in a manner similar to that in Fertilization 1 in Example 1 yielded the title compound in solid form. Melting point 140''
(Disassembly). Tenshi cum 1 piece! ) 3-2-(2-octadecylami7carponyloxymethyltetrahydro07ran-2-yl-methoxy)-hydroxyphosphinyloxy-ethane-thiazolium hydroxide internal temperature-4-su-N~side a ) Production of 2-hydroxymethyl-2-octadecylamide 7carponyloxytetrahydro 7rane 1 ( ) Zui! 4. into a mixture of 9 g (14.4 mmol) of 2,2-bishydroxymethyltetrahydro7rane in birinone at room temperature and under a nitrogen atmosphere.
A solution of 0.4 g (13,'7 mmol) of n-octadecyl incyanate in 15 val of pyridine was added. The resulting mixture is heated to 60' and at this temperature 31E? After a period of time, the solvent was removed in vacuo to yield a residue, which was partitioned into a mixture of methylene chloride and 2N hydrochloric acid. Then the organic layer is continuously saturated with salt)
17 um, 2N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride, and dried over magnesium sulfate. Then the solvent was removed and the residue was purified on silica sol using methyl-t-butyl ether as eluent. A white solid was produced by tertiary atomography. The reaction was continued as in Example 1g) Ascension h) and 2
The crude product was produced via -bromoethyl-[(2-octadecylami7carbonylogisimethyl-tetrahydro7ran-yl)methyl"-phosphoric acid diester. This was then dissolved in a 19:1 ratio mixture of tetrahydro 7 run and water, and the resulting solution was then traced into a column of 2) MU-, 3 ion-exchanged 4H IrF4. The agent was then evaporated in vacuo and chromatographed in essentially the same manner as in Example 1 above to yield the product, which was precipitated from methylene chloride using acetone to give the title compound as a milky white solid. Generated with. Melting point 1°70-175° (decomposition). Example 4 3-12-1 (2-octadecylami7carponyloxymethyltetrahydro7ran-2-yl-methoxy)
-Hydroxyphosphinyloxy]-ethane]-thiacylinyl 1-hydroxide 4- was prepared in the same manner as in Example Ih). (omitted)

[7] Starting from the bromoethyl compound of Example 3. Example 5 2-1Hydroxy(tetrahydro)-2-Coctadecyl-5-oxo-2-7ranyl)-nodoquinphosphinyloxy]-ethanethiazolium, >t'-■
-4-Oxide Analogously to Example 1a)-b) and starting from 1-epoxyeicosane instead of octadecyl-3-butenyl ether, the title compound was obtained in solid form. Melting point>122'' (decomposed) Example 6 2-F Hydroxy(tetrahydro)-2-(octadecyl-2-7ranyl)-methoxyphosphinyloxy1ethanethiazolium hydroxide-Pressure Niene IA No.1'
----------1-------a) 2-Paidyloxymethyl-2-octadecyl-tetrahydro 7-ran W
i-zukuri 11.5. (26 mmol) of 5-benzyloxymethyl-2-hydroquine-5-octadenlutetrahydride C7
120 theories containing 4.54g (39 mmol) of triethylsilane for 7 runs! of dichloromethane and the reaction mixture was cooled to −20” under nitrogen atmosphere. 4.26 g (30 mmol) was added to the cooled solution.
of boron trifluoride etherate was added, and a saturated aqueous solution of sodium bicarbonate was added. The resulting mixture was then warmed to room temperature and chromatographed on silica gel with extractive isolation to yield a colorless oil. The reaction was continued as in Example irh) to produce the title compound PIl in the form of a white solid. Yu, I″i, 198-
204'<decomposition). Example 7:'! -12-1(2-octadecylamine 7carponyloxymethyl-tetrahydro7ran-2-yl-methoxy)-hydroxyphosphinyloxygoethane"-quinolinium hydroxide-Uchihanji"-oxide 111) Starting from the pamoethyl compound of Example 3 and quinoline. Melting point〉105゜(min.
). Example 3; 3-[-1(2-octadecylami7carponyloxymethyl-tetrahydro7ran-2-yl-methoxy)-
Hydroxyphosphini, ruoxy I-hexane J-thiazolium hydroquine
------- Starting from the compound of Example 3a and 6-promohexylphosphoronochloridate analogously to Examples 18) and l+). Melting point 65-70°
(Disassembly). Example 9 3-+2-[(2-(9-octadecenyl)ami7carponyloxymethyl-tetrahydro7lan-2-yl-
methoxy)-hydroxyphosphinyloxygoethane J-thiazolium hydroxide--4-oxide Example 3n) Similarly to Example 1g) and h), n-octadecyl isocyanate was replaced with n-octadecyl isocyanate. A waxy solid was obtained using 9-nylisocyanate. Example 10 Cis-1-(2-hydroxy[[tetrahydro-5-[
octadecylami7carbonyl)oxyJmethyl17ran-2-yl1methoxyphosphinyloxyJethyl)
-Quinolinium hydroxide-filled-4-oxide O a) cis-2-[(octadecylami7carbonyl)
10.1° (0
, t) 77 mol) of cis-2,5-bis(hydroxymethyl)tetrahydro7rane were added 22.5 g (0,077 mol) of +1-octadecyl isocyanate at room temperature and under a nitrogen atmosphere. The resulting mixture was then heated to 60° and after being kept at this temperature for 12 hours the mixture was cooled to 25° to form a precipitate (7.
00 m/m of diethyl ether and washed the solid collected after filtration.Then the furnace liquor was concentrated under reduced pressure to remove oil and it was heated at 50° and 0.11III11 mercury for 30 minutes. Ial drying yielded the crude product as a pale yellow solid. The crude product was then purified on silica gel using a mixture of hexane and acetone (3:1 volume ratio) as eluent to yield a white solid. b) Preparation of cis-1-12-1hydroxy[[tetrahydro-j3-octadecyl7mi7carbonyl)oxytumethylj7ran-2-ylJmethoxyphosphinyloxy1ethyl1-bromide dissolved in 15 mff1 of dry benzene. 1゜2
8 g (3 mmol) of the compound prepared in a) above are dissolved in 611 IAI of dry benzene at 1°1
fig (4.8 mmol) of 2-bromoethyloxyphosphorodichloridate is added. The resulting solution is then cooled in a water bath and dissolved in 6 ml of dry benzene under nitrogen atmosphere.
was treated dropwise with a solution of birinone. After 5 minutes, the water bath was removed and the mixture was allowed to warm to room temperature for 5 hours. Then add 10 ul of water and heat the mixture to 60' with stirring 1. and at this temperature; after cooling to room temperature, the mixture was partitioned between noethyl ether and water; the stratified layer was then sulfurized; and a solid was obtained after removal of the solvent. C) 5 of the title compound! 1.8 g of cis-1-(2-1hydro to Quinoline was added and the resulting mixture was heated to 80° with stirring and under a nitrogen atmosphere and kept at this temperature for 16 hours.The resulting brown solution was then cooled and diluted with hexane. , a precipitate formed. The solid was then thinned out of solution and chromatographed on silica sol using a mixture of methylene dichloride, methanol and water (80:18:2 volume ratio) as eluent. The crude product was obtained as a light brown solid.The crude product was first purified on silica gel and successively eluted with methylene chloride and a mixture of methylene chloride and methanol (4:1 volume ratio). A tan-colored 7 ohm was produced, which was extracted in methanol and diluted with diethyl ether to produce 5-6 flocculent white precipitate lumps. (6:4 volume) and concentrated to yield the title compound as a beige solid upon drying, melting point 56-60° (depending on degree of hydration). Example 11 Cis- 1-(2-1hydroxy[[tetrahydro-5-
1(octatecyl7-carbonyl)oxy1methyl17ran-2-ylmethoxyphosphinyloxy1ethyl)thiazolium hydroxide. l-4-oxide Analogously to Example 10c), using naazole instead of quinoline and precipitating with diethyl ether. The crystals were collected and chromatographed on silica using a mixture of 117a form, methanol and water (1 (G5:1'6 ratio)) as eluent to give a white solid. ; and diethyl ether (1:1 volume ratio), the title compound was produced as a white solid. M, rW 105-110°. Example 12 Cis-1-(2-1 Hydroxy -5-
1(octadecyloxyjmethyl17ran-2-yl1
Methoxy-phosphinyloxy-1ethyl)-quinolinium hydroxide, device-4-oxide a) cis-2-(octadecyloxy)-methyl-
Preparation of 5-hydroxymethyltetrahydro7rane 40+nl of tetrahydro7furan and trimethyl X/
L, +i, 9 dissolved in a 1:1 mixture of oxides
Add 271 g (o, o 7 moles) of cis-2,5-bis(hydrocymetolu, 1 mole) of potassium hydroxide in the form of a dye powder;

【,hand[
1 was dissolved in a mixture of 40 ul of tetrahydrofuran and dimethyl sulfoxide over 30 minutes at 1'L. 5 g (0.04 mol) of 1-bromooctadecane were added in full. The resulting yellow mixture was stirred at room temperature (25°) under a nitrogen atmosphere for 16 hours, after which it was concentrated under reduced pressure to remove the solvent. S the sticky oil produced
OOmj! of diethyl ether and 1
Washed with 00+a1 water. The ether solution was dried and concentrated to yield the crude product as a waxy solid. 19. The crude product was then purified with silica gel using a mixture of petroleum ether and acetone (85:15 by volume) as eluent. chromatography to yield a white waxy solid after condensation 6 b) cis-me+2-thydroxy 1[tetrahydro-5-[actadecyloxy
3.8 g of gli 501ni of -yl J methoxyphosphinyloxy 1 ethyl)-bromide (
0.01 mol) of the compound prepared in a) above and 10 m
3.6 g (+1.01
5 mol) of 2-bromoenaloxy-phosphorodichloridate was added. The resulting solution is then cooled in a water bath,
It was then treated dropwise with a solution of 1.2 g of pyridine dissolved in 10 ml of dry benzene under a nitrogen atmosphere. 5
After a minute, the water bath was removed and the mixture was allowed to warm to room temperature with stirring over a period of 16 hours. Then 10 ml of water were added and the mixture was heated to 30° (30°) while stirring and kept at this temperature for 45 minutes. After cooling to room temperature, the mixture was diluted between diethyl ether and water. The fiiso J (14) was then dried over sodium sulfate, filtered and after removal of the solvent the crude product was an oily solid and 1-
So 4'f is gone. The crude product was then eluted successively with silica gel and petroleum ether and acetone (
70:30 volume ratio) mixture, acetone and petroleum ether (1:1 volume ratio) mixture, and methylene chloride and methanol (volume ratio) mixture (85:15 volume ratio) were used for chromatography. Concentration under reduced pressure produced a white waxy solid. Preparation of the title compound: (, 4 g of cis-1-1-1 hydroxy [[tetrahydro-5-1 octadecyloxy"-methyl J-7 ran-2-yl J methoxy-phosphinyloxy 1 ethyl)
-10 mj for bromide! of quinoline was added and the resulting mixture was heated to 80° under nitrogen with stirring and kept at this temperature for 16 hours.The resulting brown solution was cooled and diluted with diethyl ether, resulting in a brown precipitate. Ta. Discard the precipitate and add the mother liquor to 21! Subsequently, the crude product was concentrated under reduced pressure and in 0.2111 m Hg to give the crude product as a brown syrup.The crude product was then dissolved in methylene chloride, methanol and water (
The 80:18:2 volume ratio) mixture was chromatographed using 7 as eluent to give a tan 7 ohm after concentration under reduced pressure. This 7 ohm was then subjected to a pre@thin 117 tograph using the same eluent mixture as above to give a thick iJ? Upon drying, the title compound was obtained as a beige solid. Melting point '74-78° (decomposed).

Claims (1)

[Claims] 1. Formula I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is n-C_1_2_-_2_0 alkyl, alkenyl or alkynyl, C_1_2_-_2_4 alkoxyalkyl, phenyl or C_7_-_9 phenylalkyl , Y is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and T is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲Mathematical formulas,
There are chemical formulas, tables, etc.▼, where Ro is hydrogen or methyl, and X is CH_2 or ▲There are mathematical formulas, chemical formulas, tables, etc.▼
is a 5- or 6-membered monocyclic ring optionally containing one other heteroatom selected from nitrogen or sulfur, or represents a 10-membered bicyclic ring optionally containing one other nitrogen atom, each of the salts being unsubstituted or mono-, di- or tri- - even if substituted or CF_3, halo, COO
optionally mono-substituted by H or COOCH_3 is a pharmaceutically acceptable anion, m is 1 or 2, n is 1 or 2, p is 2-8 , and y is ■ and q is 0, or y is H and q is 1]. 2. 3-[2-[(2-octadecylaminocarbonyloxymethyltetrahydrofuran-2-yl-methoxy)-hydroxyphosphinyloxy]-ethane]-thiazolium hydroxide-4 in the form of an inner salt or bromide -Oxide. 3, cis-1-(2-[hydroxy[[tetrahydro-
5-[(octadecylaminocarbonyl)oxy]methyl]-furan-2-yl]methoxyphosphinyloxy]ethyl)-quinolinium hydroxide, inner salt-4-oxide. 4. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable diluent or carrier. 5. A compound according to claim 1 for use as a medicine. 6. In the inhibition of PAF-induced platelet aggregation or PA
A compound according to claim 1 for use in the treatment of F-mediated bronchial stenosis and extravasation and PAF-induced hypotension and ischemic bowel disease. 7. Formula c ▲There are mathematical formulas, chemical formulas, tables, etc.▼■ Compound of formula■ ▲There are mathematical formulas, chemical formulas, tables, etc.▼■ [In the formula, R, Y, T, m, n, p and y are as above as defined in claim 1 and recovering the product in internal salt form or in pharmaceutically acceptable acid addition salt form. A method for producing a compound. 8. Subgroups I a′, I a″, I a substantially in the specification
′″, I b′, I b″, I b′″, I c′, I c
'', Ic'''' and the compounds according to claim 1, as described with respect to Examples 1-12.