JPS63501293A - Amide derivative - 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] Amide derivative The present invention provides novel amide derivatives and, to put it simply, thrombosensan A2 (hereinafter referred to as '' TXA2') and is effective as a therapeutic agent. Novel N-(4(Z)-6-(4-o-hydro*'/7xnyl-1,3) -Dioxane-cis-5-yl)hexenoyl]-sulfonamide Complainant Ru. The present invention also provides novel pharmaceutical compositions containing one of said novel derivatives and novel pharmaceutical compositions containing one of said novel derivatives. This invention relates to a method for producing a mido derivative and an intermediate for use in producing the same.

TXA2 is an effective aggregator of platelets and a strong vasoconstrictor. It is publicly known. TXA2 is also an effective contractile agent of bronchial and tracheal smooth muscle.

Therefore, TXA2 can be used in a wide variety of disease states, such as ischemic heart disease, myocardial stiffness, etc. thrombosis, angina, cerebrovascular disease such as transient cerebral ischemia, migraine and stroke, peripheral vascular disease Diseases such as atherosclerosis, tubular abnormalities, hypertension and lipid imbalance Blood coagulation defects and pulmonary artery embolism, bronchial asthma, bronchitis, pneumonia, respiratory distress and may be involved in emphysema. Therefore, compounds that antagonize the effects of TXAg or any other disease in which it is desired to antagonize the effects of TXA2. Anticipated to have therapeutic value in the prevention or treatment of any one or more diseased conditions be done.

European Patent Application Publication No. 94239 by the present applicant KFi, Formula 2 : [In the formula, Ra and Rh each represent a hydrogen atom, an alkyl group, a halo-noalkyl group, or an alkyl group. rukenyl group and optionally substituted aryl group are arylalkyl groups; , RC is a hydroxy group, an alkoxy group or an alkanesulfonamide group, and n is one-to-two, A is an ethylene group or a vinylene group, and Y is optionally an alkali group. (2-50) polymethylene group substituted by a kill group and benzene mB J11 or 2 optional substituents 'l? r: supported] and dioxic A series of 4-phenyls with cis relative stereochemistry in the 4th and 5th positions of the San ring. Nyl-1,3-dioxan-5-ylalkenoic acid derivatives are described. Toko is represented by the above formula 2, as defined below, in which the benzene ring B is is droxyphenyl, n is 1, A is 7-subinylene, and Y is ethyl By a new group of amide derivatives in which R is ren and R is sulfonamide, It has been found that this shows particularly effective TXA2 antagonism (this fact was demonstrated in the present invention). ).

According to the invention, formula I: [In the formula, R1 is a group represented by the formula: R30,OR'R5-, and in the formula, R3 (1-6G) an alkyl group or a phenyl group, the latter group optionally containing a halide , cyanogen, nitro, trifluoromethyl and (1-40)alkoxy. and R4 and R5 are (1-4C)alkyl, independently of each other. group; and R2 is a (1-6C) alkyl group, benzyl or phenyl, The latter two optionally include oro, (1-4C) alkyl, (1-4C) ) can carry all alkoxy, trifluoromethyl, cyanogen or nitro substituents and the substituents at the 4- and 5-positions of the dioxane ring in formula I and the substituent R1 are in the cis phase. N-C4(z)-6-(4-O -Hydroxyphenyl-s1. 3-dioxan-5-yl)hexenoyl A sulfonamide or a pharmaceutically acceptable salt thereof is provided.

It is clear that they exist and can be isolated in optically active and optically active forms. The present invention , racemate and any optical compound capable of antagonizing one or more of the effects of TXA2. Both active forms (or mixtures thereof) are known to the individual skilled in the art.

Although the chemical formula IC is shown to have a particular configuration, this does not necessarily mean that its absolute It does not correspond to placement.

Special representations of R4 or R5 include, for example, methyl or ethyl, and especially methyl. be. It is generally advantageous to have no more than 4 carbon atoms together with R4 and R5. It is.

If R2 or J'tR3 is phenyl or R2 is benzene as defined in Genesis In the case of a dihydride, a special list of optimal substituents that can be present, e.g. For example, halogenated fluoro, chloro or bromo5(1-10)alkyl groups Regarding 5, it is methoxy or ethoxy.

Special pharmaceutically acceptable salts of the sulfonamide derivatives of formula I are eg Ligium M4 salts and alkaline earth metal salts such as lithium salts, sodium salts, potassium salts salts, 1gnesicum salts and calcium salts, aluminum salts and ammonium salts, and and salts with organic amines and quaternary bases that form physiological Ic-acceptable cations. ・For example, methylamine, dimethylamine, trimethylamine, ethylenediamine , piperidine, morpholine, pyrrolidine, piperazine, ethanolamine, tri- Ethanolamine, N-methylglucami/, tetramethylammonium hydroxide hydroxide and benzyltrimethylammonium hydroxide.

The special R1 which is particularly important is, for example, 1-[(1-4C)alkoxy 2-1-methylethyl, and 1-methyl-1-phenoxyethyl (optional) Fluoro, chloro, bromo, cyano or nitro substituent supported on phenoxy group ) and special cases covered by R2, such as methyl, ethyl, and fluoro, chloro, bromo, Schiff/, nitro, trifluoromethyl or methane Incorporating phenyl bearing a toxy substituent.

Special cases where R2 is a (1-60) alkyl group include, for example, methyl, ethyl ole, propyl or inglovir.

Advantageously R1 represents 1-methoxy-1-methylethyl or 1ti-methyl- 1-phenoxyethyl and R2 preferably represents methyl or ethyl It is.

Special cases where R3 represents a (1-60) alkyl group include, for example, methyl, ethyl Rumata #iGlobil.

A particular compound of formula I that requires 1 cM is shown in Example 1 below. This compound, or a pharmaceutically acceptable salt thereof is provided as another feature of the invention. .

Compounds of formula I can be prepared using conventional methods known to those skilled in the art for the preparation of structurally similar compounds. It can be produced by mechanochemical methods. Such a manufacturing method is another aspect of the present invention. R1, R2, R3, R4 and H5J, i represent any of the above: The aldehyde represented by the formula: %formula% [In the formula, R' is an alkyl group or an aryl group (especially phenyl) and M+ cations, such as alkali metal cations, such as lithium, sodium and potassium cation].

This method generally indicates that substituents adjacent to the dil bond have preferential cis relative stereochemistry. A compound of formula (2) having the above tk', ie, the 'z' isomer, is produced.

The process is advantageously carried out in a suitable solvent or diluent, for example an aromatic solvent such as benzene. , toluene or chlorobenzene, ethers such as 1,2-dimethoxyethane, t -butyl methyl ether, dibutyl ether or tetrahydrofuran, dimethyl in sulfoxide or tetramethylene sulfone, or in such solvents or diluents. carried out in one or more mixtures. The method generally operates at temperatures ranging from -80°C to 40°C, for example. It can be carried out at a temperature within the range of It is advantageous to carry out at or near temperature.

(b) 2■: In formula C, R'' is a suitable protecting group, such as a (1-6C) alkyl group (e.g. methyl or is ethyl), an acyl group (e.g. acetyl, benzoyl, methanesulfonyl or p -toluenesulfonyl), allyl group, tetrahydropyran-2-yl group or tri- The protecting group is removed from the phenol derivative represented by (which is a methylsilyl group).

The exact protecting group removal conditions used will depend on the nature of the protecting group R'. Therefore, example For example, if it is methyl or ethyl, the deprotection reaction can be carried out in a suitable solvent (e.g. For example, N,N-dimethylformamide or 1,3-dimethyl-3,4,5,6-thi with natriwamthioethoxide in trahydro2(IH)-pyrimidinone) This can be carried out, for example, by heating at a temperature of 60 to 160°C. Protection When the protecting group is acyl, the protecting group can be removed, for example, in a suitable aqueous solvent [e.g. 1 to 40) alkanol] at a temperature within the range of 0 to 60°C. It is removed by hydrolysis in the presence of sodium hydroxide or potassium hydroxide). can be removed. the protecting group is allyl or tetrahydropyran-2-yl in some cases, for example by treatment with strong acids such as trifluoroacetic acid; In the case of trimethylsilyl, this is e.g. Can be removed by reacting with butylammonium or sodium fluoride can.

(c) Formula ■: ■ [In the formula, one of ql and Q2 is a hydrogen atom, and the other is a hydrogen atom or the formula: -C RaRb-0)1' (Ra and R1 in the formula) are the same or different (1-40 ) is an alkyl group) is an erythro-diol derivative represented by the formula: R1, CO, H aldehyde or its acetal, hemiacetal or hydrate react with.

Aldehydes [or their hydrates, or their (1-40) alkanols (e.g. meth acetal or hemiacetal] with alcohol or ethanol) is generally used in excess. use.

The reaction is generally carried out using acidic catalysts, such as hydrogen chloride, hydrogen chloride, sulfuric acid, phosphoric acid, and methanesulfonic acid. acid, p-)luenesulfone or a hostile resin, preferably in a suitable solvent or 112i [Agent 1 such as toluene, xylene or an ether such as tetrahydrofuran] Ran, dibutyl ether, methyl t-butyl ether or 1,2-dimethoxye It is carried out in the presence of tungsten and at a temperature in the range from 0 to 80<0>C.

The starting material of the formula (1) in which both Ql and Q2 are hydrogen atoms is, for example, the starting material of the formula (2): [wherein both Ra and Rb are alkyl groups, such as methyl or ethyl] by mild acid-catalyzed hydrolysis or alcoholysis of the dioxane ring of the compound You can get it. Hydrolytic or alcoholic decomposition, generally as a solvent Lukanols (e.g. ethanol or 2-propanol) or ethers (e.g. (trahydrofuran) using an aqueous acid such as hydrochloric acid at 10-80°C. It should be carried out at a temperature within the range of .

Q.1. One of Il:Q," is a hydrogen atom and the other is of the formula: -CRaRb , The starting material of the above formula (2), which is a group of OH, is a hydrogen atom in which both Ql and Q2 are hydrogen atoms. It is an intermediate material for the above-mentioned starting material of formula (1). However, the intermediate substance are generally not isolated or characterized1. ugly, therefore, non-invention is A modification of method (c) is provided, wherein one of Rh and Rh is a hydrogen atom, methyl or is ethyl and the other is methyl or ethyl. : R1, CO, H or its acetal, hemiacetal or hydrate and acid advantageously in the range 10 to 80' C. and optionally in a suitable solvent or diluent (for example one of those mentioned above). It is more difficult to react in the presence of

The starting materials used in the process are those for producing structurally related compounds. General methods of organic chemistry known to S can be produced by a method similar to that described in the patent specification.

The protected phenol derivatives of formula (1) above are, for example, similar to (2) VC, but Similar to method (a) above using an aldehyde in which the phenol group is protected with the group R# It can be manufactured by using the method described above. The starting material of formula V is, for example For example, a method similar to that described in European Patent Application No. 94239. can be obtained using the method.

The necessary Wittzig reagents can be prepared, e.g. by conventional methods, e.g. Phosphorium is combined with a strong base, e.g. sodium hydride, linium diyne':) obtained by treatment with potassium tert-butyl amide, potassium t-ptoside or butyl lithium. can be done. These are made of VC immediately before carrying out the above condensation step fal on the spot. It is common to build

The necessary starting material for 2) is, for example, a corresponding protected acid of the formula: b2N, 5o2R2 sulfonamide and a suitable dehydrating agent, e.g. cyclohexylcarbodiimide and optionally an organic base such as 4-(dimethyl amine) pyridine in the presence of a suitable solvent or diluent, such as methylene chloride. Reacting at a temperature in the range 0 to 50°C, advantageously at or near room temperature more advantageous.

Selective K, reactive derivatives of acids of formula d) is an alkali metal salt of a suitable sulfonamide (e.g. IJ Wham salt). , advantageously at or near room temperature and in a suitable bath or diluent, such as an ether. The reaction can be carried out in dimethyl, N, N-dimethylformamide or methylene chloride. Ru.

If a salt of a compound of formula ■ is desired, the salt provides a physiologically acceptable cation. or by any other conventional method. Ru.

Additionally, if a suitably active form of a compound of formula I is desired, optically active starting materials can be used. and carry out one of the aforementioned methods. Optionally, the racemic form of the compound of formula I is a suitable organic compound. Base, e.g. ephedrine + N,N,N-trimethyl(1-phenylethyl) Reaction with optically active form of ammonium hydroxide or 1-phenylethylamine diastereomeric mixtures of the salts thus obtained can be used, e.g. fractional crystallization from a suitable solvent such as (1-40) alkanol, and then The optically active form of the compound can be prepared using an acid, e.g. an aqueous mineral acid, e.g. diluted chloride water, using conventional methods. It can be liberated by treatment with basic acid.

Many of the intermediates defined here, such as the phenol derivative of formula ■, are new substances. This is another feature of the present invention.

As mentioned at the beginning, the compound of formula One or more antagonists of certain effects on the vascular system and/or the lungs. The antagonistic effect is Can be demonstrated by one or other of the following standard tests: TXA2 mimetic known as falU46619 (R,L).

Jones et aria’ Chemistry, Biochemis try and Pharmacological Activity of Proatanoids’ S, M.

Roberts and F., edited by Scheinmann, page 211: Pergam. Piper and V. on Press, 1979) were used as agonists. Rabbit aortic strip model developed by anθ (Nature, 196 9.223.29-35) or rat aorta) I) Tube model (Pros taglandins, 1982.24.667-689) as the agonist. and (b) Born (Nature, 1962. 194.927-929) and includes the following procedures: Platelet loss test chart (1) To generate a dose-response curve, add TXA2 to the mimic U46619. coagulating human citrated platelet-rich plasma by; (Material) Presence of increased amount of test compound (generally within the range of 10-5M to 10-10M) 046619 in the presence of a dose-response surface for simulated platelet aggregation; and (i*rl KB showing the ability to aggregate U46619 in the presence and absence of test compounds and (cl) by intravenous administration of TXA2 mimic, ty46619. Induction was performed using an anesthetized guinea pig model of Konzθtt-Roθeler. measurement of inhibition by the test compound of bronchoconstriction and the following treatments: Contraction test: (1) Increasing concentrations of 046619 in physiological saline solution (0,2-4 U46619-induced Qi by intravenous administration of a certain volume of my/ky The cumulative dose-response curve for bronchial constriction was detected and the bronchial yield 'fr, theoretical 1 c Table as the maximum value at which air cannot pass through the test animal □i1 Oral administration of test compound Cumulative dose for U46619-induced bronchoconstriction at 30-minute intervals after 2 hours of warming. Generate a response curve: and (iii) Dose ratio for the test compound showing the ability of TXA2 antagonism (this is Bronchial yield of 1c50% in presence and absence of test compound + U4 required to elicit (This is the ratio of the concentrations of 5619)'fc is calculated.

Antagonism of the action of TXA2 on the vasculature can be demonstrated, for example, in the following format: Wear: (a) Jl [: rats (AMerley Park strain) were treated with sodium bene Anesthetize with doparbital and monitor blood pressure in the carotid artery. TXA2 mimic U4661 9 = 20-30 dragons/Hg in cardiac systolic blood pressure (2640-6970 passes 5μ:9/9 intravenously via the jugular vein to cause an increase in cal).

This method is repeated twice to confirm the suitability of the responses. The test compound is then administered intravenously. administered directly to the stomach intravenously (via the condylar vein) or orally (via the cannula); and U46 5 minutes after administration of the test compound to the test animal and then every 10 minutes thereafter. Administer U46619 until the pressor effect of 619 is no longer blocked. .

Furthermore, the antagonism of the action of TXA2 in vivo is similar to that described in (a) above, for example. Test animals such as rabbits, rats, guinea pigs or dogs using standard methods The effect of the test compound on platelet aggregation obtained after administering the test compound to It can also be proven through evaluation. However, dog platelet For aggregation = X, the platelet coagulant 7 denosine diphosphate 0.4 to 1.2 It is necessary to use a defined threshold concentration.

By way of example, the compounds described in the accompanying examples below can be prepared using the method described above (axis = 5.4X10-'M.

In general, other compounds of formula Having TXA2 antagonistic properties, for example (a) PA2>6-Ox test (b) K B 1.0 x 10-6M; Test (2 hours oral administration at cl 10 ta/to 9 or less) Later dose ratio〉5 and/or test (al, test 1cl over (at), oral administration for at least 1 hour at 9 or below without obvious toxicity. Significant suppression of the 046619-induced blood pressure increase was achieved by using the drug.

As already mentioned, compounds of formula I are capable of antagonizing one or more of the effects of TXA2. For use in the treatment or prevention of disease or undesirable conditions in desired warm-blooded animals. Administered by route. Therefore, for example, the range of 0.01 to 51n9/body TLkg Depending on the route of administration, the severity of the condition, and the body shape and age of the patient being treated. It should be administered up to 4 times per day, with modifications.

Compounds of formula ■ are generally compounds of formula I as defined above or pharmaceutically acceptable versions thereof. used in the form of a pharmaceutical composition consisting of a salt and a pharmaceutically acceptable diluent or excipient. used. Such compositions are provided as another subject of the invention and are available in a wide variety. There may be a variety of dosage forms. e.g. tablets, capsules, solutions or in suspension form; in suppository form for rectal administration; for administration by intravenous or intramuscular injection. in the form of a sterile solution or suspension; for administration by inhalation, an aerosol or nebulizer lactose, etc., in the form of a liquid solution or suspension, and for administration by insufflation. may be in powder form with a pharmaceutically acceptable inert solid diluent6. Pharmaceutical compositions may be prepared using pharmaceutically acceptable diluents and excipients well known to those skilled in the art. It can be obtained by a conventional method. Tablets and capsules for oral administration are of the formula ■ To minimize contact of the active ingredient with stomach acid, e.g. cellulose acetate phthalate Advantageously, it is formed with an enteric coating consisting of.

The pharmaceutical compositions of the present invention are also effective in the disease or condition to be treated. may contain one or more chemicals known as For example, platelet aggregation inhibition Antihypertensive drugs, hyperlipidemia drugs, antihypertensive drugs, beta-sympathetic drugs, or vasodilators may can be usefully present for use in the treatment of vascular diseases or conditions. similar Pharmaceutical compositions of the invention for use in treating diseases or conditions of the lungs, for example antihistamines, steroids (e.g. beclomethanone dipropionate) g), sodium cromoglycate, phosphogesterase inhibitor or beta A sympathomimetic agent can be effectively present. The composition according to the invention is also advantageous and thromboxane A2 synthetase, e.g. ) or Flegler) (U, 63557).

In addition to their uses in therapeutic medicine, compounds of formula TX in laboratory animals such as cats, dogs, rabbits, monkeys, rats, and mice. Also as a pharmacological tool for the development and standardization of test systems for evaluating the effects of A2. It is valid. Also, the compound of formula 1 Artificial extracorporeal circulation A warm-blooded animal's blood and connecting tube (or a part thereof) during Seiki transfer ) can also be used in supplement +C to maintain the viability of for this purpose The salts that are technically acceptable are those with a change in blood in the range of, for example, 0.1 to 10 m/l. should generally be administered such that no steady state is achieved.

Example The present invention will be explained in the following examples, provided that unless otherwise specified, The following assumptions are made: (1) Evaporation was carried out by rotary evaporation in vacuum: ( The operation should be carried out at room temperature within the range of 18-26°C and under an inert gas such as argon. The test was carried out in a gas atmosphere.

(ii+) E, Merck, Darmetadt, W, Gerzar Merck Silicadel (type 9385), commercially available from Medium pressure liquid chromatography (MPLC) chromatography was performed.

(1v) Straw collection is given by way of example only and requires the maximum value that can be achieved. I don't.

M 7' roton NMR spectra were performed using tetramethylsilane (TM) as an internal standard. S) k 90-200 Ml in the CDCl3 used (standardly determined with z) and the common abbreviations for indicating the main peaks are 20--1 line, m = multiplet, and -31 line, br=Guangdi, d-2l line for TMS per million copies. Shown as a logical shift (delta value).

(vl) The final of everything! The paraboloid was made into a 10-m body and was separated by 1,000 m.

Example 1 Ethanethiol ((L75)) was prepared from 1, 1,3-di Methyl-3,4,5,6-tetrahydro-2(IH)-pyrimidinone (DMP Sodium hydride (4851n9, in oil DIApt N-meta 7 sulfonyl-4(Z)-6-(C2,4,5 -cis]-2-ci-methyl-1-phenoxyethyl)-4-0-methoxyphene Solution of nyl-1,3-zooxan-5-yl)hexenamide r(A) (871 da) liquid was added. The mixture was stirred at 80° C. for 3.5 hours and at 100° C. for 1 hour.

It was then cooled to 10° C. and poured into an ice/water mixture (1001d). The aqueous mixture The compound was washed with dichloromethane (2×50 width). Aqueous phase f: pH 3 with 2M hydrochloric acid It was dispersed and extracted with a needle (3X501d). These extracts were mixed with water (2X 50g) and saturated saline (50m), then dried. evaporated. The obtained oil was purified with hexane/ethyl vinegar/acetic acid ( 60: 40: 1 vlv) k using t7, flash chromatograph N-methane A-honylu 4(Z)-6 was purified as a colorless oil by -(C2,4,5-cis)-2-1-methyl-1-phenoxyethyl)-4-0 -Hydroxyphenyl-1,3-dioxan-5-yl)hexenamide (45 6m9) k obtained; nMR: 1.37 (6H, s).

i, s 8 (2Hp m), 2.53 (4H-m) - 2,67 (IH , m), 3.22 (3H, s), 4.00 (IH.

dmJ-11Hz), 4.22 (IH, ddJ-11,1Hz).

4.78 (IH, e), 5.32 (IH, d, T-2nZ) + 5.40 (2H, m), 7.08 (9H, m); m/e521 (M”NH,)+.

Starting material (A) was obtained as follows: (1) Dry Tny (75d) (4-O-methoxyphenyl-2,2-dimethyl-1,6-dioxane-silane) Su-5-yl)acetaldehyde (European Patent Application Publication No. 94239A- 1) A solution of 41) ('15.8 g) was dried with Tay (40 g) under an argon atmosphere. (3-carboxypropyl)triphenylphosphonium dulomide (5 1,48,V) and potassium t-butoxy! & (26,88g) The ylide was added to the stirred, ice-cooled bath. The mixture was stirred at 4°C for 15 minutes and then Stir at ambient temperature for 1.5 hours and then pour into ice/water (11). Obtained The mixture was washed with 50% v/v ether/hexane (2x250m/). .

Most of the neutral material was removed. The aqueous phase was acidified to pH 5 with acetic acid and ether ( 4×300 mJ). These extracts were added sequentially to water (3 x 150 mJ) and saturated saline (2X10QmA), and then dried (MgSO4) L, and evaporated. The residue was dissolved in toluene/ethyl acetate/acetic acid (80:20). : 2 vlv). 10%v of the obtained solid /v acetate ethyl/hetisane (250+d) to give 4(Z)-6-(4 -0-methoxyphenyl-2,2-dimethyl-1,3-dioxane-cis-5- Il) Hexe:yft(B) (13,0g) k obtained; m-p-99-101 °O* NMR: 1.52 (3H, s) -1-54 (1H-m), 1- 56 (5H-8), 1-80 (IH-m).

2.28 (4H9m) - 2,49 (IH-m) + 3-77 (IH, tiaJ =11. I H2), 3.82 (3H, 8).

4.16 (IH, amy = 11 Hz), 5.28 (2H, m) + 5.45 (IH, d, T-2Hz), 6-85 (111, aaJ=7.IHz) , 6.97 (IH9tdy-7, IHz).

7.22 ('IH, taJ=8.IHz), 7.48 (IH.

am J = 8Hz).

2-methyl-2-phene containing (M)p-)luenesulfonic acid (10rR9) Hexenoic acid (B) (1,5,!q) in noxinoropionaldehyde (3,0!q). ? ) suspension was stirred at ambient temperature for 18 hours and then heated at 60° C. for 6 hours. cold The cooled solution was diluted with ether (30j17) and diluted with 0.5M sodium hydroxide. Extracted with lxlod. The aqueous extract was washed with ether (2ON) and then These were acidified with acetic acid to FJ (5) and extracted with ether (3X15). The extract was washed sequentially with water (2X10g) and saturated saline (10d), then Dry MgSO4') was evaporated. The residue was dissolved in hexane/ethyl acetate/ Dissolved in acetic acid (85:15:1 v/v) and purified by MPLO. 4(Z)-6-(C2,4,5-cis)-2-(1-methyl-1-phenokyl [ethyl]-4-0-methoxyphenyl-1゜3-dioxan-5-yl)hexyl Cenic acid (C) was obtained as a clear oil (655■); NMR: 1.34 ( 3H, s) 1-42 (3E, a), 1.57 (IH, m).

1.89 (In, m), 2.30 (4H, m), 2.49 (I HlmL 3- 81 (6T1-s L 5.9B (IH-dm, T-11Hz), 4 ．． 15 (IH, da, r=11.1Hz).

4.80 (IH-8), 5.24 (IH, dJ-2Hz) e5.3 2 (2H9m), 6.85 (IH, adJ-7, IHz).

7-03 (4”1m) e 7-24 (3H-m) -7-43 (I H+ ddJ-7,1,5Hz) pm/e 458 (M”+NH4).

441 (M”+H).

The necessary 2-methyl-2-phenoxyzolopionaldehyde itself is prepared as follows. The resulting solution was added dropwise under argon at -70°C to dichloromethane (21 1114) of diisobutylaluminum hydride (dibal) in Treated with 1M solution. The solution was incubated at -70°C for 1 hour and then warmed to -60°C. , sodium potassium tartrate dissolved in water (100M), then cooled to 4°C. Mu four water conservancies’! Injected into a vigorously stirred aqueous solution of IV (509). Stir for 30 minutes After stirring, the mixture was separated by passing through diatomaceous earth. The filtrate is (4×10.011 Lt) and the extract was dissolved in saturated saline (2×100 Lt). ), dried with 'MgSO4) and evaporated. 2-methyl-2-phe The residual oil containing noxyzologionaldehyde (3,18,9) is further refined. It was used without being manufactured.

(iii) Dicyclohexylcarbodiimide (1.08g) in dichloromethane Oily substance in (0,61,9)0(2,13,9),4-(dimethylamino)pyri Added to a solution of gin (0,619) and methanesulfonamide (0,489).

The mixture was stirred at 4° C. for 1 h and then at ambient temperature for 18 h. Shen The precipitated N,N'-dicyclohexylurea was removed by filtration, and dichloromethane was removed. Washed with water. The filtrate and washings were oxidized with 0.1M hydroxide) with IJum (65d). Extracted. The basic extract was acidified with acetic acid and ether (3X 5QmJ ) was extracted. These extracts were mixed with water (2X50111j) and saturated saline (50 1d), then dried with MgSO4) and evaporated.

The obtained oil was mixed with hexane/ethyl acetate/acetic acid (75:25:1 v/ v) to obtain N-methanesulfonyl-4 (z>-6-(C2,4,5-cy [S]-2-[1-methyl-1-phenoxyethyl)-4-0-methoxyphel -1,3-dioxan-5-yl)hexenamide (A) as a clear oil (1,3-dioxan-5-yl)hexenamide (A) NMR: 1-35 (5H,s), 1.42 (3 H.

a), 1.52 (IH, m), 1.94 (IE, m).

2.56 (4H, rn), 2.54 (IH, m), 3.21 (6] 11 , 8), 3.83 (6H98), 4.00 (1H9amJ-11Hz), 4. 18 (IH, aa, r=11e IE2).

4-79 (I He') -5-27 (I H-6J-2Hz).

5.37 (2H, m), 6.88 (IH9ba, r-7Hz).

6.99 (IH, t4J-7, 111z), 7-09 (3H.

"L 7.27 (3H-m L 7-42 (I H-m) tm/e 53 5 (M+NH,)+.

Example 2 One exemplary dosage form of the compositions of the invention is provided by the following capsule formulation: Ru: 1v/capsule Compound x1・・・・・・・・・・・・・・・・・・・・・・・・・・・ ・・・・・・・・・・・・ 10 Stearin Magnesicum ・・・・・・・・・ 1.5 capsules advantageously consist of hard gelatin and can be optically filled in a conventional manner. The compound F@x” is the formula defined above The compound (2) or a salt thereof, such as the compound of Example 1 or a salt thereof.

international search report

Claims (11)

[Claims] 1. Formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼I [In the formula, R1 is the formula: R3O. represents a group CR4R5-, in which R3 is (1-6c ) represents an alkyl group or a phenyl group, the latter optionally containing halogeno, cyano , nitro, trifluoromethyl and (1-4c)alkoxy carrying a container, and R4 and R5 represent (1-4c) alkyl groups independently of each other; and R2 represents a (1-6c) alkyl group, benzyl group, or phenyl group, and The latter two are optionally halogeno, (1-4c)alkyl, (1-4c)alco can carry xy, trifluoromethyl, cyano or nitro substituents; The substituents at the 4- and 5-positions of the dioxane ring in Formula I and the substituent R1 are cis-relative steric. Sulfonamide derivatives having chemical configuration] or pharmaceutically acceptable thereof salt. 2. R3 is methyl, ethyl, propyl, inpropyl or phenyl, the latter optionally fluoro, chloro, bromo, cyano, nitro, trifluoromethane carries a substituent selected from methyl, methoxy and ethoxy; R4 and R5 are mutually is methyl or methyl; and R2 is methyl, ethyl, propyl, base; or phenyl, the latter two optionally being fluoro, chloro, bromo, Methyl, ethyl, methoxy, ethoxy, trifluoromethyl, cyano or nitro A compound according to claim 1, which carries a substituent. 3. R1 is 1-[(1-4c)alkoxy]-1-methylethyl or 1-methyl -1-phenoxyethyl, the latter optionally containing fluorocarbons on the phenoxy group. carries a bromo, chloro, bromo, cyano or nitro substituent, and R2 is methyl, ethyl, thyl or phenyl, the latter group optionally being fluoro, chloro, bromo, or phenyl. Claims carrying ano, nitro, trifluoromethyl or methoxy substituents A compound according to item 1. 4. R1 is 1-methoxy-1-methylethyl or 1-methyl-1-phenoxyene 2. A compound according to claim 1, which is chill. 5. 5. A compound according to claim 4, wherein R2 is methyl or ethyl. 6. N-methanesulfonyl-4(Z)-6-([2,4,5-cis]-2-[1 -Methyl-1-phenoxyethyl]-4-o-hydroxyphenyl-1,3-di oxan-5-yl)hexenamide or a pharmaceutically acceptable salt thereof. 7. Alkali metal salts, alkaline earth metal salts, aluminum salts and ammonium salts , and with an organic amine and a quaternary base forming a physiologically acceptable cation. Salt according to any one of claims 1 to 6, selected from salts. 8. A compound of formula I according to any one of claims 1 to 7, or from a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or excipient. A pharmaceutical composition comprising: 9. Claims having as additional active ingredient an inhibitor of thromboxane A2 synthesis The composition according to item 1. 10. A compound of formula I according to any one of claims 1 to 6 or In the method of manufacturing the pharmaceutically acceptable salt, (a) Formula II: ▲There are mathematical formulas, chemical formulas, tables, etc.▼The aldehyde shown by II is expressed as: R′3P=CH. (CH2)2CO. N-. SO2R2M+ [wherein R' is (1 ~6c) is an alkyl group or an aryl group, and M+ is a suitable cation] React with a certain Weitzchig reagent; (b) Formula III: ▲There are mathematical formulas, chemical formulas, tables, etc.▼III [In the formula, R'' is a suitable protecting group. ] removing the protecting group from the phenol derivative represented by; (c) Formula IV: ▲There are mathematical formulas, chemical formulas, tables, etc.▼IV [In the formula, one of Q1 and Q2 is a hydrogen atom. and the other is a hydrogen atom or has the formula: -CRaRb. OH group, in which Ra and and Rb are the same or different (1-4c) alkyl groups] The rhodiol derivative has the formula: R1. C.O. H aldehyde or its acetal, Reaction with a hemiacetal or hydrate; then an optically active form of a compound of formula I If desired, one of the above methods (a) to (c) may be used in an optically active form of the appropriate starting material. or by dissolving the isomer using a suitable optically active base; and If a pharmaceutically acceptable salt is desired, the free acid form of a compound of formula I can be prepared as a pharmaceutically acceptable salt. react with a suitable base that provides a cation acceptable to; and In the formula, R1 and R2 are defined in any one of claims 1 to 5. A method for producing an amide derivative, characterized in that it represents. 11. N-methanesulfonyl-4(Z)-6-([2,4,5-cis]-2-[ 1-Methyl-1-phenoxyethyl]-4-o-methoxyphenyl-1,3-di oxan-5-yl)hexenamide or a salt thereof.