JPH05502235A - imidazoles - 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] imidazoles The present invention relates to therapeutically useful imidazole derivatives, methods for their production, and methods for their production. Pharmaceutical compositions containing the same, and its use in methods of treating the human and animal body. regarding their use.

The present invention provides acylcoenzyme-A:cholesterol-〇-acyl transfer. improvement by administration of inhibitors of ACAT (EC2, 3, 1, 26) conditions that can lead to, for example, atherosclerosis in vein grafts, hyperlipidemia pharmaceutical composition for the treatment of cholesterol ester storage diseases or atheroma. General formula for use in the preparation of compositions: % formula % (1) During the ceremony, [DPIM] is as depicted hereinafter, and R and R1 are the same or are different, and each has a hydrogen or halogen atom or a straight or branched is a chain alkyl group having 1 to 5 carbon atoms, W has 2 to 5 carbon atoms and is a methylene group or a straight chain or an alkyl group optionally substituted with a branched alkyl group having 1 to 4 carbon atoms; It is a chilene chain, Y is the formula (■■), (I I I), (IV), (V) Mataha (VI ), in the formula, The symbols R2 are the same or different and each is a hydrogen atom or a methyl is the basis, The symbols R3 are the same or different and each is a hydrogen atom or a straight chain or a branched alkyl group having 1 to 4 carbon atoms, Each of the symbols R4 is a hydrogen atom, or two symbols R4 and both of them R5 is a hydrogen atom or a carbonyl group together with the carbon atom to which R5 is attached. or a hydroxy group, and Z is an oxygen atom or a sulfur atom or a formula [C(R”) 2] - or a group of NR3, m is 0 or an integer from 1 to 5, n is O or an integer from 1 to 5, and p is O or 1, where m+n +p=3.4 or 5, and q is 0, 1 or 2, or a pharmaceutically acceptable acid addition salt thereof.

The present invention also provides a mitigating effective amount of a compound of general formula (1) as defined above or a preparation thereof. administering a pharmaceutically acceptable acid addition salt to a host to ensure improvement in the patient's condition; consisting of acylcoenzyme-A: cholesterol-O-acyltrans Conditions that can be alleviated by administration of inhibitors of ferases, e.g. vein grafts Atherosclerosis, hyperlipidemia, and cholesterol ester storage in the fragments a human or animal host suffering from a disease or atheroma, or treating a patient thereof; provide a method for

The present invention also provides acylcoenzyme-A cholesterol-〇-acyltran Conditions that can be alleviated by the administration of inhibitors of spherase, e.g. Atherosclerosis, hyperlipidemia, and cholesterol ester storage in explants A novel method of treating the human and animal body by treating atheroma or atheroma Compounds of the defined general formula (1) or their pharmaceutical formulations for use in Acceptable vine acid addition salts are provided.

The present invention also provides that W is a methylene group or a straight chain having 2 to 4 carbon atoms. Y is a group other than the group of formula (V) described hereinafter, and the symbol R 4 is a hydrogen atom and Z is an oxygen atom or the formula [C(R3)2], in the formula q is 0 or 1, or NR'', or the symbols R4 and The carbon atom to which they both join forms a carbonyl group, and Z has the formula [C( R3) 2]. , where a is 0, and R, R1 and R3 are as defined above. A compound of formula (1), or a pharmaceutically acceptable acidification thereof, as defined above. Formulations containing salts and pharmaceutically acceptable carriers or coatings provides a chemical composition.

The present invention also provides that W is a methylene group or a straight chain having 2 to 4 carbon atoms. When it is an alkylene group, Y is a group other than the group of formula (■) described hereinafter, and the symbol R 4 is a hydrogen atom and Z is an oxygen atom or a formula [C(R3)2co0, where q is 0 or 1, or NR3, or the symbol R4 and its The carbon atom to which both of them join forms a carbonyl group, and Z has the formula CC(R ’)d　, where a is 0, R5R1 and R3 are as defined above The novel imidazole derivative of formula (I) or its pharmaceutically acceptable provides a vine acid addition salt.

where R and R1 are the same or different and each is hydrogen or A halogen atom or a linear or branched alkali having 1 to 5 carbon atoms. is a kill group, and W is a methylene group or a linear alkyl group having 2 to 4 carbon atoms. is a kylene chain, Y is a group of formula (V) described hereinafter, and the symbols R3 are the same or different, each containing a hydrogen atom or a straight or branched chain is an alkyl group having ~4 carbon atoms, and the symbol R4 is a hydrogen atom , and Z is an oxygen atom or the formula [C(R3)z]. , where q is 0 or 1. or NR3, or the symbol R4 and both of them are conjugated. form a carbonyl group with the carbon atom, and Z has the formula [C(R3)2]. ,formula Compounds within the scope of general formula (I), in which q is O, and their A pharmaceutically acceptable acid addition salt, alone or with a pharmaceutically acceptable carrier or The combination with coating is based on the Japanese patent 0. P.

(2), No. 64-40467 (Application No. 62-196117).

However, in that specification, those compounds and their pharmaceutical compositions are The composition has been described as having anti-ulcer and anti-inflammatory activity. those compounds and their pharmaceutical compositions include acylcoenzyme-A, cholesterol-〇 - as an inhibitor of acyltransferases or in conditions such as vein grafts atherosclerosis, hyperlipidemia, cholesterol ester storage disease or Any suggestion that it may be useful in the treatment of atheroma or atheroma It doesn't exist anywhere in the book.

Thus, the utility disclosed herein is completely unexpected.

A particularly important feature of the invention is that at least one of the symbols has a value selected from: Compounds of general formula (I) and their pharmaceutically acceptable acid addition salts (1) R is hydrogen or chlorine atom or methyl is a group: (i) R' is a hydrogen or chlorine atom or a methyl group: (ii i) W is a methylene group or an alkylene chain having 2.3 or 4 carbon atoms; be.

(iv) Y is phthalimide, optionally substituted maleimide, pyrrolidinium , piperidinyl, perhydroazepinyl, piperazinyl or morpholino group. be. and/or (v) R'' is a hydrogen atom or a methyl or ethyl group .

Other symbols are as previously defined.

Important compounds of the invention include: IA N-[2-(4,5-di Phenylimidazol-2-ylthio)ethyl comorpholine IAA N-[2-(4,,5-diphenylimidazol-2-ylthio)ethyl 3 Morpholine hydrochloride IB N-[3-(4,5-diphenylimidazol-2-ylthio)propyl 1 Morpholine IBA N-[3-(4,5-diphenylimidazol-2-ylthio)propyl 17 Ruforin dihydrochloride ICN-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]pipe lysine ICA N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl] Beveridine dihydrochloride ID N-[3-(4,5-diphenylimidazol-2-ylthio)propyl] -N’-Methylbiperilazine IE N-[2-(4,5-diphenylimidazo 2-ylthio)ethylpyrrolidin-2-one IF N-[2-(4,5-diphenylimidazol-2-ylthio)ethylcobi loridin IG N-[3-(4,5-diphenylimidazol-2-ylthio)provirco Piperidine IGA N-[:3-(4,5-diphenylimidazol-2-ylthio)pro Pill] Biperidine dihydrochloride IHN-[2-(4,5-diphenylimidazol-2-ylthio)ethyl 1 part hydroazepine IHA N-[2-(4,5-diphenylimidazol-2-ylthio)ethylco Barhydroazebine dihydrochloride ■I cis- and trans-2,6-cystyrene N-[4-(4゜5-dife Nylimidazol-2-ylthio)butyl 3-morpholine 11A N- and trans-2,6-cystyrene N-[4-(4°5-diph) Phenylimidazol-2-ylthio)butyl 3-cellforin dihydrochloride 2A N-[2-(4,5-diphenylimidazol-2-ylthio)ethylcoma Reimido 28 N-[3-(4,5-diphenylimidazol-2-ylthio)propyl] Phthalimide 2CN-[4-(4,5-diphenylimidazol-2-ylthio)butyl]phthalate Ruimide 2D N-[3-(4,5-diphenylimidazol-2-ylthio)propyl 3 Morpholine-3,5-dione 2E3.5-dimethyl-N-[3-(4,5-diph) Phenylimidazol-2-ylthio)propylcopiperidine-2,6-dione 2F N-[2-(4,5-diphenylimidazol-2-ylthio)ethylcomalei Mido 2G N-[3(4,5-diphenylimidazol-2-ylthio)propyl]- 4-methylmaleimide 2HN-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]pyro Lysine-2,5-dione 2I N-[3-(4,5-diphenylimidazol-2-ylthio)propyl] Pyrrolidine-2,5-dione 2J N-[3-(4,5-diphenylimidazole) -2-ylthio)propylcopiveridine-2,6-dione 2 and 4. ．． 4-dimethy Ru-N-[2-(4,5-diphenylimidazol-2-ylthio)ethylcopipe Lysine-2,6-dione 2L4.4-dimethyl-N=[3-(4,5-dife Nylimidazol-2-ylthio)propylcopiperidine-2,6-dione 2M N-[3-(4,5-diphenylimidazol-2-ylthio)probilco4 -Methylpiperidine-2,6-dione 2N N-[3-(4,5-diphenyl midazol-2-ylthio)propyl]-4-ethyl-4-methylpiperidine-2 ,6-dione 20 N-[3-(4,5-diphenylimidazol-2-ylthio)propyl] -thiomorpholine-3,5-dione 2P4.4-dimethyl-N-[3-(4,5 -diphenylimidazol-2-ylthio)propylcopiperidine-2,6-dio N-2Q N-[3-(4,5-di-1)-tolylimidazol-2-ylthio)p Lopyl 1 Morpholine-3,5-dione 2RN-[3-(4,5-di-2-chloro Phenylimidazol-2-ylthio)propyl]-4,4-dimethylpiperidine -2゜6-dione 2S N-[4-(4,5-diphenylimidazol-2-ylthio)butylcomo Luphorin-2,6-Sion 2T3,3-dimethyl-N-[3-(4,5-diphenylimidazol-2-yl thio)propylcopiperidine-2,6-dione 3A[3-R,Sl-3-[ (4,5-diphenylimidazol-2-ylthio)methyl]-1-methylpiperi Zine 3AA　[3-R,Sl　-3-[(4,5-diphenylimidazole-2- ylthio)methyl]-1-methylpiperidine hydrochloride 3B[5-R,Sl-5 -[(4,5-diphenylimidazol-2-ylthio)methyl]-2-pyrrolidi 3C[6-R,S-6-[(4,5-diphenylimidazol-2-yl) thio)methyl]-2-piperidinone 3D [6-R,S-4,4-dimethyl -6-[(4,5-diphenylimidazol-2-ylthio)methyl]-2-pipe lysine non 3E　[4-R,Sl　-4-[(4,5-diphenylimidazol-2-ylti e) Ethyl]-1-methylpiperidine 3F [2-R, Sl　-2-[(4,5 -diphenylimidazol-2-ylthio)methyl]-1-methylpiperidine 4A N-[3-(4,5-diphenylimidazol-2-ylthio)propylco 5 -Hydroxypyrrolidin-2-one 48 N-[3-(4,5-diphenylimi Dazo-2-ylthio)propyl]-5-hydroxymorpholine-3-onco IA-4B are compounds for ease of reference later in this specification. assigned to.

Compounds within the scope of the invention have correlated pharmacological activity in humans and mammals. Positive evidence demonstrated by the following in vivo and in vitro tests believed to be relevant: exhibits pharmacological activity.

In assays performed in vitro, 0.5% W/W cholesterol and Prepared from the livers of rats fed a diet supplemented with 0.25% W/W folic acid for 7 days. Microsomes were treated with a compound according to the invention at a concentration of 0.5.1 or 10 μg/ml. in the presence of radiolabeled oleyl-CoA. Living The degree of ACAT inhibition achieved is shown in Table ■.

In the in vivo test, the same as above, supplemented with an additional 0.03% W/W test compound. The compound according to the invention was measured after 3 days using rats fed a diet of For control animals supplemented with pure cholesterol, plasma cholesterol Increase in concentration was inhibited, for example, by the amounts shown in Table II.

Table 1 Compound concentration inhibition % IAA 10 90 1B 10 91 1C1090 ID 10 88 IE 10 86 1F 10 72 IGA 10 66 IHA 10 77 2A 1 68 2B 1 86 2C186 2D 1 88 2E 1 94 2F 1 69 2G 1 90 2H169 Table I (continued) Compound concentration inhibition % 3F 0.5 84 Table■ Compound inhibition % 3AA 88 Compounds of formula (1) can be prepared by application and adaptation of known methods, Known method means a method conventionally used or described in the literature. do.

Thus, according to one feature of the invention, the compound of formula (I) defined above [DP I M]-3-M"" (VIr) in the formula, [DPrM] is as defined above and M is an alkali metal, preferably A salt of sodium or potassium, which is an atom, has the general formula: %formula%) During the ceremony, X is a group which can be substituted by a thiolate salt, e.g. halogen, e.g. A chlorine atom or an alkyl or aryl group (e.g. methanesulfonyloxy or or 4-toluenesulfonyloxy), and W and Y are as defined above. prepared by reacting with a compound or its acid addition salt, which is . This reaction is carried out using an inert organic solvent, e.g. dimethylformamide or tetrahydride. Performed in Lofuran at room temperature to 100°C, optionally in the presence of a proton acceptor. . The proton acceptor is organic, e.g. an amine (e.g. triethylamine) or inorganic, e.g. alkali metal carbonates (e.g. potassium carbonate). Something can happen.

According to another feature of the invention, Y is of formula (II), (II) or (IV) and the other symbols are as defined above, compounds of general formula (1) are of the formula %formula%() During the ceremony, The various symbols are as defined above, and compounds of the general formula (X), (XI) or or (XII), wherein Z, R2 and R3 are as defined above. prepared by reacting with substances. This reaction is generally performed in an inert organic solvent. , for example in xylene, optionally with an acidic catalyst, for example 4-toluenesulfonate. The process is carried out in the presence of phosphoric acid with azeotropic removal of water at reflux removal.

According to further features of the invention, Y is a radical of formula (V) and the other symbols are Compounds of formula (I), as defined above, wherein Y is a group of formula (IV) metal hydrogenation of the corresponding compound of formula (1), where the other symbols are as defined above. a reducing agent such as lithium aluminum hydride, an inert solvent such as dihydride, Reduction in ethyl ether or tetrahydrofuran at 0°C to room temperature It is prepared by

According to further features of the invention, Y is of formula (V), where R4 is a hydrogen atom, and the other symbols are as defined above, compounds of formula (I) in which Y is A group of formula (iv), two symbols R4 and the carbon atom to which they are both bonded and form a carbonyl and the other symbols are as defined above, the corresponding formula ( I) into a corresponding compound where Y is of formula (IV) and Y is of formula (V). prepared by reduction under conditions similar to those described above for reduction. be done.

According to further features of the invention, the formula: % formula %() During the ceremony, Wl has a methylene group or 2 to 4 carbon atoms, and also has one or more linear or may be substituted with a branched alkyl group having 1 to 4 carbon atoms. a straight-chain alkylene chain, other symbols as defined above, The compound has the formula.

[DP IM]-3-WICO-Y (XV) In the formula, The various symbols are as defined above, and Y is a compound of formula (IV). Y is subjected to conditions analogous to those described above for reduction to the corresponding compound of formula (V). It is prepared by reducing the

Thus, compounds of formula (VII) can be used to convert bases, such as sodium hydride, into formula: %formula%() During the ceremony, [DPIM] is prepared by reacting with the compound, as previously defined. can be manufactured. This reaction is conveniently performed in situ.

The compound of formula (X) is a compound of the formula (Vlr) defined above with the general formula X-W-N H2 (XI I I) During the ceremony, X and W are as previously defined, and a compound of formula (viB) and a compound of formula ( VIII) under conditions similar to those described above for the reaction with compound VIII). It can be prepared by

Compounds of formula (IX) also include compounds of formula (1), where Y is a phthalimide group. The reaction is carried out with hydrazine in a solvent such as ethanol at a temperature up to reflux. It can be prepared by

The compound of the formula (XV) is a compound of the formula (VIN) with the general formula: X-Wl-CO-Y (XVI I) During the ceremony, The symbols are as defined previously, Regarding the reaction between the compound of formula (VII) and the compound of formula (VIII) It can be prepared by reacting under conditions similar to those described above. Ru.

As used herein, the term "pharmaceutically acceptable acid addition salts" It is an animal that is relatively non-toxic to animal organs when used in therapeutic doses. and thus the beneficial pharmaceutical properties of compounds of general formula (1). are not impaired by side effects from those anions.

Acid addition salts suitable for use in formulations can be selected from the following salts: salts derived from inorganic acids, e.g. hydrochloride, hydrobromide, phosphate, sulfuric acid Salts and nitrates, and salts derived from organic acids, such as oxalates, lactates , tartrate, acetate, salicylate, citrate, propionate, succinate , fumarate, maleate, methylene-bis-β-hydroxynaphtonite, Gentisade and di-p-tolyl tartrate.

According to another feature of the invention, the acid addition salt of the compound of formula (1) is the parent compound of formula (I) The products are prepared with appropriate acids and by application or adaptation of known methods.

Salts of compounds of formula (I) are useful in themselves as active compounds, as well as salts of compounds of formula (I). I) For the purpose of purification of the parent compound, for example, the difference in solubility between the salt and the parent compound can be exploited. L) is useful by using techniques well known to those skilled in the art.

The parent compounds of formula (1) can be reconstituted from their salts by application or adaptation of known methods. can live.

For example, the parent compounds of general formula (I) can be modified from their acid addition salts to alkali, e.g. , by treatment with aqueous sodium bicarbonate solution or aqueous ammonia solution Can be played.

In this specification, references to compounds of formula (I) are made wherever the context permits. includes reference to their pharmaceutically acceptable acid addition salts. It is intended that

The compound of formula (1) can be prepared by physical means such as crystallization or chromatography. It can be purified by

The invention is further illustrated by the following examples. Reference examples illustrate the preparation of intermediates Ru.

Spectra of N, M, R, recorded at 200MHz or 400MHz did. Chemical shifts are expressed in ppm relative to tetramethylsilane.

Abbreviations have the following meanings: s=single, d=double, t=triple, q=quadruple, qui==quintuple, m=multiple, dd= double double, dt = triple double, br = wide signal.

Infrared spectra were recorded in potassium bromide discs. Main absorption peak position Describe the location.

Sodium hydride (1.2 g, 80% dispersion in 40 mmol oil) was dried 4,5-diphenylimidazole-2-thi in tetrahydrofuran (180 ml) Added to a stirred suspension of ol (1.5 g, 4.1 mmol) at ambient temperature. did. After 0.5 hours, N-(2-chloroethyl)morpholine hydrochloride (3.72 g, 20 mmol) was added followed by triethylamine (3 ml). this The mixture was heated under reflux for 48 hours, then poured into water (300 ml) and evaporated. Extracted with ether (2 x 200ml). This ether solution was dissolved in aqueous 2N hydrochloric acid (20 0 ml). Next, the acidic aqueous solution was made basic with Na0H) and A Extracted with tel (2×150 ml). This ether solution was dried (MgS04) , evaporated and the residue recrystallized from toluene to give N-[2-(4,5 -diphenylimidazol-2-ylthio)ethyl 1 morpholine (4.9 g), Obtained as a colorless solid, melting point 129-132°C; [Elemental analysis knee C, 68,9; H, 6,3: N, 11.6%: C21823N3 Calculated value for 0S -C,69,0;H,6,3:N.

11.5%: N, M, R, (CDCI3 & D20): 2.55 (4H, br t, J=4 Hz), 2.86 (2H, t, J=6Hz), 3.11 (2H, t, J=6 Hz), 3.5 (4H, brt, J=4Hz), 7.2-7.6 (10H , m)].

Proceeding in the same manner, but with N-(2-chloroethyl)morpholine, 1) N(3-chloroethyl)morpholine: 1i) N(2-chloroethyl)pipe Lysine: and 1ii) N-(3-chloroethyl)-N゛　-methylpiperazine If you replace it with i) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl 1 Morpholine, melting point 135-137°C; ii) N-[2-(4,5-dife Nylimidazol-2-ylthio)ethyl]piperidine, melting point 143-145°C: and 1ii) N-(4,5-diphenylimidazol-2-ylthio)propyl ]-N'-methylpiperazine was obtained.

Acetyl chloride (20 ml) was stirred into cold (10°C) ethanol (90 ml), It was added dropwise while maintaining the temperature below 30°C. 0. After 5 hours, ethanol N-[2-(4,5-diphenylimidazol-2-ylthio) in (10 ml) A solution of ethyl 1 morpholine (15 g, 41 mmol) is added and 0. 5 Stir for hours. This mixture is then evaporated and the residue extracted from ethanol. Upon recrystallization, N-[2-(4,5-diphenylimidazol-2-ylthio) Ethyl comorpholine dihydrochloride (1,46 g) was obtained as a colorless solid, mp. 247℃.

[Elemental analysis K, 55,1; H, 5,95: C1,15,3; N, 8.9%: Calculated value for Cz+Hz3N3S・2HCI-H,O・-C,55,3; Ratio 5.96; C1,15,5; N, 9.2%.

N, M, R, (CD3SOCD3 & D20): 3.23-3.95 ( 12H.

m), 7.34-7.56 (IOH, m)].

Sodium hydride (0.48 g, 80% dispersion in 16 mmol oil) was added to the dry 4,5-diphenylimidazole-2-thiol (3, 78 g, 15 mmol) was added to a stirred suspension at ambient temperature. 0.5 After an hour, N-(2-tosyloxyethyl)pyrrolidin-2-one (5.66 g, 20 mmol) was added and then stirred for 3 hours. Add this mixture to water (500ml ), stirred and extracted with ether (2x200ml). This ether solution was dried (MgS04) and flash chromatographed (19:1 dichloromethane). ethanol/methanol as eluent). The product was diluted with 1:1 ethyl acetate. When crystallized from /petroleum ether (60-80°C), N-[2-(4°5-diphthalate) henylimidazol-2-ylthio)ethyl]pyrrolidin-2-one is a colorless solid. Obtained as a solid, melting point 128-130°C: [Elemental analysis knee c, 69.4; H, 5,75; N, 11.7%; Calculated value for C2□H21N30S Knee C,6 9,4;H,5,82;N.

11.6%.

N1M, R, (CDCl2): 2.14 (2H, q, J=7Hz), 2.5 8 (2H, t, J = 7Hz), 2.96 (2H, t, J = 6Hz), 3.46 (2H, t, J=7Hz), 3.64 (2H, t, J=6Hz), 7°1- 7.4.5 (6H, m), 7.46-7, 74 (4H, m), 12.3 (1 N-[2-(4,5-diphenyl) in tetrahydrofuran (20 ml) midazol-2-ylthio)ethyl]pyrrolidin-2-one (3.2 g, 9 mmol) A solution of lithium aluminum hydride in diethyl ether (300 ml) (1,07 g, 28 mmol) was heated with argon at ambient temperature. Added under atmosphere. Stir for 05 hours, then add ethyl acetate (50 ml) to the ice-cooled solution. slowly while cooling, then water (300 ml), then 0. 5 Stir for hours. The organic layer is separated, dried (MgSO4) and evaporated. A gum was obtained which was subjected to flash chromatography (9:1 dichloromethane/ methanol as eluent). Product in ethyl acetate (5mj) and adding petroleum ether (60-80°C; 50ml) gives N- [2-(4,5-diphenylimidazol-2-ylthio)ethyl]pyrrolidine ( 1.9 g) was obtained as a colorless solid, melting point 102-103°C.

[Elemental analysis: C, 72.3; H, 6.4; N, 12.1%.

Calculated values for CHH23N3S: C, 72, 2; H, 6, 6; N, 12. 0%: N, M, R, (CDCIs & DzO) + 1.53-1.64 (4H, m ).

2.6-2.68 (4H, m), 3.03-3.1 (4H, m), 7.2- 7.33 (6H, m), 7.41-7.55 (4H, m)].

] Potassium t-butoxide (4.44 g, 39.6 mmol) was added to 4°5-diphenyl Stirred suspension of nylimidazole-2-thiol (10 g, 39.6 mmol) at ambient temperature to form a yellow solution.

After stirring for 0.5 h, N-(3-chloroethyl)piperidine hydrochloride (11,7 g, 59.4 mmol) was added. The mixture was stirred for 18 hours, evaporated and The residue was mixed with ethyl acetate (200 ml) and water (250 ml), saturated water. Washed with aqueous sodium bicarbonate solution (200ml) and water (200ml). Yes The organic phase was dried (MgSO4) and the organic phase was crystallized from aqueous ethanol. , N-[3-(4,5-diphenylimidazol-2-ylthio)propylcopibe Lysine (3.98 g) was obtained as a colorless solid, melting point 118-120<0>C.

Acetyl chloride (25 ml) was stirred in cold (<10°C) ethanol (70 ml). , was added dropwise while maintaining the temperature below 10°C. After stirring for 0.5 h, N-[3-(4,5-diphenylimidazole 2) in ethanol (10ml) -ylthio)propylcopiveridine (3,98 g) was added and 0.2% of the solution was added. Stirred for 5 hours. This mixture is then evaporated and the residue is dissolved in ethanol/ Crystallization from ether gives N-[3-(4,5-diphenylimidazole-2- ylthio)propyl]piverizine dihydrochloride (2.62 g) as a colorless solid. Obtained, melting point 180-185°C.

[Elemental analysis -C, 59,3; H, 6,5 + C1, 14,8; N, 9.1; S, 6.6%: Calculated knee c for C23H27N, S.2HCI-H2C, 59.0. H .

6.67; C1,15,1; N, 8.97; S, 6.84%] Potassium t-but Oxide (4.44 g, 39.6 mmol) was dissolved in 4°5-diphenylimidazole A stirred suspension of 2-thiol (Log, 39.6 mmol) was added at ambient temperature. Upon addition, a yellow solution formed.

After stirring for 0.5 h, 2-(hexamethyleneimino)ethyl chloride monohydrochloric acid Salt (11.9 g, 60 mmol) was added. The mixture was stirred for 18 hours and filtered. filter and rinse the solid with a small portion of dimethylformamide until the washings are colorless. So, I washed it. The insoluble material was dissolved in ethyl acetate (500 ml) and aqueous potassium carbonate. solution (10%, 250 ml) until complete dissolution occurs. did. The organic phase was washed with water (2 x 100 ml), dried (MgSO4) and Upon evaporation, N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl Circobarhydroazepine (10.8 g) was obtained as a colorless solid.

Acetyl chloride (25 ml) was stirred in cold (10°C) methanol (150 ml). and was added while maintaining the temperature below 10°C. After stirring for 05 hours, methane N-[2-(4,5-diphenylimidazol-2-yl) in solution (100 mI) Add a solution of thio)ethylcobarhydroazepine (10°8g) and leave for 5 minutes. Stir for a while. Add decolorizing charcoal (1 g), stir for 15 minutes, and filter the mixture. passed. Evaporation of the filtrate to a small volume and addition of ether yields N-[2 -(4,5-diphenylimidazol-2-ylthio)ethyl]perhydroazebi The dihydrochloride salt was obtained as a colorless solid, melting point 225-230°C.

[Elemental analysis Knee (:, 59.8; H, 6, 7, CI, 15.4; N, 9.2; S , 7.4%: Calculated value for C23H2□N3S・2HCI・%H20・-C,60,1; H, 6,58; C1,15,4; N, 9.15; S, 6,98%] i) Sodium hydride Thorium (0.6 g, 80% dispersion in 20 mmol oil) was added to dry tetrahydrogen. 4,5-diphenylimidazole-2-thiol ( 4.45 g, 17.7 mmol) was added at ambient temperature to a stirred suspension of . After stirring for 0.5 hours, N-(2-bromoethyl)phthalimide (5.08 g , 20 mmol) was added and the solution was heated under reflux for 6 hours. then The mixture was poured into water (500ml) and ethyl acetate (2 x 200ml) Extracted with. The extract is dried (MgS O4) and evaporated to form a gum. is obtained, and when crystallized from toluene, N-[2-(4,5-diphenyl imidazol-2-ylthio)ethyl]phthalimide (5-05 g) Obtained as a dark cream solid, melting point 165-166°C.

[Elemental analysis K, 70, 8: H, 4, 5; N, 9.8%: CzsHnN30z Calculated values for S: C, 70, 6: H, 4, 5: N.

9.9%.

N, M, R, (CDCI3 & D20): 3.22 (2H, t, J=5Hz ).

3.98 (2H, t, J=5Hz), 7.23-7.45 (6H, m).

7.54 (2H, d, J=7Hz), 7.62 (2H, d, J=7Hz).

7.73-7.78 (2H, m), 7.86-7.92 (2H, m)] .

Proceeding in a similar manner but replacing N-(2-bromoethyl)phthalimide Instead, N-(3-bromoethyl)phthalimide and N-(4-promoethyl) Using phthalimide, the following compounds were obtained: i) N-[3-( 4,5-diphenylimidazol-2-ylthio)propyl]phthalimide, colorless Solid, melting point 188-190°C; [Elemental analysis -C,70,7+H,4,7;N , 9.2%; Calculated value for C26H21N302S -C,71,05;H ,4,8;N.

9.6%: N, M, R, (CDCIs & DzO): 2.03 (2H, qu fn , J=7Hz), 3.05 (2H, t, J=7Hz), 3.96 (2H, t , J47Hz), 7.2-7.4 (6H, m), 7.42-7.62 ( 4H, m).

7.73 (2H, dd, J=6 and 3Hz), 7.82 (2H, dd.

J=6 and 3Hz)]; and i i i) N-[4-(4,5-diphenylimidazol-2-ylthio) Ptylphthalimide, colorless solid, melting point 170-171°C: [Elemental analysis: C ,71,'7;H,5,0;N,9.3:S,7.4%:CxtlhsNsO2 Calculated value for S Knee C+ 71.5; H, 5, 1; N.

9.3; S, 7.1%.

N, M, R, (CDCIs & DzO): 1.62 1.93 (4H, m ).

3.15 (2H, t, J=6Hz), 3.74 (2H, t, J=6Hz).

7.2-7.39 (6H, m), 7.4-7.6 (4H, m), 7.62= 7.78 (4H, m)].

Diglycol anhydride (8.34, g, 32.3 mmol) was dissolved in boiling xylene ( 500 ml) with stirring. Then 2-(3-aminopropylthio) -4,5-diphenylimidazole (5.0 g, 162 mmol) was boiled The mixture was stirred for 45 min with vigorous stirring, azeotropically removing the water that formed. Portions of 1 g were added at intervals.

After the last addition, heat under reflux for 15 hours and allow the mixture to cool and drain. Canted. This solution is evaporated and the residue is flushed with silica gel. Dichromatography (39:1 dichloromethane/methanol, as extractant) ). Recrystallization of the product from acetonitrile yields N-[3-( 4,5-diphenylimidazol-2-ylthio)propyl 3morpholine-3,5 -dione (3.7 g) was obtained as a colorless solid, melting point 164-166°C: [Elemental analysis - C, 64.6; H, 5.1; N, 10.2; S, 8.0%.

Calculated value for C2□H21N 303 S: -C,64,9;H,5,2 ;N.

10.3:S, 7.9%.

N, M, R, (CDC1! & C20): 1.98 (2H, qu in, J=7Hz), 3.09 (2H, t, J=7Hz), 4.02 (2H, t, J=7Hz), 4.34 (4H, s), 7.2-7.37 (6H, m), 7 ．． 45-7.57 (4H, m) 2.4-Dimethylglutaric anhydride (7.35 g, 51.7 mmol) was boiled. The mixture was added to xylene (500 ml) with stirring. 2-(3-aminopropyl thio)-4,5-')phenylimidazole (4.0 g.

12.9 mmol) into the boiling mixture while removing the water that forms azeotropically. was added in 1 g portions at 1 hour intervals with vigorous stirring. Reflux for 2 hours and then toluenesulfonic acid monohydrate (0.4 g.

2.1 mmol) was added and refluxed for 8 hours. Let this mixture cool and then Cantation and then evaporate the solution. Remove the resulting residue with silica gel. Rush chromatography (97:3 dichloromethane/methanol, eluent and It was purified by Recrystallization of the product from acetonitrile yields 3.5- Dimethyl-N-[3-(4,5-diphenylimidazol-2-ylthio)propyl Lucopiveridine-2,6-dione (3,23 g) was obtained as a colorless solid. , melting point 132-134°C): [Elemental analysis knee C+ 69.0: H, 6, 2, N, 9.8; S, 7.4%: C2 Calculated values for 5H27N302S Knee C, 69,3; H, 6,3; N.

9.7; S, 7.4%: N, M, R, (CDCI3 & C20): 1.27 (6H, d, J=7Hz ).

1.49 (IH, q, J=12Hz), 1.73-2.04 (4H, m).

2.02 (IH, dt, J=4 and 12Hz), 2.53-2.82 (2 H, m), 2.93 (2H, t, J=6Hz), 4.13 (2H, t, J=7Hz), 7.22-7.34 (6H, m), 7.48-7.62 ( 4H.

m)] N, M, R, spectrum shows that this is a 9.1 mixture of sy and anti isomers It was shown that

Proceeding in a similar manner but replacing 2,4-dimethylglutaric anhydride , a suitable anhydride and 2-(3-aminopropylthio)-4,5-diphenyl Using the appropriate amine in place of imidazole, the following compounds were prepared: 1i) N-[2(4,5-diphenylimidazol-2-ylthio)ethylcomale Imide, yellow solid, melting point 132-133°C: [Elemental analysis: C, 67,0; H, 4,5:N, 11.1%; Calculated value for CHHI□N302S Knee C, 67 , 2; H, 4, 53; N.

11.2%: N, M, R, (CDCIs & DzO) + 3.13 (2H, t, J=6H z).

3.82 (2H, t, J=6Hz), 7.2-7.45 (6H, m), 7゜46-7.7 (4H, m)]; i i i) N-[3-(4,5-diphenylimidazol-2-ylthio) ropyru]-4-methylmaleimide, pale yellow solid, melting point 136-138°C; [Elemental analysis K, 68, 2: H, 5, 15; N, 10.4; S, 8.1%: C Calculated value for zsH2+N5O2S Knee C+ 68.5; H, 5,2; N.

10.4; S, 7.94%; N, M, R, (CDCI! & DzO): 1.94 (2H, qu in, J =7Hz), 2.06 (3H, d, J = 4Hz), 3.02 (2H, t, J =7Hz), 3.78 (2H, t, J = 7Hz), 6.32 (LH, d, J =4Hz), 7.22-7.38 (6H, m), 7.45-7.56 (4H .

m)].

1v) N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl] Pyrrolidine-2,5-dione, colorless solid, melting point 189-191°C; [Elemental analysis -C, 66, 8: H, 5, 1: N, 11.1: S, 8.5%; C2 Calculated value for 1Hl 9N 30□S Knee C, 66,8; H, 5,04; N.

11.14; S, 8.5%]; v) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]py Loridine-2,5-dione, colorless solid, melting point 177-179°C.

[Elemental analysis K, 67, 6; H, 5, 4; N, 10.6%; C2□H2, N3 Calculated values for 0□S: C, 67, 5; H, 5, 4; N.

10.7%]; v i) N-[3-(4,5-diphenylimidazol-2-ylthio)pro Pircopiperidine-2,6-thion, colorless solid, melting point 154-155°C: [Elemental analysis K, 68, 2; H, 5, 8; N, 10.4%; CzsH23N3 02sJ: rcD calculated knee C, 68, 1: H, 5, 7: N.

10.36%].

vii) 4,4-dimethyl-N-[2-(4,5-diphenylimidazole-2- ylthio)ethylcopiperidine-2,6-dione, pale yellow solid, mp 86-88 ℃; [Elemental analysis knee C, 68,2, H, 6,2'7; N, 9.6; S, 7.5%: C Calculated value for 24H25N30□S Knee C+ 68.7; H, 6,0; N.

10.0; S, 7.6%]; viii) 4,4-dimethyl-N-[3-(4,5-diphenylimidazol-2) -ylthio)propylcopiperidine-2,6-sion, colorless solid, melting point 155 -157℃.

[Elemental analysis knee C, 69.0; ratio 6.24; N, 9.6: S, 7.4%; C2 Calculated value for 5H2□N302S -C, 69, 26; H, 6, 28: N, 9.7; S, 7.4%].

ix) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl 4-methylpiperidine-2,6-dione, colorless solid, melting point 160-162 °C; [Elemental analysis, -C, 68,9; H, 6,03; N, 9.9%.

Calculated value for C24H2s N 302 S Knee C, 68,’7; H, 6, 0;N.

10.0%.

x) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- 4-Ethyl-4-methylpiperidine-2,6-dione, pale yellow solid, melting point 134 -136℃: [Elemental analysis knee C, 69,6; H, 6,5; N, 9.3. S, 7.3%: C26 Calculated value for H2QN302S Knee C, 69, 77; H, 6, 53 + N, 9 ．． 4; 3.7.16%].

x i) N-[3-(4,5-diphenylimidazol-2-ylthio)pro Pyrcothiomorpholine-3,5-dione, cream solid, melting point 164-166 ℃： C elemental analysis - C, 62,3; H, 4, 84: N, 9.8; S, 15.0%; C2 2H21N30□S 2i: Tsu L'teno calculated value knee C, 62,, 4: H, 5, 0 ;N.

9.9:S, 15.14%]: xii) 4,4-dimethyl-N-[3-(4,5-di-p-+-rylimidazole) -2-ylthio)propylcopiperidine-2,6-sion, cream solid, molten Point 175-177°C: C elemental analysis: -C, 69,8; H, 6,65: N, 9. 1; S, 6.95%; Calculated value for C2□H31N 302 S・-C ,70,25;H,6,77:N,9.1;S,6.95%]; xi i 1) N-[3-(4,5-di-p-tolylimidazol-2-ylthio ) Propyl 1morpholine-3,5-dione, pale yellow solid, melting point 148-149°C : [Original! Analysis: -C, 66,4; H, 5,7; N, 9.5; S, 7.4%: Calculated value for C24H2s N 30s S Knee C, 66, 18; H, 5 , 8:N.

9.65:S, 7.36%]: x i v) N-[3-(4,5-diphenylimidazol-2-ylthio) propyl]4,4-dimethylpiperidine-2,6-sion:xv)N-[4-( 4,5-diphenylimidazol-2-ylthio)butylcomorpholine-3.5- Dione, colorless solid, melting point 153-155°C.

[Elemental analysis: -C, 65,1; H, 5,45: N, 10.0; S, 7.5% ; Calculated value for C23H23N 303 S Knee C, 65, 5; H, 5, 5 ;N.

9.97; S, 7.61%], and xvi) 3.3-dimethyl-N-[3- (4,5-Schiff-ni-1-limidazol-2-ylthio)propylcopiperidi -2,6-dione, colorless solid, melting point 168-170°C: [Elemental analysis -C, 69,3 + H, 6,3; N, 9.7; S, 7.2%.

Calculated value for C25H2□N302S -C, 69,26; H, 6,28; N, 9.69; S, 7.4%] l) 4,5-diphenylimidazole-2-thio in anhydrous THF (180 ml) A suspension of 20 mmol (5.04 g, 20 mmol) in sodium hydride (80 mmol) in oil % dispersion, 1.2 g, 40 mmol) and the mixture was brought to room temperature. and stirred for 30 minutes. (Sat)-3-chloromethy in anhydrous THF (20 ml) -1-methylpiperidine hydrochloride (368 g, 20 mmol) and sodium hydride Also, a mixture of Stirred for 30 minutes at room temperature. Mix the two mixtures together and add triethylamine (3.0 ml) was added and the whole mixture was stirred under reflux overnight. room temperature After cooling to , the reaction mixture was poured onto ice water (300 ml) and diluted with ether (300 ml). 200 ml). - Combined ether extracts with 2 molar hydrochloric acid (3X1 00ml). While cooling this acidic solution with ice, add 50% sodium hydroxide. um solution and extract the product into ether (3 x 100 ml). did. - The combined extracts are dried (MgSO4) and evaporated, resulting in a white color. A solid (2.0 g) was obtained.

When crystallized from toluene, [3-R,SF　-3-[(4,5-diphenyl- midazol-2-ylthio)methyl]-1-methylpiperidino (1°5 g) Obtained as a colored crystalline solid, melting point 167-169°C; 6; H, 6, 9; N, 11.5; S, s, s%; C2□H2'5N About 3S Calculated values: -C, 72.7; H, 6.9; N, 11.6; S, 8.8%.

N, M, R, (CDCI3): 1.92 (3H, s), 1.40 2. 70 (9H, m), 3.20 (2H, m), 7.20-7.50 (I OH, m) IR (KBr): 696.765.1445.1494.2926 and 3433 cm”].

1i) [3-R,SF　-3-[(4,5-dife) in xtanol (30 ml) Nylimidazol-2-ylthio)methyl]-1-methylpiperidine (4.1 g, 11.3 mmol) in ethanol while stirring and cooling with ice. A solution of hydrogen chloride [acetyl chloride (40 ml) was added to cold (10°C) methanol (180 ml). l) by stirring and adding the mixture while maintaining the temperature below 10°C. ] was added. The mixture was warmed to room temperature and stirred for 2 hours. ether( 200 ml) and the white precipitate was collected by filtration and fresh (After washing, [3-R,SF　-3-[(4,5-diphenylimidazo 2-ylthio)methyl]-1-methylpiperidine hydrochloride (4.6 g) Obtained as a colored powder, melting point 175-177°C; [actual value knee c, 59.7; Ratio 6.5; N, 9.0; C1,14,3:S.

6.8%; C22H25N3S・1.8HC]・Calculated value for N20 knee c, 59.2 ; H, 6,5; N, 9.4; C1, 14, 3; S, 7.2%].

i) 5-iodomethyl-2-pyrrolidinone (1,83 g, 8.1 mmol), 4,5-diphenylimidazole-2-thiol (1,8 3 g, 73 mmol) and anhydrous potassium carbonate (0°70 g, 5.1 mmol) The mixture was stirred at room temperature overnight. Evaporate this mixture into small chunks and The residue was suspended in water (70ml). The product was collected by filtration and dried. , and upon crystallization from ethanol/ether, [5-R,Sl　-5-[( 4,5-diphenylimidazol-2-ylthio)methyl]-2-piperidinone (98 g) was obtained as a white solid, melting point 218°C; 68,6; H, 5,5; N, 12.0; S, 9.1%: C*oH+*N305m ”) Calculated value of I, Nr Knee C+ 68.7; H, 5,5; N.

12.0; S, 9.2%.

N, M, R, (CDCIs): 1.85 & 2.35 (48,2m), 3 ．． 00 & 3.27 (2H, 2dd, J=14Hz and 4Hz), 3.91 (IH, m), 7.2-7.7 (IOH, m) rR (KBr): 698,76 2 and 1680 cm-']li) proceed in a similar manner but with 5-iodine 6-iodomethyl-2-pyrrolidinone instead of domethyl-2-pyrrolidinone and flash chromatography of the crude product (1 in ethyl acetate). 0% ethanol) and then crystallized from ethanol/ether. , [6-R,5F-6-[(4,5-diphenylimidazol-2-ylthio) methyl]-2-piperidinone was obtained as a white solid, mp 209-21 0℃: [Actual measurement value -C, 69.4; H, 5.8; N, 11.6: S, s, e%; C2 Calculated value knee c for 1H2□N30S, 69.4:H,5,8;N.

11.6; S, 8.8%.

N, M, R, (CD3SOCD3) ・1.4-2.0 & 2.05-2.10 (68,2m), 3.24 (2H, m), 3.63 (IH, m), 7.20 -7.55 (IOH, m) IR (KBr): 697.763 and 1634 cm-'].

111) Proceeding in a similar manner but with 5-iodomethyl-2-pyrrolidino 4,4-dimethyl-6-iodomethyl-2-pyrrolidinone was used instead of , and the crude product was purified by flash chromatography (ethyl acetate). Then, [6-R,Sl-4,4-dimethyl-6-[(4,5-diphenylimida Sol-2-ylthio)methyl]-2-piperidinone was obtained as a white solid. Melting point: 148-150℃: [Actual measurement knee C, 70,3; H, 6,6IN, 10.4%: C23H25N30 Calculated value for S -C, 70,6; H, 6,4; N.

10.7%; N, M, R, (CDsSOCDs): 0.94 & 0.98 (6H, S) , 1.2-1.8 (2H, m), 1.96 (2H, m), 3.26 (2 H, m).

3, 73 (IH, m), 7.20-7.58 (IOH, m) IR (KBr ): 695,763.1488 and 1636 cm-'].

The starting material for iodomethylraltam was described by S. Knapp et al. Null of Organic Chemistry (J, Org, Chei) Anhydrous TH 4.5-diphenylimidazole-2-thiol (8 g, A suspension of 31.7 mmol) of sodium hydride (80% dispersion in oil, 0.3 mmol) was dissolved in sodium hydride (80% dispersion in oil; 97 g, 32.7 mmol) and the mixture was incubated at room temperature for 30 min. Stir for a while. (±)-4-[2-(p-toluene) in anhydrous THF (20 ml) 1-methylpiperidine (94g, 31.6ml) mol) and the mixture was stirred at room temperature for 18 hours, then The mixture was refluxed for 24 hours. After cooling to room temperature, the reaction mixture was poured into ice water (500 ml). , and extracted with ether (4X100ml). - Add the combined extracts to hydrochloric acid (2 mol, 4 x 100 ml). While cooling this acidic solution with water, add 50% hydroxy acid. basified with sodium chloride solution and dissolved the product in ether (3X500ml). extracted inside. - Dry the combined extracts (Mg S04) and evaporate. and the residual solid (5.54 g) was subjected to silica gel flash chromatography. - (9:1 dichloromethane/methanol as eluent) to give [ 4-R,Sl-4-[(4,5-diphenylimidazol-2-ylthio)ethyl Lugault 1-methylpiperidine (2.28 g) was obtained as a molten solid. Point 74CHH2? N! Calculated value for S: C, 73, 16; H, 7, 2: N .

11.3; S, 8.5%].

West) Proceeding in a similar manner but with (±)-4-[2-(p-toluene) (±)-2-( instead of sulfonyloxy)ethyl 1-methylpiperidine using p-toluenesulfonyloxy)methyl-1-methylpiperidine and The crude product was crystallized from toluene and then converted to the hydrochloride salt followed by the free salt. When regenerated from [2-R,Sl　-2-[(4,5-diphenylimidazole) 2-ylthio)methyl]-1-methylpiperidine was obtained as a colorless solid. , melting point 62-64°C: [actual value K, 71,4; H, 6,9, N, 11.2. S, 8.2%; Calculated value for C2□H25N3S-XH20 knee c, 71 ．． 7; H, 6,98; N, 11.42; S, 8.71%].

Proceeding in a manner similar to that of Example 4, but with N used as starting material -[2-(4,5-diphenylimidazol-2-ylthio)ethyl]pyrrolidine -2-one instead of cis and trans-2゜6-cystyrene N-[4-( 4,5-diphenylimidazol-2-ylthio)butan-1-oil 1 morphol The reaction was carried out for 4 hours, then water was added and then the aqueous When worked up by adding sodium hydroxide solution, cis- and trans-2,6- Cystyrene N-[4-(4,5-diphenylimidazol-2-ylthio)butyl 1 morpholine was obtained, melting point 50-60°C (slow melting).

[Elemental analysis K, 70,0; H, 7,4; N, 9.8: S, 7.6; H2O, 1.4%: Calculated value for Cx5H3+N5OS: C, 69, 73; H, 7, 49; , N, 9.76: S, 7.44; H2O, 2,09%].

Proceeding in a manner similar to that of Example 2, but starting with the following compounds: did: 1) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl 1 mole Ruhorin; i i) N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl piperidine: and 111) Cis and trans-2,6-cystyrene N-[4-(4°5-dife Mixture of nylimidazol-2-ylthio)butyl 3-morpholine.

The following product was obtained 1) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl 17 Luforin dihydrochloride, melting point 173-175°C: elemental analysis C, 54, 7; H, 6 ,02;C1,14,9:N,9.1;S,6.41;H2O,6,4%: C2zH2sN, o S ・2 HCI ・1, 75 H20i: Tweet (7 ) Calculated value knee C, 54,7; H, 5,94; C1, 15,09; N, 8.7: S , 6.64:H2O, 6,52%].

Sono) N-[2-(4,5-diphenylimidazol-2-ylthio)ethylcopipe Lysine dihydrochloride, melting point 237-240°C.

[Elemental analysis -C, 60,06; H, 6,4; C1, 16,0; N, 9.6:, S, 7.3%: C2□H25N　3　S・Calculated value for 2HC1・-C,60,54;H, 6゜24; C1, 16, 25, N, 9.63; S, 7.35%]: and 1i i) cis and trans-2,6-cysty-N-[4-(4°5-diphenyl Mixture of imidazol-2-ylthio)butylcomorpholine dihydrochloride, melting point 208 -210℃: [Elemental analysis knee C, 60,6; H, 6,9; C1, 13,9,: N, 8.5; S , 6.47%.

C252H3125N! OS・2 HCI l: Twiteno calculated value knee C+ 6 0.72; H, 6,73; C1, 14, 34; N, 8.5: S, 6.48%].

Proceeding in a manner similar to that of Example 4, but starting with the following compounds: did: 1) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]pi Loridine-2,5-dione: and i) N-[3(4,5-diphenyl Holin-3,5-dione for imidazol-2-ylthio)probil como: formation of I got something: 1) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- 5-hydroxypyrrolidin-2-one, melting point 185-187°C: and i i) N-[3(4,5-diphenylimidazol-2-ylthio)propyl Luco-5-hydroxymorpholin-3-one, melting point 105°C (yield at 87°C) ).

Reference example 1 1) Sodium hydride (14 g, 80% dispersion in mmol oil) was added to dry T 4.5-Siphaerimidazole-2-thiol (5, 04 g, 20 mmol) at ambient temperature. 05 o'clock After stirring for a while, 3-bromopropylamine hydrobromide (4.38g, 20ml mol) was added. This mixture was then heated under reflux for 1 hour and then water (100% 0 ml) and extracted with ethyl acetate (2×500 ml). -Together The extract was dried (MgSO4) and evaporated. The residue was dissolved in ethyl acetate/ethyl acetate. After grinding with 1:1:70 ml of water and collecting the solids, 2-( 3-aminopropylthio)-4,5-diphenylimidazole (4.8 g) was obtained. It was done. Prepared by recrystallizing the analytical sample from toluene to obtain colorless crystals. produced, melting point 162-163°C: [Elemental analysis knee C, 70, 1+8. 6.3; N, 13.5%; Cl8HI. Calculated values for N, S, C, 69, 9, H, 6,2:N, 136%; N, M, R, (CDCIs & D20): 1.88 (2H, q Ll 1 n, J = 7Hz), 2.93 (2H, t, J = 7Hz), 3.2 (2H , t, J=7Hz), 7.2-7.32 (6H, m), 7.47-7.53 ( 4H, m)].

it) Proceeding in a similar manner but with 3-bromopropylamine hydrobromide When using 2-bromoethylamine hydrobromide instead of salt, 2-(2- Aminoethylthio)-4,5-diphenylimidazole was obtained, melting point 152 -1.54℃.

[Elemental analysis Knee C, 68.6; H, 5.8; N, 14.1; S, 10.5%: C l　7　H+□N3S Calculated value knee C, 69, 1; H, 5, 8; N, 1 4.2; S, 10.85%.

N, M, R, (CDC13 & D20): 3.1 (4H, br s), 7. 16-7.36 (6H, m), 7.42-7.56 (4H, m).

Reference example 2 N-[4,-(4,5-diphenylimidazol-2-ylthio)butylchoftal Imide (10.2 g, 22.5 mmol) [in Example 1 (ii) [prepared as follows] was mixed with ethanol (250ml) and hydrazine hydrate ( 1.25 g, 25 mmol) was heated under reflux for 22 hours. Then salt An aqueous solution of acid (2N: 50ml) was added and boiled for 0.5h. then The mixture was cooled (10° C.), the solids were filtered and discarded. Evaporate the filtrate The residue was dissolved in water (250ml) and filtered. The filtrate is then aqueous Make basic (>pH 10) with sodium hydroxide solution (2N) and this mixture was extracted with ethyl acetate (3X200ml). - Dry the combined extracts (MgS 2-(4- Aminobutylthio)-4,5-diphenylimidazole (4.5 g) is a colorless Obtained as crystals, melting point 138-139°C.

[Elemental analysis knee C, '70.7; H, 6, 6, N, 13.0%; C breath 9 H21 N 3 Calculated value for S Knee C, 70, 6; H; 6.5; N, 1 Example 1 Proceeding in a similar manner to that of , but using cis- and trans- as starting materials. using a mixture of su-N-(4-chlorobutanoyl)-2,6-dimethylmorpholine. When used, cis- and trans-2,6-cystyrene N-[4-(4,5-di Phenylimidazol-2-ylthio)butane-1-oylcomorpholine was obtained. Melting point: 147-149C0 In clinical practice, compounds of the invention may be administered parenterally, rectally or orally. can do.

Solid compositions for oral administration include compressed tablets, powders, powders and granules. Contains. In such solid compositions, one or more active compounds may be present. mixed with at least one diluent such as starch, sucrose or lactose Ru. The composition may also contain additional agents other than inert diluents, as in normal practice. Substances such as lubricants such as magnesium stearate may be included.

Liquid compositions for oral administration are prepared using inert materials commonly used in this field. Pharmaceutically acceptable emulsions, solutions, suspensions, solos, liquids and liquids containing diluents. and elixirs. Besides an inert diluent, such compositions can also be used as an adjuvant. containing, for example, wetting and suspending agents, and sweetening, flavoring, and preservative agents. I can do it. Compositions according to the invention for oral administration may also contain diluents or excipients. containing one or more active substances, with or without excipients; These include capsules of absorbable material, such as gelatin.

Compositions according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and Includes organic solutions, suspensions and emulsions. Examples of organic solvents or +5 turbidity media are , propylene glycol, polyethylene glycol, vegetable oils, e.g. olive oils and injectable organic esters, such as ethyl oleate. The composition is , also adjuvants such as stabilizers, preservatives, wetting agents, emulsifiers and dispersants. can contain.

They include, for example, filtration through bacteria-retaining filters, admixture of sterilizing agent compositions, It can be sterilized by heating, irradiation, or heating. Before use, they should also be A non-sterile drug that can be dissolved in sterile water or some other sterile injectable medium. It can be prepared in the form of a solid composition of fungi.

Solid compositions for rectal administration are formulated according to known methods and containing at least Both include suppositories containing one compound of formula (1).

The percentage of active ingredients in the compositions of the invention may vary and may vary as appropriate. It is necessary to construct the ratio in such a way that a suitable dosage is obtained.

As will be appreciated, several unit dosage forms can be administered at about the same time.

The dosage to be used is determined by the physician and depends on the desired therapeutic effect, route of administration, depending on the patient's condition and duration of treatment.

In adults, the dosage by oral administration is generally about 0.5 to about 70, preferably About 1 to about 10 mg/kg body weight/day.

Pharmaceutical compositions according to the invention are illustrated by the following composition examples.

Composition Example 1 Each of the following ingredients: N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl 1 morpholy 20mg Lactose 100mg Starch 6 Qmg Textrin 40mg Magnesium stearate 1mg A gelatin capsule of size No. containing The following ingredients: 3,5-dimethyl-N-[3-(4,5-diphenylimidazol-2-ylthio ) Propylcopiperidine-2,6-dione 0mg Lactose 100mg Starch 60mg Textrin 40mg Magnesium stearate 1mg A gelatin capsule of size No. containing The following ingredients: [3-R,Sl　-3-[(4,5-diphenylimidazol-2-ylthio)methane [chill]-1-methylpiperidine 20mg lactose 100mg Starch 60mg Textrin 4 Qmg Magnesium stearate 1mg No. size gelatin capsules containing the following were prepared according to conventional procedures.

Summary book General formula: % formula % (1) During the ceremony, [DPIM] is the general formula: , R and R1 are hydrogen, halogen or alkyl, and W is a linear 1 alkylene having ~6 carbon atoms and optionally substituted with alkyl groups; the law of nature, is a group of, in the formula, R2 is hydrogen or methyl; R3 are the same or different and each is hydrogen or alkyl , and R4 is hydrogen, or two symbols R4 and both of them are conjugated. together with carbon atoms to form a carbonyl group, and R5 is hydrogen or hydroxyl. It is shi, Z is oxygen, sulfur, formula [C(R3)! or NR” group, and m is O or is 1 to 5, n is O or 1-5, and p is 0 or 1, where m + n + p = 3.4 or 5 , q is 0.1 or 2, Imidazole derivatives with Atherosclerosis, hyperlipidemia, cholesterol or ester storage disease or atherosclerosis Acylcoenzyme-A useful for conditions such as cholesterol: Cholesterol - It is an inhibitor of acyltransferases.

IPlerpH+. 1141 A, +c+n-□. PCT/EP 901021 47I ceramics ('RNfflAml,, ←　1.6゜　PCT/EP　90102 147 International Search Report PCT/EP 90102147 S^　43522

Claims (1)

[Claims] 1. Acylcoenzyme-A: Cholesterol-O-acyltransferase Pharmaceutical compositions for the treatment of conditions that can be ameliorated by the administration of inhibitors of General formula: [DPIM]-S-W-Y(I) for use in the preparation of During the ceremony, [DPIM] is the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (DPIM), and R and R1 are the same. are or are different, and each is a hydrogen atom or a halogen atom or a straight chain a branched or branched alkyl group having 1 to 5 carbon atoms, and W is methyl having 2 to 5 carbon atoms and having a ren group or a straight chain and a straight or branched chain an alkylene chain optionally substituted with an alkyl group having 1 to 4 carbon atoms; and Y is the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II)▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. There are ▼ (V) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ It is a group of (VI), and in the formula , The symbols R2 are the same or different and each is a hydrogen atom or a methyl is the basis, The symbols R3 are the same or different, and each hydrogen atom ro straight-chain or a branched alkyl group having 1 to 4 carbon atoms, Each of the symbols R4 is a hydrogen atom, or two symbols R4 and both of them R5 is a hydrogen atom or a carbonyl group together with the carbon atom to which R5 is attached. or a hydroxy group, and Z is an oxygen atom or a nitrogen atom or a formula [C(R3)2 ]q or a group of NR3, m is 0 or an integer from 1 to 5, n is 0 or an integer from 1 to 5, and p is 0 or 1, where m+n +p=3, 4 or 5 and q is 0, 1 or 2, or a pharmaceutically acceptable acid addition salt thereof. 2. Atherosclerosis, hyperlipidemia, and cholesterol in vein grafts In the preparation of pharmaceutical compositions for the treatment of ester storage diseases or atheroma A compound according to paragraph 1 above for use. 3, provided that W is a methylene group or a linear alkylene having 2 to 4 carbon atoms When it is a group, Y is other than the group of formula (V), the symbol R4 is a hydrogen atom, and Z is an oxygen atom or a group of the formula [C(R3)2]q, where q is 0 or 1, or NR3, or the symbol R4 and the carbon atom to which both of them are bonded. the child forms a carbonyl group, and Z has the formula [C(R3)2]q, where a is 0. human and animal groups, where R, R1 and R3 are as previously defined. A compound of formula (I) according to paragraph 1 above for the therapeutic treatment of the body of a human being; is a pharmaceutically acceptable acid addition salt thereof. 4. Atherosclerosis, hyperlipidemia, and cholesterol in vein grafts Treating the human and animal body by treating ester storage diseases or atheroma A compound according to paragraph 3 above for use in the method. 5, provided that W is a methylene group or a linear alkylene having 2 to 4 carbon atoms When it is a group, Y is other than the group of formula (V), the symbol R4 is a hydrogen atom, and Z is an oxygen atom or a group of the formula [C(R3)2]q, where q is 0 or 1, or NR3, or the symbol R4 and the carbon atom to which both of them are bonded. the child forms a carbonyl group, and Z has the formula [C(R3)2]q, where a is 0. , wherein R, R1 and R3 are as defined above, an imidazole derivative of formula (I) or a pharmaceutically acceptable acid addition thereof salt. 6. At least one of the symbols has a value selected from: (i) R is hydrogen; or a chlorine atom or a methyl group; (ii) R1 is hydrogen or a chlorine atom or is a methyl group; (iii) W is a methylene group or a 2, 3 or 4 carbon atom is an alkylene chain with children; (iv) Y is phthalimide, optionally substituted maleimide, pyrrolidinium with ru, piperidinyl, perhydroazevinyl, piperazinyl or morpholino group. and/or (v) R3 is a hydrogen atom or a methyl or ethyl group ; other symbols are as defined previously; A compound according to item 5 above, and a pharmaceutically acceptable acid addition salt thereof. 7. Formula (A) [DPIM]-S-M+(VII) During the ceremony, [DPIM] is as defined in paragraph 1 above, and M is alkali metal is a genus atom, The general formula for the salt is: X-W-Y (VIII) During the ceremony, X is a group that can be substituted by a thiolate salt, and W and Y are or an acid addition salt thereof, as defined in Section 5 above. (B) Y is a group of formula (II), (III) or (IV), and the other symbols are As defined in Section 5 above, the formula: [DPIM]-S-W-NH 2(IX) In the formula, The various symbols are as defined in Section 5 above, and the compound is represented by the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(X)▲There are mathematical formulas, chemical formulas, tables, etc.▼( XI) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (XII) In the formula, Z, R2 and R3 are as defined in Section 5 above. let; (C) Y is a group of formula (V) and the other symbols are as defined in paragraph 5 above. formula (I), in which Y is a group of formula (IV) and the other symbols are as above. Reducing the compound, as defined in Section 5 above, with a metal hydride reducing agent. do; (D) Y is a group of formula (V), in which R4 is a hydrogen atom, and the other symbols are as defined in paragraph 5 of the formula (I), in which Y is a group of formula (IV); and the two symbols R4 and both of them represent the joining carbon atom and carbonyl. and the other symbols are as defined in Section 5 above. (E) the compound of formula (I) is reduced with a reducing agent of the genus hydride; [DPIM]-S-W1-CH2-Y (XIV) where, W1 has a methylene group or 2 to 4 carbon atoms, and also has one or more apical chains. or may be substituted with a branched alkyl group having 1 to 4 carbon atoms. A straight alkylene chain with other symbols as defined in Section 5 above. Ru, When we have the formula: [DPIM] -S-W1CO-Y (XV) In the formula, The various symbols are as defined in Section 5 above. If necessary, reduce the compound of general formula (I) with a reducing agent of of the general formula (I) according to item 5 above, Methods of preparing compounds. 8. The imidazole derivative of formula (I) described in item 5 above or its pharmaceutically acceptable acceptable acid addition salts, and pharmaceutically acceptable carriers or coatings. A pharmaceutical composition comprising: 9. An improving effective amount of the compound of general formula (I) according to item 1 above or its pharmaceutical composition Acylcoenzyme-A:cholesterol-O, consisting of acceptable acid addition salts - a condition that can be improved by the administration of acyltransferase inhibitors Pharmaceutical compositions useful in treatment. 10. An improving effective amount of the imidazole derivative of general formula (I) according to the above item 1 or acylcoin, which comprises administering to a host a pharmaceutically acceptable acid addition salt thereof; Enzyme-A: administration of an inhibitor of cholesterol-O-acyltransferase human or animal host suffering from a condition that can be improved by treatment, or How to treat patients. 11. General formula: [DPIM]-S-W-Y(I) During the ceremony, [DPIM] is the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (DPIM), and R and R1 are the same. are or are different, and each is a hydrogen atom or a halogen atom or a straight chain a branched or branched alkyl group having 1 to 5 carbon atoms, and W is methyl having 2 to 5 carbon atoms and having a ren group or a straight chain and a straight or branched chain an alkylene chain optionally substituted with an alkyl group having 1 to 4 carbon atoms; and Y is the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II)▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. There are ▼ (V) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ It is a group of (VI), and in the formula , The symbols R2 are the same or different and each is a hydrogen atom or a methyl is the basis, The symbols R3 are the same or different and each is a hydrogen atom or a straight chain or a branched alkyl group having 1 to 4 carbon atoms, Each of the symbols R4 is a hydrogen atom, or two symbols R4 and both of them R5 is a hydrogen atom or a carbonyl group together with the carbon atom to which R5 is attached. or a hydroxy group, and Z is an oxygen atom or a sulfur atom or a formula [C(R3)2 ]q or a group of NR3, m is 0 or an integer from 1 to 5, n is 0 or an integer from 1 to 5, and p is 0 or 1, where m+n +p=3, 4 or 5 and q is 0, 1 or 2, or a pharmaceutically acceptable acid addition salt thereof. Acylcoenzyme-A: Cholesterol-O-acyltransferer for use when treating conditions that can be improved by administration of inhibitors of drugs.