AU4799699A - Imidazole compounds - Google Patents

Imidazole compounds Download PDF

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Publication number
AU4799699A
AU4799699A AU47996/99A AU4799699A AU4799699A AU 4799699 A AU4799699 A AU 4799699A AU 47996/99 A AU47996/99 A AU 47996/99A AU 4799699 A AU4799699 A AU 4799699A AU 4799699 A AU4799699 A AU 4799699A
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Prior art keywords
hydroxy
imidazole
compound
carboxamide
preparation
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AU47996/99A
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AU748710B2 (en
Inventor
Takayoshi Kinoshita
Masako Kuno
Katsuya Nakamura
Isao Nakanishi
Nobuya Nishio
Hiroyuki Okumura
Akihiro Sato
Nobuo Seki
Tadashi Terasaka
Kiyoshi Tsuji
Susumu Tsujimoto
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Astellas Pharma Inc
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Fujisawa Pharmaceutical Co Ltd
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Priority claimed from AUPP4840A external-priority patent/AUPP484098A0/en
Priority claimed from AUPP7355A external-priority patent/AUPP735598A0/en
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Priority to AU47996/99A priority Critical patent/AU748710B2/en
Priority claimed from PCT/JP1999/003939 external-priority patent/WO2000005217A1/en
Publication of AU4799699A publication Critical patent/AU4799699A/en
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Publication of AU748710B2 publication Critical patent/AU748710B2/en
Assigned to ASTELLAS PHARMA INC. reassignment ASTELLAS PHARMA INC. Alteration of Name(s) in Register under S187 Assignors: FUJISAWA PHARMACEUTICAL CO., LTD.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

WO 00/05217 PCT/JP99/03939 IMIDAZOLE COUMPOUNDS AND THEIR USE AS ADENOSINE DEAMINASE INHIBITORS 5 Technical Field This invention relates to novel imidazole compounds having pharmacological activity, to a process for their production and to a pharmaceutical composition containing the same. 10 Background Art Adenosine (Ado) is an endogenous purine nucleoside released by cells as part of the normal metabolic machinery. Ado has wide variety of biological activities, namely potent antiinflammatory and immunosuppressive properties, protective effects in cardiovascular 15 and cerebrovascular ischemia, anticonvulsant effects and modulation effects of platelet aggregation, lipolysis, glycogenesis, blood flow and neurotransmission. Ado shows the biological activities by binding to its receptors anchored in the cell membrane. Therefore, it is the beneficial treatment for many diseases to perform the 20 pharmacological elevation of extracellular Ado concentrations. Adenosine deaminase (ADA) catalyzes an essentially irreversible deamination of adenosine or deoxyadenosine to inosine or deoxyinosine, respectively. In the last 10 years, ADA, which was considered to be cytosolic, has been found on the cell surface of many cells. Thus, 25 blocking ADA activity with specific inhibitor is the potent way to elevate Ado concentrations in biological systems and the beneficial treatment for many diseases. Some compounds have known to have inhibitory activity of ADA (J. Med. Chem. 27, 274-278, 1984; ibid. 31, 390-393, 1988; ibid. 34, 30 1187-1192, 1991; ibid. 35, 4180-4184, 1992; ibid. 37, 305-308, 1994; ibid. 37, 3844-3849, 1994; and W098/02166). Known imidazole compounds with pharmaceutical activity other WO 00/05217 PCT/JP99/03939 2 than ADA inhibitory activity are described in U.S. Patent No. 4,451,478 and W097/26883. Furthermore, some imidazole derivatives having ADA inhibitory activity have been reported, for example, as described in Drug 5 Developement Reseach 28, 253-258, 1993. Disclosure of the Invention This invention relates to novel imidazole compounds, which have pharmaceutical activity such as ADA inhibiting activity, to a process 10 for their production, to a pharmaceutical composition containing the same and to a use thereof. One object of this invention is to provide the novel imidazole compounds, which have an ADA inhibiting activity. Another object of this invention is to provide a process for 15 production of the imidazole compounds. A further object of this invention is to provide a pharmaceutical composition containing the imidazole compound as an active ingredient. Still further object of this invention is to provide a use of 20 the imidazole compound for manufacturing a medicament for treating or preventing various diseases, or a method of treating or preventing various diseases by administering the imidazole compound in an effective amount to elevate adenosine concentration. 25 The imidazole compounds of this invention can be represented by the following formula (I): R4 30 Ri-A R 1 -A R32 WO 00/05217 PCT/JP99/03939 3 wherein R 1 is hydrogen, hydroxy, protected hydroxy, or aryl optionally substituted with suitable substituent(s);
R
2 is hydrogen or lower alkyl;
R
3 is hydroxy or protected hydroxy; 5 R 4 is cyano, (hydroxy)iminoamino(lower)alkyl, carboxy, protected carboxy, heterocyclic group optionally substituted with amino, or carbamoyl optionally substituted with suitable substituent (s); and - A - is - Q - or -O-Q-, wherein Q is single bond or lower alkylene, 10 provided that when R 2 is lower alkyl, then R 1 is hydroxy, protected hydroxy, or aryl optionally substituted with suitable substituent (s), its prodrug, or their salt. 15 The compound (I), its prodrug, or their salt can be prepared by the following processes. In the following formulae, compounds may be prodrugs or their salts. Process 1 20 R4 N R4 N + lA' R3C R3 25 HR1-AR3 2 (III) (IV) (I) wherein R', R 2 , R 3 , R 4 , and A are each as defined above, and X is hydroxy or a leaving group, provided that R 3 is not hydroxy. 30 In this process the compound (I) can be produced by reacting the compound (IV), where X is hydroxy, with alkanesulfonyl chloride WO 00/05217 PCT/JP99/03939 4 (i.e., methanesulfonyl chloride, etc.) or arylsulfonyl chloride (i.e., toluenesulfonyl chloride, etc. ) in the presence of a base such as triethylamine or pyridine in a solvent such as dichloromethane, chloroform, tetrahydrofuran, or diethyl ether from 00C to room 5 temperature for about 1 hour and reacting the resulting sulfonate with the compound (III) in the presence of a base such as sodium hydride, potassium tert-butoxide, or potassium carbonate in a solvent such as dimethylformamide (DMF) from room temperature to 1000C for 5 to 100 hours. Alternatively, the compound (III) can be reacted with the 10 compound (IV) in the presence of a base such as sodium methoxide, potassium tert-butoxide, or sodium hydride to give the compound (I). The compound (I) wherein R 3 is hydroxy can be obtained by the following process: 15 Process 2 R4 R4 N 20 Reduction N> R1-A OR' R--A OH (II) (I-1) 25 In the reaction formula R 1 and R 4 are as defined above and R' is a hydroxy protective group. In process 2, the compound (I-1) can be produced by reducing 30 the compound (II) using a reducing agent such as sodium borohydride in a solvent such as methanol, ethanol, tetrahydrofuran, or water at 00C to reflux temperature for 30 minutes to 72 hours.
WO 00/05217 PCT/JP99/03939 5 When the compound (I) contains a protected hydroxy group, the protected hydroxy group can be converted to a hydroxy group by a known method, for example, by reacting the compound with a deprotecting 5 agent such as palladium hydroxide on carbon/cyclohexane, iodotrimethylsilane or tetrabutylammonium fluoride in a solvent such as ethanol, chloroform or tetrahydrofuran. The compound (I) where R 4 is (hydroxy) iminoamino (lower) alkyl, heterocyclic group or substituted carbamoyl can be prepared from the 10 compoupd (I) where R 4 is cyano or protected carboxy by reacting the latter with the compound corresponding to R 4 of the former with or without a condensing agent such as sodium methoxide at room temperature to 120 0 C for 2 to 72 hours. 15 The starting compound (II) can be prepared by the following reaction. R4 OR' N 20 IN> + R 1 -A OR N O R1-A H 0 (III) (IV-1) (1 25 In the reaction formula R 1 , R 4 , R', and A are as defined above. This reaction can be performed in the same manner as in Process 1. In the following, suitable examples of the definitions to be 30 included within the scope of the invention are explained in detail. The term "lower" means a group having 1 to 6 carbon atom(s), WO 00/05217 PCT/JP99/03939 6 unless otherwise provided. Suitable "lower alkyl" and lower alkyl moiety of "lower alkoxy" include a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, or the like, 5 with methyl being preferred. Suitable "lower alkylene" may be straight or branched one having 1 to 8 carbon atom(s), such as methylene, ethylene, trimethylene, tetramethylene, pentametylene, hexamethylene, or the like. Suitable "protected hydroxy" includes lower alkoxy optionally 10 substituted with aryl; acyloxy; or tri(lower)alkylsilyloxy (i.e., trimethylsilyloxy, tert-butyldimethylsilyloxy, etc.); or the like. Suitable hydroxy protective groups in the protected hydroxy group include lower alkyl optionally substituted with aryl; acyloxy; tri(lower)alkylsilyloxy (i.e., trimethylsilyloxy, tert 15 butyldimethylsilyloxy, etc.); or the like. Suitable "halogen" includes fluorine, chlorine, bromine, or iodine. Suitable "aryl" and aryl moeity of "aroyl" include phenyl, naphthyl, tolyl, xylyl, or the like, with phenyl and naphthyl being 20 preferred. Suitable "protected carboxy" includes lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, etc.), aryloxy carbonyl (e.g., phenoxycarbonyl, 4-nitrophenoxycarbonyl, etc.), 25 ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, 4 nitrobenzyloxycarbonyl, etc.), or the like. Suitable carboxy protective groups in the protected carboxy group include lower alkyl (e.g., methyl, ethyl, or tert-butyl), halo(lower)alkyl (e.g., 2-iodomethyl or 2,2,2-trichloroethyl), 30 ar(lower)alkyl (e.g., benzyl, trityl, 4-methoxybenzyl, 4 nitrobenzyl, phenethyl, bis(methoxyphenyl)methyl, 3,4 dimethoxybenzyl or 4-hydroxy-3,5-di-tert-butylbenzyl), aryl (e.g., WO 00/05217 PCT/JP99/03939 7 phenyl, naphthyl, tolyl, or xylyl), and the like. More suitable examples are lower alkyl such as methyl, ethyl, or tert-butyl, and ar(lower)alkyl such as benzyl. Suitable "acyl" and acyl moiety of "acyloxy" include lower 5 alkanoyl, aroyl, or the like. Suitable "lower alkanoyl" includes formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, or the like. Suitable "aroyl" may be benzoyl, naphthoyl, toluoyl, xyloyl, 10 or the like. In the definition, unless stated otherwise, "lower alkanoyl" and "aroyl" may be substituted with one or more substituent(s) selected from halogen, cyano, nitro, lower alkyl, and a combination thereof. 15 Suitable "acyloxy" includes acetyloxy, trifluoroacetyloxy, or the like. Suitable "leaving group" may be halogen, acyloxy (e.g., acetyloxy, trifluoroacetyloxy, etc.), lower alkylsulfonyloxy (e.g., methanesulfonyloxy, etc.), triarylphosphinoxy (e.g., 20 -0-P+(C 6
H
5
)
3 , etc.), or the like. Suitable "substituent (s) " of "carbamoyl" include amino, hydroxy, lower alkyl, lower alkylsulfonyl, and aminoimino(lower)alkyl optionally substituted with hydroxy, or the like. Suitable "substituent(s)" of "aryl" include lower alkyl 25 optionally substituted with hydroxy or protected carboxy; lower alkoxy optionally substituted with aryl; hydroxy; amino; acyl; halogen; carboxy; protected carboxy; carbamoyl; lower alkylenedioxy, or the like. Suitable "heterocyclic group" contains at least one hetero atom 30 selected from nitrogen, sulfur, and oxygen atom and may be saturated or unsaturated, monocyclic or polycyclic heterocyclic group. Preferable examples of the heterocyclic group include N-containing WO 00/05217 PCT/JP99/03939 8 heterocycyclic group described below. (1) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl. 5 pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H 1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; (2) saturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g., 10 pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.); (3) unsaturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,4-oxadiazolinyl, 1,3,4-oxadiazolyl, 15 1,2,5-oxadiazolyl, etc.), etc.; (4) saturated 3 to 7-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl, etc.); (5) unsaturated 3 to 7-membered, preferably 5- or 6-membered 20 heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), etc.; (6) saturated 3 to 7-membered preferably 5- or 6-membered 25 heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiomorpholinyl, thiazolidinyl, etc.) and the like. Among the above, more preferable heterocyclic group included in R 4 is above-mentioned (1), in which the most preferable one is triazolyl 30 or tetrazolyl. Suitable salts of the compounds of the present invention are WO 00/05217 PCT/JP99/03939 9 pharmaceutically acceptable conventional non-toxic salts and can be an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartarate, oxalate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), an inorganic acid 5 addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt with an amino acid (e.g. aspartic acid salt, glutamic acid salt, etc.), or the like. The "prodrug" means the derivatives of compounds of the present invention having a chemically or metabolically degradable group, 10 which becomes pharmaceutically active after biotransformation. The compounds of formula (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers. Furthermore certain compounds of formula (I) which contain alkenyl groups may exist as cis- or trans-isomers. In each instance, the 15 invention includes both mixtures and separate individual isomers. The compounds of the formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers. The compound of the formula (I) and its salt can be in a form 20 of a solvate, which is included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate. Also included in the scope of invention are radiolabelled derivatives of compounds of formula (I) which are suitable for 25 biological studies. The compound of the present invention can be purified by any conventional purification methods employed for purifying organic compounds, such as recrystallization, column chromatography, 30 thin-layer chromatography, high-performance liquid chromatography and the like. The compounds can be identified by conventional methods such as NMR spectrography, mass spectrography, IR spectrography, WO 00/05217 PCT/JP99/03939 10 elemental analysis, and measurement of melting point. The compound (I), its prodrug, or their salt can be administered alone or in the form of a mixture, preferably, with a pharmaceutical 5 vehicle or carrier. The active ingredient of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains a compound (I), as an active ingredient, in admixture with an organic or inorganic carrier or excipient 10 suitable for external (topical), enteral, intravenous, intramuscular, parenteral or intramucous applications. The active ingredient can be formulated, for example, with the conventional non-toxic, pharmaceutically acceptable carriers for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solution (saline, for 15 example), emulsion, suspension (olive oil, for example), aerosols, pills, powders, syrups, injections, troches, cataplasms, aromatic waters, lotions, buccal tablets, sublingual tablets, nasal drops and any other form suitable for use. The carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch 20 paster, magnesiumtrisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active compound is included in 25 a pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the diseases. The active ingredient can be formulated into, for example, preparations for oral application, preparations for injection, 30 preparations for external application, preparations for inhalation, preparations for application to mucous membranes. Mammals which may be treated by the present invention include WO 00/05217 PCT/JP99/03939 11 livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans, preferably humans. While the dosage of therapeutically effective amount of the compound (I) will vary depending upon the age and condition of each 5 individual patient, an average single dose to a human patient of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, and 1000 mg of the compound (I) may be effective for treating the above mentioned diseases. In general, amounts between 0.01 mg/body and about 1,000 mg/body may be administered per day. 10 The compound (I) or its pharmaceutically acceptable salts of this invention possesses ADA inhibiting activity and are thus useful in immunomodulation, especially immunosuppression, antiinflammation and treatment and prevention of various diseases for which Ado is 15 effective. Examples of the diseases are as follows: a) Autoimmune diseases and inflammatory conditions, e.g., various pains collagen diseases, autoimmune diseases, various immunity diseases, and the like in human beings or animals, and more particularly for the treating and/or preventing inflammation and pain 20 in joint and muscle (e.g. rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, etc.), inflammatory skin condition (e.g. sunburn, eczema, etc.), inflammatory eye condition (e.g. conjunctivitis, etc.), lung disorder in which inflammation is involved (e.g. asthma, bronchitis, pigeon fancier's 25 disease, farmer's lung, etc.), condition of the gastrointestinal tract associated with inflammation (e.g. aphthous ulcer, Crohn's disease, atrophic gastritis, ulcerative colitis, coeliac disease, regional ileitis, irritable bowel syndrome, etc.), gingivitis, (inflammation, pain and tumescence after operation or injury), 30 pyrexia, pain and other conditions associated with inflammation, systemic lupus erythematosus, scleroderma, polymyositis, polychondritis, periarteritis nodosa, ankylosing spondylitis, WO 00/05217 PCT/JP99/03939 12 inflammatory chronic renal condition (e.g. nephrotic syndrome, glomerulonephritis, membranous nephritis, etc.), acute nephritis, rheumatic fever, Sjogren's syndrome, Behcet disease, thyroiditis, type I diabetes, dermatomyositis, chronic active hepatitis, acute 5 hepatitis, myasthenia gravis, idiopathic sprue, Grave's disease, multiple sclerosis, primary billiary cirrhoris, Reiter's syndrome, autoimmune hematological disorders (e.g. hemolytic anemia, pure red cell anemia, idiopathic thrombocytopenia; aplastic anemia, etc.), myasthenia gravis, uveitis, contact dermatitis, psoriasis, Kawasaki 10 disease, sarcoidosis, Wegner's granulomatosis, Hodgkin's disease, or the like; b) Organ or tissue allo-or xeno-transplant rejection, e.g., kidney, liver, heart, lung, combined heart-lung, bone marrow, islet cells, pancreatic, skin, chromaffin or dopamine producing cells, 15 small bowel, or corneal transplantation. Treating and/or preventing graft-versus-host disease, such as occurs following bone marrow transplantation; c) Various leukemias, including virus induced, or various induced lymphomas; and 20 d) Diseases that arise from, or are aggravated by, insufficient blood flow through a particular organ or portion thereof, e.g., heart attacks or strokes, the microvascular disease of diabetes mellitus, atherosclerosis, or events resulting in a less prolonged loss of blood flow (e.g., angina pectoris, transient ischemic attacks, bowel 25 ischemia, kidney ischemia, intermittant claudication of skeletal muscle, migraine headaches, Raynaud's phenomenon), or the like. Any patents, patent applications, and publications cited herein are incorporated by reference. 30 In order to illustrate the usefulness of the object compound (I), the pharmacological test data of the compound (I) are shown in WO 00/05217 PCT/JP99/03939 13 the following. Adenosine Deaminase (ADA) Enzyme Assay Test Compound: 5 1-(1-Hydroxy-4-phenyl-2-butyl)imidazole-4-carboxamide (Example 1) Test method: The reaction velocity (V) is measured by a change in absorbance 10 at 265 nm (A265) resulting from the deamination of adenosine. Human ADA was expressed and purified from ADA-deficient bacterial strain. Reaction mixtures in a total volume of 200 [tl contained 25 mU/ml of ADA and varying concentrations of adenosine and test compounds in 10 mM phosphate buffer saline (pH 7.4). The reaction was started by 15 addition of ADA to a mixture of adenosine and test compound. The reaction was followed at room temperature by recording decrease in A265 for 5 minutes in SPECTRAmax 250 (Molecular Devices, USA) to automatically calculate Vmax. The inhibition constant (Ki) values of test compounds were determined by Dixon plot. 20 Results: Test Compound: Ki=5.9 sM Endotoxin-induced Cytokine Production 25 Test Compound: 1-(1-Hydroxy-4-phenyl-2-butyl)imidazole-4-carboxamide Test method: BALB/c mice (male, 7 weeks old) were injected i.v. with 0.1 mg/kg 30 of lipopolysaccharides (LPS) in a total volume of 0.2 ml saline. Heparinized blood samples were taken one hour after LPS injection and plasma was collected by centrifugation. TNF-a (inflammatory WO 00/05217 PCT/JP99/03939 14 cytokine) and IL-10 (anti-inflammatory cytokine) amounts in plasma were assayed by ELISA. Test compounds were administered 30 minutes before LPS injection. 5 Results TNF-a (ng/ml) IL-10 (pg/ml) Vehicle 4.7 ± 0.4 71 ± 9.2 Test Compound 3.1 ± 0.5 137 ± 14 (320 mg/kg) Best Mode for Carrying out the Invention The following Preparation and Examples are given for the purpose 10 of illustrating the present invention in detail, but are not to be construed to limit the scope of the present invention. Preparation 1 A mixture of methyl 4 -imidazolecarboxylate (5.0 g) and ammonium 15 chloride (539 mg) in aqueous 28% NH 3 solution (75 ml) was heated at 1000C in a steel sealed tube for 5.5 hours. After cooling, the reaction mixture was concentrated in vacuo. The residue was stirred in a mixed solvent of acetone, ethanol and water (5:5:1, total 25 ml). The resulting precipitates were collected by filtration and 20 washed with the same mixed solvent, and dried in vacuo to give 4-imidazolecarboxamide (4.63 g) as a white solid. mp: 211-214 0 C IR (KBr): 3500-2600, 1652 cm-' NMR (DMSO-d 6 , 6): 7.06 (1H, br s), 7.34 (1H, br s), 25 7.58 (1H, s), 7.69 (1H, s) MASS: 112 (M+H)* WO 00/05217 PCT/JP99/03939 15 Preparation 2 Triethylamine (583 mg) was added dropwise to a stirred mixture of ethyl (R)-2-hydroxy-4-phenylbutyrate (1.0 g) and methanesulfonyl chloride (660 mg) in dichloromethane (10 ml) at ice-bath temperature. 5 After 40 minutes, the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over magnesium sulfate , and concentrated in vacuo to give ethyl
(R)-
2 -methylsulfonyloxy-4-phenylbutyrate (1.37 g) as an oil. This material was used immediately without further purification. NaH (60% 10 in mineral oil, 192 mg) was added to a solution of 4 imidazolecarboxamide (534 mg) in DMF (8 ml) at roomtemperature. The reaction mixture was stirred for 30 minutes. The methanesulfonate prepared above was added and the resulting mixture was stirred for 3 hours at 60 0 C. 15 The reaction mixture was cooled to 10*C in an ice bath, and the insoluble material was filtered and washed thoroughly with methylene chloride. The filtrate and the washing were combined and then washed with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel (45 20 g) chromatography eluting with chloroform/methanol (30:1) to give ethyl 2
-(
4 -carbamoyl-1-imidazolyl)-4-phenylbutyrate (556 mg). IR (neat): 3500-2800, 1741, 1666 cm- 1 NMR (CDCl 3 ,c5): 1.26 (3H, t, J=7.lHz), 2.3-2.68 (4H, m), 4.20 (3H, q, J=7.lHz), 4.60 (1H, dd, J=9.8, 9.8Hz), 25 5.44 (1H, br s), 6.96 (1H, br s), 7.08-7.35 (5H, m), 7.46 (1H, s), 7.72 (1H, s) MASS: 302 (M+H)* Preparation 3 30 2-Hydroxyoctanoic acid (1.0 g) was stirred in 10% hydrogen chloride methanol solution (20 ml) at room temperature. After 1.5 WO 00/05217 PCT/JP99/03939 16 hours, the reaction mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with aqueous NaHCO 3 solution and dried over sodium sulfate. Evaporation of the solvent under reduced pressure 5 gave methyl 2-hydroxyoctanoate (0.684 g) as a colorless oil. IR (neat): 3463, 2952, 2927, 2859, 1735 cm-' NMR (CDCl 3 ,6): 0.88 (3H, t, J=6.5Hz), 1.25-1.90 (10H, m), 2.70 (1H, br s), 3.79 (3H, s), 4.19 (1H, br) MASS: 175 (M+H)+ 10 Preparation 4 The following compounds were obtained according to a similar manner to that of Preparation 2. 15 (1) Methyl a-( 4 -carbamoyl-1-imidazolyl)phenylacetate was prepared from methyl mandelate and 4-imidazolecarboxamide obtained in Preparation 1. IR (KBr): 3500-2800, 1752, 1675 cm' NMR (CDCl 3 ,6): 3.84 (3H, s), 5.48 (1H, br s), 5.93 20 (1H, s), 7.06 (1H, br s), 7.24-7.46 (5H, m), 7.60 (1H, s), 7.67 (1H, s) MASS: 260 (M+H)* (2) Methyl 2-(4-carbamoyl-1-imidazolyl)octanoate was prepared 25 from 4-imidazolecarboxamide obtained in Preparation 1 and methyl 2-hydroxyoctanate obtained in Preparation 3. mp: 63.5-65.5'C IR (KBr): 3400-2800, 1753, 1671 cm-1 NMR (CDC1 3 ,6): 0.87 (3H, t, J=6.5Hz), 1.05-1.45 (6H, 30 m), 1.90-2.20 (4H, m), 3.77 (3H, s), 4.71 (1H, dd, J=9.6, WO 00/05217 PCT/JP99/03939 17 5.6Hz), 5.52 (1H, s), 7.10 (1H, S), 7.59 (1H, s), 7.72 (1H, S) MASS: 268 (M+H)* 5 Preparation 5 NaH (60% in mineral oil, 60 mg) was added to a stirred solution of 4-imidazolecarboxamide (obtaiend in Preparation 1) (167 mg) in DMF (3.5 ml), and the reaction mixture was stirred for 1.5 hours at 55 0 C. Ethyl 2-bromovalerate (0.153 ml) was added to this mixture, 10 and the reaction mixture was stirred for 3 hours at 55-60 0 C. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel (12 g) chromatography eluting with 15 chloroform/methanol (25:1) to give ethyl 2-(4-carbamoyl-1 imidazolyl)valerate (150 mg). mp: 95'C IR (KBr): 3343, 3197, 2964, 1751, 1681 cm~ 1 NMR (DMSO-d ,6): 0.86 (3H, t, J=7.2Hz), 1.13 (2H, m), 20 1.20 (3H, t, J=7.lHz), 2.05 (2H, q, J=7.2Hz), 4.14 (2H, q, J=7.lHz), 5.16 (1H, t, J=7.2Hz), 7.10 (1H, s), 7.30 (1H, s), 7.73 (1H, s), 7.78 (1H, s) MASS: 240 (M+H)+ 25 Preparation 6 1-( 2 -Oxotetrahydrofuran-3-yl)imidazole-4-carboxamide was obtained from 4 -imidazolecarboxamide obtained in Preparation 1 and a-bromo-y-butyrolactone according to a similar manner to that of Preparation 5. 30 IR (KBr): 3700-3100, 1779, 1745, 1600 cm' WO 00/05217 PCT/JP99/03939 18 MASS: 196 (M+H)+ Preparation 7 Trifluoromethanesulfonic acid (1.13 g) was added to a stirred 5 mixture of ethyl (S)-(-)-lactate (5.90 g) and benzyl 2,2,2 trichloroacetimidate (15.15 g) in cyclohexane (70 ml) and methylene chloride (35 ml) at room temperature under nitrogen atmosphere. After being stirred for 18 hours, the reaction mixture was filtered. The filtrate was diluted with cyclohexane, and then washed 10 successively with saturated NaHCO 3 solution (100 ml)and H 2 0 (100 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel (260 g) chromatography eluted with hexane/ethyl acetate (30:1) to give ethyl (S)-2 (benzyloxy)propionate (6.48 g). 15 IR (neat): 3100-2800, 1743, 1139 cm~ 1 NMR (CDCl 3 5): 1.26 (3H, t, J=7.OHz), 1.44 (3H, d, J=6.8Hz), 4.05 (1H, q, J=6.8Hz), 4.22 (2H, q, J=7.OHz), 4.40-4.75 (2H, m), 7.10-7.39 (5H, m) MASS : 231 (M+Na)' 20 [C] 28.5 -76.00 (C=0.50, EtOH) Preparation 8 A solution of 1.OM DIBAL (diisobutylaluminum hydride) in hexane (10 ml) was added dropwise to a stirred solution of ethyl (S)-2 25 (benzyloxy)propionate (obtained in Preparation 7) (2.08 g) in methylene chloride (20 ml) at -78 0 C (dry-ice/acetone) for 5 minutes under nitrogen atmosphere. After 20 minutes, methanol (1.6 ml) was added dropwise to the mixture at -78 0 C, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was filtered 30 through a pad of Celite, and the solid on the filter was washed with WO 00/05217 PCT/JP99/03939 19 methylene chloride. The combined filtrates were concentrated in vacuo. The obtained residue was purified by silica gel (35 g) chromatography eluted with hexane/ethyl acetate (30:1) to give (S)-2-(benzyloxy)propionaldehyde (810 mg). 5 IR (neat): 3100-2800, 1735, 1095 cm' NMR (CDCl,65): 1.33 (3H, d, J=6.9Hz), 3.90 (1H, m), 4.60 (2H, m), 7.10-7.40 (5H, m), 9.67 (1H, s) MASS: 163 (M-H)+ [a] 2 = -34.7 (C=0.50, EtOH) 10 Preparation 9 Trimethylsulfoxonium iodide (1.22 g) was added to a stirred suspension of sodium hydride (60% in mineral oil, 234 mg) in dimethylsulfoxide (12 ml) and dimethoxyethane (10 ml) at -3 0 C to -4 0 C 15 under nitrogen atmosphere. After 10 minutes, a solution of (S) 2-(benzyloxy)propionaldehyde (obtained in Preparation 8) (800 mg) in dimethoxyethane (2 ml) was added dropwise to the mixture for a period of 5 minutes at the same temperature, and the resulting mixture was stirred for 30 minutes at room temperature. The mixture was poured 20 into a cold saturated ammonium chloride solution (50 ml) and extracted with ethyl acetate (100 ml) . The organic layer was washed with brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel (20 g) chromatography eluted with hexane/ethyl acetate (30:1) to give (3S)-3-benzyloxy-1,2 25 epoxybutane (507 mg). IR (neat): 2981, 2927, 2865, 1241, 1103 cm~' NMR (CDCl,6 ): 1.29 (3H, m), 2.40-3.55 (4H, m), 4.50 4.85 (2H, m), 7.10-7.40 (5H, m) MASS: 201 (M+Na)+ 30 WO 00/05217 PCT/JP99/03939 20 Preparation 10 A solution of 2.OM benzylmagnesium chloride in tetrahydrofuran (2.38 ml) was added dropwise to a stirred mixture of lithium chloride (20.2 mg) and copper(II) chloride (32 mg) in tetrahydrofuran (10 ml) 5 at -78 0 C (dry-ice/acetone) for a period of 10 minutes under nitrogen atmosphere. A solution of (3S)-3-benzyloxy-1,2-epoxybutane (obtained in Preparation 9) (425 mg) in tetrahydrofuran (10 ml) was added dropwise to this mixture at -78 0 C over 10 minutes. The resulting mixture was stirred at -78 0 C for 2.5 hours and then allowed 10 to warm to room temperature, and stirred overnight. The reaction mixture was treated with saturated ammonium chloride solution (20 ml) at an ice-bath temperature, and then diluted with ethyl acetate (100 ml). The organic layer was washed with H 2 0 (50 ml) and brine (50 ml), dried over magnesium sulfate and concentrated in vacuo. The 15 residue was purified by silica gel (20 g) chromatography eluted with hexane/ethyl acetate (10:1) to give (2S)-2-benzyloxy-5 phenylpentan-3-ol (620 mg). IR (neat): 3444, 2931, 2865 cm~' NMR (CDCl,&): 1.14-2.00 (3H, m), 1.60-1.85 (1H, m), 20 2.55-3.00 (3H, m), 3.30-3.85 (3H, m), 4.35-4.75 (2H, m), 7.05-7.40 (10H, m) MASS: 293 (M+Na)+ Preparation 11 25 The following compounds were obtained according to a similar manner to that of Preparation 10. (1) (2S)-2-benzyloxy-6-phenylhexan-3-ol was prepared from (3S) 3 -benzyloxy-1,2-epoxybutane (obtained in Preparation 9) and 30 phenethylmagnesium chloride.
WO 00/05217 PCT/JP99/03939 21 IR (neat): 3436, 2933, 2861 cm NMR (CDCl 3 ,,5): 1.05-1.20 (3H, m), 1.30-2.00 (4H, m), 2.00-2.80 (3H, m), 3.25-3.85 (2H, m), 4.35-4.75 (2H, m), 7.05-7.45 (10H, m) 5 MASS: 285 (M+Na)* (2) (2S)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol was prepared from
(
3
S)-
3 -benzyloxy-1,2-epoxybutane (obtained in Preparation 9) and 1-naphthylmethylmagnesiumchloride (J. Am. Chem. Soc. 1943, 65, 295). 10 IR (neat): 3700-3100, 3100-2800, 1087, 1076 cm-' NMR (CDCl 1 ,d): 1.10-1.20 (3H, m), 1.75-2.00 (2H, m), 2.15 2.75 (1H, m), 2.95-3.95 (4H, m), 4.40-4.75 (2H, m), 7.20-7.60 (9H, m), 7.65-7.20 (3H, m) 15 (3) ( 2
S,
3
S)-
2 -(benzyloxy)-5-(2-methphnylpen ntan-3-ol was preparared from the compound obtained in Preparation 9 and 2 methylbenzyl chloride. NMR (CDCl 3 , 5): 1.19 (3H, d,J=6Hz), 1.6-1.8 (2H, m), 2.32 (3H, s), 2.64 (lH,d,J=3Hz), 2.6-3.0 (2H,m), 3.3-3.6 (2Hm), 4.43 20 (lH,d,J=llHz), 4.67 (lH,d,J=llHz), 7.1-7.3 (9H, m) MASS: 307 (M+Na)* (4) ( 2
S,
3
S)-
2 -(benzyloxy)-5-(2-chlorophenyl)pentan-3-ol was prepared from the compound obtained in Preparation 9. 25 NMR (CDCl 3 , 6 ): 1.17 (3H, d,J=5Hz), 1.6-1.9 (2H, m), 2.64 (lH,d,J=3Hz), 2.7-3.1 (2H,m), 3.4-3.5 (2H,m), 4.44 (lH,d,J=12Hz),4.67 (lH,d,J=12Hz), 7.1-7.4 (9H, m) MASS: 327 (M+Na)* 30 (5) ( 2
S,
3
S)-
2 -(benzyloxy)-5-(2-methoxyphenyl)pentan-3-ol was prepared from the compound obtained in Preparation 9.
WO 00/05217 PCT/JP99/03939 22 NMR (CDC1 3 , 6): 1.18 (3H, d,J=6Hz), 1.6-1.9 (2H, m), 2.6-3.0 (3H,m), 3.4-3.5 (2H,m), 3.82 (3H,s), 4.44 (lH,d,J=12Hz),4.66 (lH,d,J=12Hz), 6.8-7.0 (2H, m), 7.1-7.4 (7H,m) 5 MASS: 323 (M+Na)* (6) ( 2
S,
3
S)-
2 -(benzyloxy)-5-(2-hexyloxyphenyl)pentan-3-ol was prepared from the compound obtained in Preparation 9. NMR (CDC1 3 , ( ): 0.90 (3H,t,J=6Hz), 1.18 (3H, d,J=6Hz), 1.2-1.6 10 ( 6 Hm), 1.
6 -1.
9 (4H,m),2.66(lH,d,J=3Hz),2.7-2.9(2H,m), 3.4-3.5 (2H,m), 3.96 (2H,t,J=6Hz), 4.44 (lH,d,J=llHz),4.66 (lH,d,J=llHz), 6.8-7.0 (2H, m), 7.1-7.3 (7H,m) MASS: 393 (M+Na)* 15 (7) ( 2
S,
3
S)-
2 -(benzyloxy)-5-(2,3-dichlorophenyl)pen ntan-3-ol was prepared from the compound obtained in Preparation 9. NMR (CDC1 3 , (5): 1.19 (3H, d,J=5Hz), 1.6-1.9 (2H, m), 2.65 (lH,d,J=3Hz), 2.7-3.1 (2H,m), 3.3-3.5 (2H,m), 4.43 20 (lH,d,J=llHz),4.67 (lH,d,J=llHz), 7.0-7.5 (8H, m) MASS: 361 (M+Na)* (8) (2S,3S)-2-(benzyloxy)-5-(2-phenethyloxyphenyl)pentan-3-ol was prepared from the compound obtained in Preparation 9. 25 NMR (CDC1 3 , 6): 1.14 (3H, d,J=6Hz), 1.6-1.8 (2H, m), 2.5-3.0 (3H,m), 3.10 (2H,t,J=7Hz), 3.3-3.5 (2H,m), 4.18 (2H,t,J=7Hz), 4.43 (lH,d,J=llHz), 4.65 (lH,d,J=llHz), 6.7-7.4 (14H,m) MASS: 413 (M+Na)* 30 (9) ( 2
S,
3
S)-
2 -(benzyloxy)-5-(2,3-dimethylphenyenpntan-3-ol was prepared from the compound obtained in Preparation 9.
WO 00/05217 PCT/JP99/03939 23 NMR (CDCl 3 , 6) 1.19 (3H, d,J=6Hz), 1.6-1.8 (2H, m), 2
.
2 2 (3H s), 2.28 (3H, s), 2.6-3.0 (3H,m), 3.3-3.6 (2H,m), 4.43 (1H,d,J=llHz),4.67 (lH,d,J=llHz), 7.02 (3H,s), 7.2-7.4 (5H, m) 5 MASS: 321 (M+Na)* (10) ( 2
S,
3
S)-
2 -(benzyloxy)-5-[2,3-(methylenedioxy)phenyl] pentan-3-ol was prepared from the compound obtained in Preparation 9. 10 NMR (CDCl, 6 ): 1.19 (3H, d, J=6Hz), 1.6-1.9 (2H, m), 2.6 2.9 (3H, m), 3.3-3.5 (2H, m), 4.43 (1H, d, J=12Hz), 4.67 (1H, d, J=12Hz), 5.92 (2H, s), 6.6-6.8 (3H, m), 7.33 (5H, S) MS: 337 (M+Na)* 15 Preparation 12 To a stirred solution of Pd(OAc) 2 (340 mg), nBu 3 P (613 mg), and Et 3 N (1.99 g) in DMF (30 ml) was added methyl 2-hydroxy-3-butenoate (1.76 g) followed by 1-iodonaphthalene (5.0 g), and the reaction 20 mixture was stirred at 100 0 C for 2.5 hours. The reaction mixture was poured into water (300 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel (130 g) column chromatography eluting with hexane/ethyl acetate (50:1) 25 to give methyl 4 -(l-naphthyl)-2-oxobutyrate (254 mg) as a red oil. IR (neat): 3050, 2954, 1739, 1725 cm-' NMR (CDCl,,) : 3.25-3.55 (4H, m), 3.86 (3H, s), 7.25-8.10 (7H, m) 30 Preparation 13 NaBH 4 (22 mg) was added portionwise to an ice cooled solution of methyl 4 -(l-naphthyl)-2-oxobutyrate (obtained in Preparation 12) WO 00/05217 PCT/JP99/03939 24 (252.5 mg) in THF(5 ml)-H 2 0(1 ml). After the addition was completed, the reaction mixture was stirred at ice-bath temperature for 30 minutes. Water (4 ml) was added, and the resulting mixture was stirred for several minutes and then extracted with ethyl acetate. The organic 5 layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel (5 g) column chromatography eluting with hexane/ethyl acetate (10:1) to give methyl 2 -hydroxy-4-(1-naphthyl)butyrate (84.4 mg) as a colorless oil. 10 IR (neat): 3700-3100, 3052, 2954, 1739, 1236, 1103 cm 1 NMR (CDC1, 1 6): 2.03-2.31 (2H, m), 2.91 (1H, d, J=5.2Hz), 3.23 (2H, t, J=7.9Hz), 3.75 (3H, S), 4. 29 (1H, m), 7.30-8.10 (7H, m) 15 MASS: 245 (M+H)* Preparation 14 NaBH 4 (1.82 g) was added portionwise to an ice cooled solution of ethyl (R)- 2 -hydroxy-4-phenylbutyrate (2.0 g) in methanol (40 ml). 20 After the addition was completed, the reaction mixture was stirred at room temperature for 45 minutes. Water (20 ml) was added, and the resulting mixture was stirred for several minutes and then evaporated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. 25 Evaporation of the solvent under reduced pressure gave (R)-4 phenylbutane-1,2-diol (1.63 g) as a colorless oil. This material was used for the next reaction without further purification. Imidazole (1.96 g) was added to an ice cooled solution of the diol in DMF (20 ml) followed by tert-butyldimethylsilyl chloride 30 (1.52 g). After 1 hour, the ice-bath was removed and then the mixture was stirred overnight at room temperature. The reaction mixture was poured into water (200 ml) and WO 00/05217 PCT/JP99/03939 25 extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel (50 g) column chromatography eluting with hexane/ethyl acetate (50:1) to give (R)-1-(tert 5 butyldimethylsilyloxy)-4-phenylbutan-2-ol (2.10 g) as a colorless oil. IR (neat): 3800-3100, 2950, 2931, 2859, 1253, 1116, 1081 cm-' NMR (CDCl 3 ,6): 0.52 (6H, s), 0.90 (9H, s), 1.60-1.85 10 (2H, m), 2.45 (1H, d, J=3.6Hz), 2.60-2.95 (2H, m), 3.35-3.75 (3H, m), 7.15-7.35 (5H, m) MASS: 281 (M+H)* Preparation 15 15 The following compounds were prepared by a similar procedure to that of Preparation 12. (1) Methyl 4
-(
3 -methylphenyl)-2-oxobutyrate was prepared as a pale yellow oil from 3-iodotoluene and methyl 2-hydroxy-3-butenoate. 20 IR (neat): 2954, 2923, 1731, 1238, 1074 cm-1 NMR (CDCl 3 , a5): 2.33 (3H, s), 2.92 (2H, t, J=7.5Hz), 3.18 (2H, t, J=7.5Hz), 3.86 (3H, s), 6.90-7.25 (4H, m) (2) Methyl 4-[ 3- (trifluoromethyl)phenyl ] -2-oxobutyrate was prepared 25 as an oil from 3-iodobenzotrifluoride and methyl 2-hydroxy-3 butenoate. IR (neat): 2958, 1739, 1728, 1241 cm-1 NMR (CDCl 3 , (5): 3.03 (2H, t, J=7.4Hz), 3.22 (2H, t, J=7.4Hz), 3.87 (3H, s), 7.35-7.55 (4H, m) 30 (3) Methyl 4-[ 3 -(tert-butyldimethylsilyloxy)phenyl]-2-oxo butyrate was prepared as a yellow oil from 3-(tert- WO 00/05217 PCT/JP99/03939 26 butyldimethylsilyloxy)iodobenzene and methyl 2-hydroxy-3 butenoate. IR (neat): 2954, 2935, 2857, 1731, 1594, 1244 cm-1 NMR (CDCl 3 , ( ): 0.19 (6H, s), 0.98 (9H, s), 2.90 (2H, t, J=7.66Hz), 5 3.16 (2H, t, J=7.6Hz), 3.86 (3H, s), 6.65-6.85 (3H, m), 7.15 (1H, m) MASS: 323 (M+H )* Preparation 16 10 The following compounds were prepared by a similar procedure to that of Preparation 13. (1) Methyl 2 -hydroxy-4-(3-methylphenyl)butyrate was prepared as a colorless oil from the compound obtained in Preparation 15(1). 15 IR (neat): 3700-3100, 3016, 2954, 2859, 1733, 1234, 1099 cm- 1 NMR (CDCl 3 , 6): 1.80-2.20 (2H, m), 2.33 (3H, s), 2.65-2.85 (3H, m), 3.76 (3H, s), 4.20 (1H, m), 6.95-7.25 (4H, m) MASS: 209 (M+H)+ 20 (2) Methyl 2-hydroxy-4-[3-(trifluoromethyl)phenyl]butyrate was prepared from the compound obtained in Preparation 15(2). IR (neat): 3700-3200, 3016, 2956, 1739, 1328, 1122, 703 cm- 1 NMR (CDCl 3 , 6): 1.85-2.25 (2H, m), 2.70-2.95 (3H, m), 3.76 (3H, s), 4.18 (1H, m), 7.35-7.55 (4H, m) 25 (3) Methyl 2 -hydroxy-4-[3-(tert-butyldimethylsilyloxy) phenyl]butyrate was prepared as a colorless oil from the compound obtained in Preparation 15(3). IR (neat): 3700-3100, 2954, 2857, 1739, 1595, 1479, 1444, 1273 30 cm NMR (CDCl 3 , 6): 0.19 (6H, s), 0.98 (9H, s), 1.80-2.20 (2H, m), 2.65-2.80 (3H, m), 3.77 (3H, s), 4.18 (1H, m), 6.65-6.90 WO 00/05217 PCT/JP99/03939 27 (3H, m), 7.13 (lH, m) MASS: 325 (M+H)* Preparation 17 5 The following compounds were prepared by a similar procedure to that of Preparation 2. (1) Methyl 2-(4-carbamoyl-1-imidazolyl)-4-(1-naphthyl)butyrate was prepared from the compound obtained in Preparation 1 and the 10 compound obtained in Preparation 13. IR (KBr): 3343, 3185, 1745, 1662 cm 1 NMR (CDCl 31 &) 2.40-3.25 (4H, m), 3.73 (3H, m), 4.71 (lH, m), 5.42 (1H, brs), 6.98 (1H, brs), 7.19 (1H, d, J=6.9Hz), 7.35-7.60 (4H, m), 7.74-7.95 (4H, m) 15 MASS: 338 (M+H)+ (2) Methyl 2
-(
4 -carbamoyl-1-imidazolyl)-4-(3-methylphenyl) butyrate was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 16(1). 20 IR (neat): 3800-2800, 1745, 1658 cm- 1 NMR (CDCl 3 , (5): 2.25-2.75 (7H, m), 3.75 (3H, s), 4.64 (1H, m), 5.43 (1H, br s), 6.85-7.25 (5H, m), 7.45 (1H, s), 7.71 (1H, S) MASS: 302 (M+H)* 25 (3) Methyl 2
-(
4 -carbamoyl-1-imidazolyl)-4-[3-(trifluoromethyl) phenyl]butyrate was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 16(2). IR (neat): 3700-2800, 1743, 1236 cm-' 30 NMR (CDCl 3 , 5 ): 2.25-2.80 (4H, m), 3.77 (3H, m), 4.65 (1H, m), 5.43 (1H, br s), 6.96 (lH, br s), 7.20-7.55 (5H, m), 7.73 (1H, s) WO 00/05217 PCT/JP99/03939 28 MASS: 356 (M+H)* (4) Methyl 2
-(
4 -carbamoyl-1-imidazolyl)-4-(3-hydroxyphenyl) butyrate was prepared from the compound obtained in Preparation 1 5 and the compound obtained in Preparation 16(3). IR (neat): 3700-2800, 1745, 1664, 1590, 1267, 1234 cm- 1 NMR (CDCl 3 , (5): 2.20-2.80 (4H, m), 3.76 (3H, s), 4.65 (1H, m), 5.64 (lH, brs), 6.50-6.85 (3H, m), 6.90-7.30 (2H, m), 7.55 (1H, s), 7.73 (IH, s) 10 MASS: 304 (M+H)* Preparation 18 To a stirred solution of Pd (OAc) 2 (40 mg, 0.18 mmol), nBu 3 P (71 mg, 0.35 mmol), and Et 3 N (232 mg, 2.29 mmol) in DMF (5 ml) 15 was added 3-butene-1,2-diol (155 mg, 1.76 mmol) followed by 4 iodotoluene (500 mg, 2.29 mmol), and the reaction mixture was stirred at 10 0 0C for 1.5 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate) and evaporated in vacuo. The 20 residue was purified by silica gel (10 g) column chromatography eluting with toluene/ethyl acetate (50:1) to give 1-hydroxy-4 (p-tolyl)butan-2-one (230 mg, 73.4%) as a pale yellow solid. To an ice cooled solution of 1-hydroxy-4-(p-tolyl)butan-2 one in DMF (5ml) was added imidazole (264 mg, 3.88 mmol) followed 25 by tert-butyldimethylsilyl chloride (234 mg, 1.55 mmol). After 30 minutes the ice-bath was removed and then the mixture was stirred overnight at room temperature. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated 30 in vacuo. The residue was purified by silica gel (8 g) column chromatography eluting with hexane/ethyl acetate (50:1) to give 1-(tert-butyldimethylsilyloxy)-4-(4-methylphenyl)butan-2-one (350 WO 00/05217 PCT/JP99/03939 29 mg, 67.9%) as a colorless oil. IR (neat): 2933, 2857, 1726, 1255, 1105, 842 cm-' NMR (CDCl 3 , (5): 0.07 (6H, s), 0.91 (9H, s), 2.31 (3H, s), 2.75-2.95 (4H, m), 4.14 (2H, s), 7.08 (4H, s) 5 Preparation 19 1-(Tert-butyldimethylsilyloxy)-4-[3-(ethoxycarbonyl) phenyl]butan-2-one (1.62 g, 42.7%) was prepared as a colorless oil by a similar procedure to that of Preparation 18 from ethyl 3 10 iodobenzoate and 3-butene-1,2-diol. IR (neat): 2929, 2858, 1720, 1238, 1103 cm-' NMR (CDC1, 5 ): 0.07 (6H, s), 0.91 (9H, s), 1.40 (3H, t, J=7.lHz), 2.75-3.05 (4H, m), 4.15 (2H, s), 4.37 (2H, q, J=7.lHz), 7.30-7.45 (2H, m), 7.85-7.95 (2H, m) 15 MASS: 351 (M+H)* Preparation 20 To a stirred solution of Pd (OAc) 2 (75 mg, 0.34 mmol), nBu 3 P (136 mg, 0.67 mmol), and Et 3 N (442 mg, 4.37 mmol) in DMF (10 ml) 20 was added 3-butene-1,2-diol (296 mg, 3.36 mmol) followed by methyl 3-bromophenylacetate (1.0 g, 4.37 mmol), and the reaction mixture was stirred at 100 0 C for 5 h. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate) and evaporated in 25 vacuo. The residue was purified by silica gel (25 g) column chromatography eluting with toluene/ethyl acetate (20:1) to give methyl 3
-(
4 -hydroxy-3-oxobutyl)phenylacetate (193 mg, 24.4%) as an oil. IR (neat): 3700-3100, 2950, 1732, 1261, 1159, 1069 cm-' 30 NMR (CDCl 3 , (5): 2.73 (2H, t, J=7.5Hz), 2.96 (2H, t, J=7.5Hz), 3.06 (1H, t, J=4.8Hz), 3.60 (2H, s), 3.70 (3H, s), 4.19 (2H, d, J=4.8Hz), 7.05-7.35 (4H, m) WO 00/05217 PCT/JP99/03939 30 MASS: 237 (M+H)* Preparation 21 The following compounds were prepared by a similar procedure 5 to that of Preparation 13. (1) 1-(tert-Butyldimethylsilyloxy) -4- ( 4-methylphenyl )butan-2-ol was prepared as a colorless oil from the compound obtained in Preparation 18. 10 IR (neat): 3442, 2931, 2859, 1463, 1254, 1116 cm-1 NMR (CDCl 3 , (): 0.06 (6H, s), 0.90 (9H, s), 1.60-1.85 (2H, m), 2.32 (3H, s), 2.44 (1H, d, J=3.5Hz), 2.55-2.90 (2H, m), 3.30-3.80 (3H, m), 7.10 (4H, s) MASS: 295 (M+H)* 15 (2) 1-(tert-Butyldimethylsilyloxy)-4-[3-(ethoxycarbonyl)phenyl] butan-2-ol was prepared as a colorless oil from the compound obtained in Preparation 19. IR (neat): 3700-3100, 2933, 2860, 1718, 1279, 1110 cm-' 20 NMR (CDCl 3 , 6): 0.07 (6H, s), 0.90 (9H, s), 1.40 (3H, t, J=7.lHz), 1.65-1.85 (2H, m), 2.46 (1H, d, J=3.4Hz), 2.65-3.00 (2H, m), 3.35-3.75 (3H, m), 4.37 (2H, q, J=7.lHz), 7.30-7.45 (2H, m), 7.80-7.95 (2H, m) MASS: 353 (M+H)+ 25 (3) Methyl 3 -[4-(tert-butyldimethylsilyloxy) -3-hydroxybutyl] phenylacetate was prepared as a colorless oil from the compound obtained in Preparation 22. IR (neat): 3800-3100, 2931, 2858, 1741, 1250, 1119 cm-' 30 NMR (CDCl,, 6): 0.07 (6H, s), 0.90 (9H, s), 1.60-1.80 (2H, m), 2.45 (1H, d, J=3.6Hz), 2.55-2.95 (2H, m), 3.35-3.75 (8H, m), 7.05-7.35 (4H, m) WO 00/05217 PCT/JP99/03939 31 MASS: 353 (M+H)* Preparation 22 To an ice cooled solution of methyl 3-(4-hydroxy-3-oxo 5 butyl)phenylacetate (472 mg, 2.00mmol) in DMF (10 ml) was added imidazole (264 mg, 3.88 mmol) followed by tert-butyldimethylsilyl chloride (408 mg, 5.99 mmol). After 30 minutes the ice-bath was removed and then the mixture was stirred overnight at room temperature. The reaction mixture was poured into water (100ml) and extracted with 10 ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by silica gel (20 g) column chromatography eluting with hexane/ethyl acetate (10:1) to give methyl 3-[4-(tert butyldimethylsilyloxy)-3-oxobutyl]phenylacetate (664 mg, 94.9%) as 15 a colorless oil. IR (neat): 2952, 2933, 2856, 1738, 1250, 1153, 1101 cm-' NMR (CDCl 3 , 5): 0.07 (6H, s), 0.91 (9H, s), 2.75-3.00 (4H, m), 3.60 (2H, s), 3.69 (3H, s), 4.15 (2H, s), 7.05-7.30 (4H, M) 20 MASS: 351 (M+H)* Preparation 23 A solution of ethyl 2
-(
4 -carbamoyl-1-imidazolyl)-4-phenyl butyrate (obtained in Preparation 2) in DMF (5 ml) was added to an 25 ice-cooled solution of POCl 3 (0.71 ml) in DMF (6 ml) under nitrogen atmosphere. After 1.5 h, the solvent was poured into water (50 ml) and the solution was neutralized with saturated NaHCO 3 aq. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and 30 concentrated in vacuo. The residue was purified by silica gel (16 g) column chromatography eluting with chloroform/methanol (100:1) to give ethyl 2
-(
4 -cyano-1-imidazolyl)-4-phenylbutyrate (435mg, WO 00/05217 PCT/JP99/03939 32 101.2%). IR (neat): 3132, 2978, 2933, 2235, 1741, 1236, 1157 cm-1 NMR (CDC1, 5): 1.28 (3H, t, J=7.lHz), 2.20-2.80 (4H, m), 4.23 (2H, q, J=7.lHz), 4.63 (1H, m), 7.00-7.40 (5H, m), 7.53 5 (1H, s), 7.58 (1H, s) MASS: 284 (M+H)* Preparation 24 1-(tert-Butyldimethylsilyloxy)-3-phenoxypropan-2-ol was 10 prepared from 3-phenoxy-1, 2-propanediol and tert-butyldimethylsilyl chloride by a similar procedure to that of Preparation 22. IR (neat): 3700-3100, 2931, 2860, 1244, 1092 cm~' NMR (CDC1 3 , (5 ): 0.08 (6H, s), 0.90 (9H, s), 2.54 (1H, d, J=5.4Hz), 3.75-4.15 (5H, m), 6.85-7.05 (3H, m), 7.25-7.35 (2H, m) 15 MASS: 283 (M+H)* Preparation 25 1-Naphthylmethylmagnesium chloride was prepared from magnesium turnings (2.88 g) and 1-(chloromethyl)naphthalene (6.98 20 g) in ether (80 ml) by the method of J. Am. Chem. Soc. (1943) 65, 295. A solution of lithium chloride (167mg) and copper (II) chloride (266 mg) in THF (10 ml) was added dropwise to the ethereal solution of the Grignard reagent followed by addition of a solution of
(
2
RS,
3
S)-
3 -(benzyloxy)-1,2-epoxybutane (3.52 g) in ether (30 ml) 25 below -70 *C. The mixture was stirred at -78 0 C for 1 h, and then allowed to warm to room temperature and stirred overnight. After cooling, the mixture was quenched with saturated aqueous ammonium chloride solution (100 ml). The insoluble material was filtered through Celite and the filter cake was washed with ether. The filtrate and 30 washings were combined, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give an oil. Flash chromatography (hexane:ethyl acetate WO 00/05217 PCT/JP99/03939 33 = 9:1 -- 4:1) gave ( 2
S,
3 S)-2-benzyloxy-5-(-naphthyl)pentan-3-ol (2.66 g, 42.0%) as the first eluate and (2S,3R)-2-benzyloxy-5 (1-naphthyl)pentan-3-ol (1.36 g, 21.5%) as the second eluate. 5 ( 2
S,
3
S)-
2 -benzyloxy-5-(1-naphthyl )pentan-3-ol IR (neat): 3558, 3458, 2870, 1078 cm-' NMR (CDCl 3 , d): 1.17 (3H, d, J=6.0 Hz), 1.89 (2H, m), 2.70 (1H, d, J=4.0 Hz), 3.15 (1H, m), 3.30-3.60 (3H, m), 4.43 (1H, d, J=11.4 Hz), 4.67 (1H, d, J=11.4 Hz), 7.20-8.15 (12H, 10 m) [a ] 2 -27.80 (c 0.5, EtOH) (2S,3R)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol IR (neat): 3556, 3458, 2871, 1088 cm-' 15 NMR (CDCl 3 , d): 1.16 (3H, d, J=6.3 Hz), 1.86 (2H, m), 2.19 (1H, d, J=4.0 Hz), 3.11 (1H, m), 3.32-3.55 (2H, m), 3.87 (1H, m), 4.47 (1H, d, J=11.8 Hz), 4.60 (lH, d, J=11.8 Hz), 7.19-8.06 (12H, m) [a]D 2 1 +33.5 (c 0.5, EtOH) 20 Preparation 26 A solution of (S)-2-(benzyloxy)propanal (Bull. Chem. Soc. Jpn. (1989) 62, 3038, 16.25 g) in ether (200 ml) was added to a suspension of zinc bromide (26.75 g) in ether (50 ml) below 6 0 C and then an 25 ethereal solution of 2- (1-naphthyl)ethylmagnasium bromide, prepared from 2-(1-naphthyl)ethyl bromide (46.55 g) and magnesium turnings (9.63 g) in ether (300 ml), was added below 8 0 C. The mixture was stirred at 4 0 C for 1 h and then THF (200 ml) was added. The final mixture was stirred overnight at room temperature. After cooling, 30 the mixture was quenched with saturated aqueous ammonium chloride solution (200 ml) and insoluble material was filtered. The filtrate WO 00/05217 PCT/JP99/03939 34 was extracted with ethyl acetate and the extract was washed with brine, dried and concentrated in vacuo. Flash chromatography (hexane:ethyl acetate = 9:1) gave (2S,3S)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol (9.78 g, 30.8%) as an oil. 5 Preparation 27 To an ice-cooled solution of (2S,3S)-2-benzyloxy-5-(1 naphthyl)pentan-3-ol (obtained in Preparation 26) (7.43 g) in dichloromethane (100 ml) was added methanesulfonyl chloride (2.15 10 ml) followed by triethylamine (3.88 ml). The mixture was stirred at 4 0 C for40min. After being diluted with dichloromethane, the mixture was washed with water and brine, dried and concentrated in vacuo to give (2S,3S)-2-benzyloxy-5-(1-naphthyl)-3-pentyl methanesulfonate (9.92 g, 107.4%) as an oil. The product was used directly in the next 15 step without further purification. IR (neat): 1344, 1173 cm-1 NMR (CDCl 3 , d): 1.23 (3H, d, J=6.4Hz), 2.04-2.25 (2H, m), 2.98 (3H, s), 3.06-3.33 (2H, m), 3.82 (1H, m), 4.44 (1H, d, J=11.5Hz), 4.64 (1H, d, J=11.5Hz), 4.80 (1H, m), 7.25 20 8.02 (12H, m) Preparation 28 The following compound was prepared by a similar procedure to that of Preparation 25. 25 (1) (2S,3S)-2-(benzyloxy)-5-[2-(trifluoromethyl)phenyl]pentan-3 ol was prepared from (S)- 2 -(benzyloxy)propanal. NMR (CDCl 3 , 5 ): 1.19 (3H, d,J=6Hz), 1.6-1.9 (2H, m), 2.67 (1H,d,J=3Hz), 2.7-3.2 (2H,m), 3.3-3.6 (2H,m), 4.44 30 (lH,d,J=llHz),4.67 (lH,d,J=llHz), 7.2-7.7 (9H, m) MASS: 361 (M+Na)* WO 00/05217 PCT/JP99/03939 35 (2) ( 2
S,
3
S)-
2 -(tert-butyldimethylsilyloxy)-5-phenyl-pentan-3-ol was prepared from (S)- 2 -(tert-butyldimethylsilyloxy)propanal (Synthesis 1996, 652, 3.00 g) and 2-phenylethyl bromide. IR (neat): 3573,3473,2935,1078 cm 1 5 NMR (CDC1, d): 0.09 (6H, s), 0.90 (9H, s), 1.13 (3H, d, J=6.2Hz), 1.66-1.77 (2H, m), 2.42 (1H, d, J=5.3Hz), 2.60-2.95 (2H, m), 3.30 (1H, m), 3.65 (lH, m), 7.14-7.32 (5H, m) MS (ESI, m/z): 317(M+Na)* [a D 2 7 -31.60 (c 0.5, EtOH) 10 (3) ( 2
S,
3
S)-
2 -(tert-dimethylsilyloxy)-5-[2-(benzyloxy)phenyl] pentan-3-ol was prepared from (S)-2-(tert-butyldimethyl silyloxy)propanal. NMR (CDC1 3 , 5): 0.05 (3H, s), 0.06 (3H, s), 0.88 (9H, s), 1.08 15 (3H, d, J=6Hz), 1.6-1.9 (2H, m), 2.40 (1H, d, J=5Hz), 2.6-3.0 (2H, m), 3.2-3.4 (1H, m), 3.6-3.7 (1H, m), 5.09 (2H, s), 6.8-7.5 (9H, m) MS: 423 (M+Na)* 20 (4) ( 2
S,
3
S)-
2 -(benzyloxy)-5-(2-naphthyl)pentan-3-ol was prepared from (S)-2-(benzyloxy)propanal. IR (neat): 3442, 1078 cm~ 1 NMR (CDC1 3 , 6 ): 1.18 (3H, d, J=6Hz), 1.7-2.0 (2H, m), 2.64 (lH, d, J=3Hz), 2.7-3.1 (2H, m), 3.3-3.6 (2H, m), 4.43 (1H, d, 25 J=llHz),4.67 (1H, d, J=llHz), 7.2-7.6 (8H, m), 7.64 (1H, s), 7.6-7.9 (3H, m) MS: 343 (M+Na)* (5) ( 2
S,
3
S)-
2 -(benzyloxy)-6-(-naphthyl)hexan-3-ol was prepared 30 from (S)-2-(benzyloxy)propanal. IR (neat): 3437, 1081 cm-1 NMR (CDC1, 6): 1.18 (3H, d, J=6Hz), 1.5-1.7 (2H, m), 1.7- WO 00/05217 PCT/JP99/03939 36 2.2 (2H, M), 2.59 (1H, d, J=4Hz), 3.0-3.2 (2H, m), 3.3-3.6 (2H, m), 4.41 (1H, d, J=llHz), 4.66 (1H, d, J=llHz), 7.2-7.6 (9H, m), 7.70 (1H, d, J=8Hz), 7.7-8.1 (2H, m) MS: 357 (M+Na)* 5 Preparation 29 The following compounds were prepared according to the procedure of Preparation 27. 10 (1) (2S,3R)-2-Benzyloxy-5-(1-naphthyl)-3-pentyl methanesulfonate was prepared from (2S,3R)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol obtained in Preparation 25. IR (neat): 1346, 1171 cm-1 NMR (CDCl 3 , d): 1.23 (3H, d, J=6.4Hz), 1.80-2.25 (2H, m), 3.08 15 (3H, s), 3.10 (1H, m), 3.40 (1H, m), 3.64 (1H, m), 4.58 (2H, s), 5.04 (1H, m), 7.30-8.05 (12H, m) (2) ( 2
S,
3
S)-
2 -(tert-Butyldimethylsilyloxy)-5-phenyl-3-pentyl methanesulfonate was prepared from (2S,3S)-2-(tert 20 butyldimethylsilyloxy)-5-phenyl-pentan-3-ol (obtained in Preparation 28(2)). IR (neat): 2935, 1352, 1174 cm-1 NMR (CDCl 3 , d): 0.03 (3H, s), 0.06 (3H, s), 0.86 (9H, s), 1.17 (3H, d, J=6.2Hz), 1.80-2.20 (2H, m), 2.60-2.90 (2H, m), 25 3.01 (3H, s), 4.10 (1H, m), 4.53 (1H, m), 7.10-7.40 (5H, M) Example I1 NaBH 4 (491 mg) was added portionwise to an ice cooled solution 30 of ethyl 2
-(
4 -carbamoyl-1-imidazolyl)-4-phenylbutyrate (obtained in Preparation 2) (391 mg) in methanol (20 ml) under an nitrogen atmosphere. After the addition was completed, the reaction mixture WO 00/05217 PCT/JP99/03939 37 was stirred at room temperature for 30 minutes. Water was added, and the resulting mixture was stirred for several minutes and then evaporated under reduced pressure. The residue was partitioned between chloroform and water. The organic layer was washed with brine 5 and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave 1-(1-hydroxy-4-phenyl-2-butyl)imidazole-4 carboxamide (347 mg) as a white solid. mp: 127.0-129.5*C IR (KBr): 3500-2700, 1664 cm~' 10 NMR (DMSO-d 6 ,) : 2.06 (2H, q, J=7.6Hz), 2.39 (2H, t, J=7.6Hz), 3.63 (2H, t, J=5.5Hz), 4.10 (1H, qui, J=6.4Hz), 5.01 (1H, t, J=5.3Hz), 7.04 (1H, br s), 7.10-7.33 (6H, m), 7.70 (1H, s), 7.75 (1H, s) MASS: 260 (M+H)+ 15 Example 2 The following compounds were obtained according to the similar manner to that of Example 1. 20 (1) 1-(2-Hydroxy-1-phenylethyl)imidazole-4-carboxamide was prepared from the compound obtained in Preparation 4(1). mp: 147-149 0 C IR (KBr): 3324, 3187, 1668 cm~ NMR (CDC1,,6): 4.26 (2H, d, J=5.4Hz), 5.35 (2H, br), 25 7.05 (1H, br), 7.10-7.50 (5H, m), 7.64 (1H, s), 7.75 (1H, S) MASS: 232 (M+H)+ (2) 1-(1-Hydroxy-2-octyl)imidazole-4-carboxamide was prepared 30 from the compound obtained in Preparation 4(2).
WO 00/05217 PCT/JP99/03939 38 mp: 97.5-100.5 0 C IR (KBr): 3324, 3178, 2927, 2857, 1662 cm-' NMR (CDC1 31 ( ): 0.83 (3H, t, J=6.5Hz), 0.90-1.35 (8H, m), 1.60-1.80 (2H, m), 3.60 (2H, t, J=5.6Hz), 4.09 (1H, 5 qui, J=6.5Hz), 4.98 (1H, t, J=5.3Hz), 7.00 (1H, s), 7.22 (1H, s), 7.67 (2H, s) MASS: 240 (M+H)+ (3) 1-(1-Hydroxy-2-pentyl)imidazole-4-carboxamide was prepared 10 from the compound obtained in Preparation 5. mp: 160*C IR (KBr): 3336, 3172, 1654 cm~ 1 NMR (DMSO-d 61 5): 0.84 (3H, t, J=7.2Hz), 1.10 (2H, m), 1.70 (2H, q, J=7.5Hz), 3.61 (2H, t, J=5.4Hz), 4.12 (lH, 15 qui, J=6.5Hz), 4.99 (1H, t, J=5.4Hz), 7.01 (1H, s), 7.24 (1H, s), 7.69 (2H, s) MASS: 198 (M+H)+ (4) 1-(1, 4 -Dihydroxy-2-butyl)imidazole-4-carboxamide was 20 prepared from the compound obtained in Preparation 6. IR (KBr): 3700-3100, 1670 cm NMR (DMSO-d 61(5): 1.86 (2H, m), 3.10-3.45 (2H, m), 3.62 (2H, t, J=5.5Hz), 4.29 (1H, m), 4.60 (1H, t, J=5.OHz), 5.01 (1H, t, J=5.3Hz), 7.02 (1H, s), 7.25 (1H, s), 7.65 25 (1H, s), 7.68 (1H, s) MASS: 200 (M+H)+ (5) 1-[l-hydroxy-4-(1-naphthyl)-2-butyl]imidazole-4 carboxamide was prepared from the compound obtained in Preparation WO 00/05217 PCT/JP99/03939 39 17(1). mp: 138-140*C IR (KBr): 3600-2800, 1660, 1598 cm~' (M+H)* NMR (DMSO-d,, 5 ) : 2.17 (2H, t, J=7.7Hz), 2.70-3.10 (2H, m), 3.68 5 (2H, t, J=5.4Hz), 4.27 (1H, m), 5.04 (lH, t, J=5.3Hz), 7.06 (1H, brs), 7.20-7.60 (5H, m), 7.75-8.00 (5H, m) MASS: 310 (M+H)* (6) 1-[1-Hydroxy-4-(3-methylphenyl)-2-butyl]imidazole-4 10 carboxamide was obtained as a white solid from the compound obtained in Preparation 17(2). mp: 115.5-117.5*C IR (KBr): 3325, 3195, 3110, 2935, 2854, 1662, 1604 cm 1 NMR (DMSO-d 6 , (5): 1.90-2.50 (7H, m), 3.62 (2H, m), 4.10 (1H, 15 m), 5.01 (lH, br), 6.85-7.40 (6H, m), 7.70 (1H, s), 7.74 (1H, s) MASS: 274 (M+H)* (7) 1-{l-Hydroxy-4-[3-(trifluoromethyl)phenyl]-2-butyl} 20 imidazole-4-carboxamide was obtained as a white solid from the compound obtained in Preparation 17(3). mp: 103-106 0 C IR (KBr): 3332, 3195, 3143, 1670, 1335 cm-1 NMR (DMSO-d, 6 ): 2.11 (2H, q, J=8.OHz), 2.35-2.75 (2H, m), 25 3.64 (2H, m), 4.13 (1H, m), 5.03 (1H, br s), 7.03 (1H, br s), 7.26 (1H, br s), 7.40-7.65 (4H, m), 7.71 (1H, s), 7.77 (1H, s) MASS: 328 (M+H)* 30 (8) 1-[l-Hydroxy-4-(3-hydroxyphenyl)-2-butyl]imidazole-4 carboxamide was obtained from the compound obtaind in Preparation WO 00/05217 PCT/JP99/03939 40 17(4). IR (KBr): 3700-2800, 1658, 1600 cm-1 NMR (DMSO-d, 6 ): 1.90-2.50 (4H, m), 3.62 (2H, m), 4.14 (1H, m), 5.09 (1H, t, J=5.3Hz), 6.45-6.65 (3H, m), 6.95-7.60 5 (4H, m), 7.74 (1H, s), 7.80 (1H, S), 9.37 (1H, s) MASS: 276 (M+H)* Example 3 The following compounds were obtained according to a similar 10 manner to that of Preparation 2. (1) 1-[( 2
S)-
2 -(Benzyloxy)-5-phenyl-3-pentyl]imidazole-4 carboxamide was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 10. 15 IR (neat): 3700-2800, 1673, 1658 cm-' NMR (CDCl,,6): 0.98-1.08 (3H, m), 2.10-2.75 (4H, m), 3.60-4.00 (2H, m), 4.05-4.70 (2H, m), 5.39 (1H, brs), 6.90-7. 10 (3H, m), 7.15-7.45 (9H, m), 7.67 (1H, dd, J=6.1, 1.3Hz) MASS: 364 (M+H)*, 386 (M+Na)* 20 (2) 1-[( 2
S)-
2 -(Benzyloxy)-6-phenyl-3-hexyl]imidazole-4 carboxamide was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 11(1). IR (neat): 3500-2800, 1666, 1589, 1236, 1095 cm-' 25 NMR (CDCl, 1 5) : 0.98-1.08 (3H, m), 1.30-2.20 (4H, m), 2.30-3.20 (2H, m), 3.50-4.10 (2H, m), 4.20-4.65 (2H, m), 5.37(1H, br s), 6.95(1H, brs), 7.00-7.80 (12H, m) MASS: 378 (M+H)+ 30 (3) 1-[( 2
S)-
2 -(Benzyloxy)-5-(1-naphthyl)-3-pentyl]imidazole-4 carboxamide was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 11(2).
WO 00/05217 PCT/JP99/03939 41 IR (neat): 3700-2800, 1666, 1594, 1236, 1097 cm-' NMR (CDC1 3 , 6 ): 1.04 (3H, d, J=6.2Hz), 2.10-2.60 (2H, m), 2.70-3.15 (2H, m), 3.50-4.10 (2H, m), 4.20-4.65 (2H, m), 5.41 (1H, brs), 7.01 (1H, brs), 7.10-7.60 (9H, m), 7.65-7.95 (5H, 5 m) MASS: 414 (M+H)* (4) 1-[l-(tert-Butyldimethylsl yyloxy)-4-(4-methylphenyl)-2 butyl]imidazole-4-carboxamide was prepared from the compound 10 obtained Preparation 1 and the compound obtained in Preparation 21(1). NMR (CDC31, 6): -0.07 (3H, s), -0.05 (3H, s), 0.84 (9H, s), 1.95-2.25 (2H, m), 2.32 (3H, s), 2.35-2.80 (2H, m), 3.65-4.10 (3H, m), 5.40 (1H, br s), 6.90-7.15 (5H, m), 7.44 15 (1H, s), 7.64 (1H, s) MASS: 388 (M+H)+ (5) 1-{l-(tert-Butyldimethylsilyloxy)-4-[3-(ethoxycarbonyl) phenyl]-2-butyl}imidazole-4-carboxamide was prepared from the 20 compound obtained in Preparation 1 and the compound obtained in Preparation 21(2). IR (neat): 3700-3050, 2931, 2860, 1716, 1666, 1595, 1240, 1095 cm-' NMR (CDC1 3 , 6): -0.06 (3H, s), -0.04 (3H, s), 0.83 (9H, s), 25 1.41 (3H, t, J=7.lHz), 2.18 (2H, m), 2.40-2.80 (2H, m), 3.60-4.10 (3H, m), 3.65-4.10 (3H, m), 4.39 (2H, q, J=7. lHz), 5.37 (1H, br s), 6.95 (1H, br s), 7.20-7.42 (2H, m), 7.45 (1H, s), 7.65 (1H, s), 7.75-7.95 (2H, m) MASS: 446 (M+H)* 30 (6) 1-{1-(tert-Butyldimethylsyl loxyx)y-4-{3-[ (methoxycarbonyl) methyl]phenyl}- 2 -butyl}imidazole-4-carboxamide was prepared from WO 00/05217 PCT/JP99/03939 42 the compound obtained in Preparation 1 and the compound obtained in Preparation 21(3). IR (neat): 3800-3000, 2952, 2858, 1739, 1676, 1257, 1126 cm-1 NMR (CDC1 3 , 6): -0.07 (3H, s), -0.04 (3H, s), 0.83 (9H, s), 5 2.05-2.25 (2H, m), 2.30-2.75 (2H, m), 3.60 (2H, s), 3.70-3.85 (5H, m), 3.98 (lH, m), 5.39 (lH, brs), 6.90-7.35 (5H, m), 7.46 (1H, s), 7.65 (1H, s) MASS: 446 (M+H)* 10 (7) 1-(l-Hydroxy-3-phenoxy-2-propyl)imidazole-4-carboxamide was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 24. mp: 147.5-149.5'C IR (KBr): 3330, 3188, 1662, 1600, 1246 cm' 15 NMR (DMSO-d, 6): 3.80-4.30 (5H, m), 5.53 (1H, d, J=4.lHz), 6.85-7.10 (4H, m), 7.20-7.40 (3H, m), 7.63 (2H, s) MASS: 262 (M+H)* (8) 1-[( 2
S,
3
R)-
2 -(benzyloxy)-5-(2-methylphenyl)-3-pentyl] 20 imidazole-4-carboxamide was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 11(3). NMR (CDC1 3 , 6): 1.07 (3H,d,J=6Hz), 2.0-2.6 (4H,m), 2.18 (3H,s), 3.6-3.8 (1H,m), 3.9-4.1 (1H,m), 4.38 (lH,d,J=llHz), 4.58 (lH,d,J=llHz), 5.39 (1H,s), 6.9-7.4 (10H,m), 7.45 25 (lH,d,J=lHz), 7.67 (lH,d,J=lHz) MASS: 378 (M+H)* (9) 1-[( 2
S,
3
R)-
2 -(benzyloxy)-5-(2-chlorophenyl)-3-pentyl] imidazole-4-carboxamide was prepared from the compound obtained in 30 Preparation 1 and the compound obtained in Preparation 11(4). NMR (CDC1 3 , 6): 1.08 (3H,d,J=6Hz), 2.0-2.5 (2H,m), 2.5-2.7 (2H,m), 3.6-3.7 (1H,m), 3.9-4.1 (1H,m), 4.38 WO 00/05217 PCT/JP99/03939 43 (lH,d,J=12Hz), 4.58 (lH,d,J=12Hz), 5.37 (1H,s), 6.9-7.4 (10H,m), 7.48 (lH,d,J=lHz), 7.67 (lH,d,J=lHz) MASS: 420 (M+Na)* 5 (10) 1-[( 2
S,
3
R)-
2 -(benzyloxy)-5-(2-methoxyphenyl)-3-pentyl] imidazole-4-carboxamide was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 11(5). NMR (CDC1, 3 ): 1.04 (3H,d,J=6Hz), 2.0-2.6 (4H,m), 3.6-3.7 (1H,m), 3.80 (3H,s), 3.9-4.1 (1H,m), 4.39 (lH,d,J=12Hz), 10 4.57 (lH,d,J=12Hz), 5.38 (1H,s), 6.8-7.4 (10H,m), 7.45 (lH,d,J=lHz), 7.69 (lH,d,J=lHz) MASS: 394 (M+H)* (11) 1-[( 2
S,
3
R)-
2 -(benzyloxy)-5-(2-hexyloxyphenyl)-3-pentyl] 15 imidazole-4-carboxamide was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 11(6). NMR (CDC1, 5 ): 0.8-1.0 (3H,m), 1.05 (3H,d,J=6Hz), 1.2-1.5 (6H,m), 1.6-1.9 (2H,m), 2.0-2.6 (4H,m), 3.6-3.7 (1H,m), 3.8-4.0 (3H,m), 4.38 (lH,d,J=12Hz), 4.56 (lH,d,J=12Hz), 20 5.37 (1H,s), 6.8-7.4 (10H,m), 7.44 (1H,s), 7.67 (lH,s) MASS: 464 (M+H)* (12) 1-[( 2
S,
3
R)-
2 -(benzyloxy)-5-(2,3-dichlorophenyl)-3-pentyl] imidazole-4-carboxamide was prepared from the compound obtained in 25 Preparation 1 and the compound obtained in Preparation 11(7). NMR (CDC1, 5 ): 1.08 (3H,d,J=6Hz), 2.0-2.5 (2H,m), 2.5-2.7 (2H,m), 3.6-4.1 (2H,m), 4.38 (lH,d,J=12Hz), 4.59 (lH,d,J=12Hz), 5.45 (1H,s), 6.9-7.4 (9H,m), 7.48 (lH,d,J=lHz), 7.67 (lH,d,J=lHz) 30 MASS: 432 (M+H)* (13) 1-[( 2
S,
3
R)-
2 -(benzyloxy)-5-(2-phenethyloxyphenyl)-3- WO 00/05217 PCT/JP99/03939 44 pentyl]imidazole-4-carboxamide was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 11(8). NMR (CDC1 3 , 6 ): 0.99 (3H,d,J=6Hz), 1.9-2.6 (4H,m), 3.06 5 ( 2 H,t,J= 7 Hz), 3.5-3.6 (H,m), 3.8-4.6 (5H,m), 5.34 (1H,s), 6.7-7.0 (3H,m), 7.1-7.4 (13H,m), 7.62 (lH,d,J=lHz) MASS: 484 (M+H)* (14) 1-[( 2
S,
3
R)-
2 -(benzyloxy)-5-(2,3-dimethylphenyl)-3-pentyl] 10 imidazole-4-carboxamide was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 11(9). NMR (CDC1 3 , ():1.06 (3H,d,J=6Hz), 2.0-2.6 (4H,m), 2.09 (3Hs) 2.26 (3H,s), 3.6-3.7 (1H,m), 3.9-4.0 (1H,m), 4.38 (lH,d,J=12Hz), 4.58 (lH,d,J=12Hz), 5.39 (1H,s), 6.7-7.4 15 (9H,m), 7.46 (lH,d,J=lHz), 7.67 (lH,d,J=lHz) MASS: 392 (M+H)* (15) 1-{( 2
S,
3
R)-
2 -(benzyloxy)-5-[2-(trifluoromethyl)phenyl]-3 pentyl}imidazole-4-carboxamide was prepared from the compound 20 obtained in Preparation 1 and the compound obtained in Preparation 28(1). NMR (CDC1 3 , 6): 1.09 (3H,d,J=6Hz), 2.0-2.8 (4H,m), 3.6-3.8 (1H,m), 3.9-4.1 (1H,m), 4.39 (lH,d,J=12Hz), 4.59 (lH,d,J=12Hz), 5.40 (1H,s), 6.9-7.7 (12H,m) 25 MASS: 432 (M+H)* (16) 1-{( 2
S,
3
R)-
2 -(benzyloxy)-5-[2,3-(methylenedioxy)phenyl]-3 pentyl}imidazole-4-carboxamide was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 30 11(10). NMR (CDC1 3 , 6): 1.06 (3H, d, J=6Hz), 2.0-2.6 (4H, m), 3.6 4.0 (2H, m), 4.38 (1H, d, J=12Hz), 4.58 (1H, d, J=12Hz), WO 00/05217 PCT/JP99/03939 45 5.38 (1H, S), 5.90 (2H, s), 6.4-6.8 (3H, m), 6.96 (1H, s), 7.2-7.4 (5H, m), 7.43 (1H, d, J=lHz), 7.65 (1H, d, J=lHz) MS: 408 (M+H)* 5 (17) 1-[ ( 2
S,
3 R)-2-(tert-butyldimethylsilyloxy)-5-(2-benzyloxy phenyl)- 3 -pentyl]imidazole-4-carboxamide was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 28(3). NMR (CDC1 3 , 6): -0.07 (3H, s), -0.02 (3H, s), 0.84 (9H, s), 10 0.93 (3H, d, J=6Hz), 1.8-2.8 (4H, m), 3.7-3.9 (2H, m), 5.07 (2H, s), 5.35 (1H, s), 6.8-7.4 (11H, m), 7.61 (1H, s) MS: 494 (M+H)* (18) 1-[ ( 2
S,
3
R)-
2 -(benzyloxy)-5-(2-naphthyl)-3-pentyl]imidazole 15 4-carboxamide was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 28(4). IR (neat): 1662 cm~1 NMR (CDC1 3 , (5): 1.06 (3H, d, J=6Hz), 2.1-2.9 (4H, m), 3.6 3.8 (1H, m), 3.8-4.1 (1H, m), 4.37 (1H, d, J=12Hz), 4.57 20 (1H, d, J=12Hz), 5.45 (1H, s), 7.0 (1H, s), 7.2-7.8 (14H, m) MS: 414 (M+H )+ (19) 1-[( 2
S,
3
R)-
2 -(benzyloxy)-6-(1-naphthyl)-3-hexyl] imidazole 25 4-carboxamide was prepared from the compound obtained in Preparation 1 and the compound obtained in Preparation 28(5). IR (neat): 1658 cm- 1 NMR (CDC1, (3): 1.04 (3H, d, J=6Hz), 1.5-2.3 (4H, m), 2.9 3.2 (2H, m), 3.5-3.7 (1H, m), 3.8-4.1 (1H, m), 4.37 (1H, 30 d, J=12Hz), 4.57 (1H, d, J=12Hz), 5.51 (1H, s), 6.97 (1H, s) 7.1-8.0 (14H, m) MS: 428 (M+H)* WO 00/05217 PCT/JP99/03939 46 (20) Methyl 1-[ ( 2
S,
3 R)-2-benzyloxy-5-(1-naphthyl)-3-pentyl] imidazole-4-carboxylate was prepared from (2S,3S)-2-benzyloxy-5 (1-naphthyl)pentan-3-ol (obtained in Preparation 26) and methyl 5 imidazole-4-carboxylate. IR (neat): 2945, 1726, 1672 cm-' NMR (CDCl,, d): 1.06 (3H, d, J=6.2Hz), 2.15-2.60 (2H, m), 2.75-3.10 (2H, m), 3.65 (1H, m), 3.91 (3H, s), 3.96 (1H, m), 4.33 (1H, d, J=11.5Hz), 4.55 (lH, d, J=11.5Hz), 10 7.10-7.90 (14H, m) MASS (APCI, m/z): 429 (M+H)* [a ] 7 +13.70 (c 0.65, EtOH) Example 4 15 Twenty percent palladium hydroxide on carbon (30 mg) was added to a stirred solution of 1-[(2S)-2-benzyloxy-5-phenyl-3 pentyl]imidazole-4-carboxamide (obtained in Example 3(1))(107 mg) in cyclohexene (5 ml) and ethanol (12.5 ml). The resulting mixture was stirred at ref lux temperature for 12 hours. After cooling to room 20 temperature, the mixture was filtered through Celite, and the insoluble material on the filter was washed with ethanol. The filtrate and washing were combined and then concentrated in vacuo. The resulting residue was purified by silica gel (3 g) chromatography eluted with chloroform/methanol (50:1) to give 1-[(2S)-2 25 hydroxy-5-phenyl-3-pentyl]imidazole-4-carboxamide (69.1 mg). IR (KBr): 3338, 2969, 1658 cm' NMR (DMSO-d 6 , 5 ): 0.84-0.93 (3H, m), 2.00-2.50 (4H, m), 3.70-4.00 (2H, m), 4.95-5.10 (1H, m), 6.95-7.40 (7H, m), 7.66 (1H, d, J=2.2Hz), 7.72 (1H, d, J=4.lHz) 30 MASS: 274 (M+H)+ WO 00/05217 PCT/JP99/03939 47 Example 5 The following compounds were obtained according to a similar manner to that of Example 4. 5 (1) 1-[ ( 2
S)-
2 -hydroxy-6-phenyl-3-hexyl]imidazole-4-carboxamide was prepared from the compound obtained in Example 3(2). IR (KBr): 3700-2800, 1660, 1594 cm-' NMR (DMSO-d 6 ,( ) : 0.80-1.00 (3H, m), 1.15-1.55 (2H, m), 1.60-2.05 (2H, m), 2.40-2.70 (2H, m), 3.70-4.10 (2H, m), 4.95-5.10 (1H, 10 m), 6.90-7.35 (7H, m), 7.60-7.75 (2H, m) MASS: 288 (M+H)* (2) (2S)-2-hydroxy-5-(1-naphthyl)-3-pentylimidazole-4 carboxamide was prepared from the compound obtained in Example 3(3). mp: 95-98 0 C 15 IR (KBr): 3336, 1658, 1594 cm-' NMR (DMSO-d 6 , 6) : 0.80-1.00 (3H, m), 2.05-2.45 (2H, m), 2.60-3.15 (2H, m), 3.70-4.20 (2H, m), 5.05-5.15 (1H, m), 7.07 (1H, brs), 7.20-7.60 (5H, m), 7.70-8.00 (5H, m) MASS: 324 (M+H)* 20 Example 6 Triethylamine (1.06 g) was added dropwise to a stirred mixture of (R)-1-(tert-butyldimethylsilyl-oxy)-4-phenylbutan-2-ol (obtained in Preparation 14) (2.10 g) and methanesulfonyl chloride 25 (1.20 g) in dichloromethane (20 ml) at ice-bath temperature. After 1 hour, the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine and dried over MgSO 4 , and concentrated in vacuo to, give the methanesulfonate (2.74 g) as an oil. This material was used for the next reaction without 30 further purification. NaH (60% in mineral oil, 299 mg) was added to a solution of methyl 4-imidazolecarboxylate (942 mg) in DMF (20 ml) at room WO 00/05217 PCT/JP99/03939 48 temperature. The reaction mixture was stirred for 30 minutes. The methanesulfonate prepared above was added and the resulting mixture was stirred for 37 hours at 70 0 C. The reaction mixture was cooled to 10'C in an ice bath, and the 5 insoluble material was filtered and washed thoroughly with dichloromethane. The filtrate and the washing were combined and then washed with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel (50 g) column chromatography eluting with toluene/ethyl acetate 10 (20:1) to give methyl (S)-l-[1-(tert-butyldimethylsilyloxy)-4 phenyl- 2 -butyl]imidazole-4-carboxylate (1.52g). IR (neat): 2950, 2933, 2857, 1725, 1675, 1189, 1122 cm-1 NMR (CDC1, (5 ): -0.06 (3H, s), -0.05 (3H, s), 0.84 (9H, s), 2.10-2.25 (2H, m), 2.35-2.75 (2H, m), 3.70-3.80 (2H, m), 15 3.91 (3H, s), 4.00 (1H, m), 7.05-7.38 (5H, m), 7.51 (1H, s), 7.69 (1H, s) MASS: 3S9 (M+H)* Example 7 20 A solution of 28% NaOMe in methanol (772 mg) was added to an ice cooled solution of aminoguanidine hydrochloride (332 mg) in methanol (5 ml). After 10 minutes, methyl (S)-1-[1-(tert butyldimethylsilyloxy)-4-phenyl-2-butyl]-imidazole-4-carboxylate (obtained in Example 6) (389 mg) in methanol (2 ml) was added to the 25 mixture and the resulting mixture was stirred at ref lux for 22 hours. After cooling, the insoluble material was removed and then the filtrate was evaporated. The residue was diluted with water and the solution was acidified to pH 4 with 6N HClaq. The resulting mixture was washed with CHC1. The aqueous layer was purified by HP-20 (50 30 cc) column chromatography eluting with water/2-propanol (9:1) and lyophilized to give (S)- 2
-[
4 -(5-amino-1,2,4-triazol-3-yl)-1 imidazolyl]-4-phenylbutan-1-ol (107 mg).
WO 00/05217 PCT/JP99/03939 49 mp: 80*C (decompose) IR (KBr): 3700-2700, 1641, 1602, 1238, 1058 cm-1 NMR (DMSO-d 6 ,t5) : 1.95-2.60 (4H, m), 3.64 (2H, brs), 4.10 (1H, m), 5.02 (1H, brs), 5.40 (2H, br), 7.10-7.35 (6H, m), 7.55 5 (1H, s), 7.70 (1H, s) MASS: 299 (M+H)* Example 8 A solution of 28% NaOMe in methanol (583 mg) was added to an 10 ice cooled solution of guanidine hydrochloride (307 mg) in DMF (5 ml). After 10 minutes, methyl (S)-1-[1-(tert-butyl dimethylsilyloxy)-4-phenyl-2-butyl]imidazole-4-carboxylate (obtained in Example 6) (250 mg) in DMF (2 ml) was added to the mixture and the resulting mixture was stirred at 100 0 C for 5 hours. After 15 cooling, the reaction mixture was poured into water (30 ml) and the solution was washed with ethyl acetate. The aqueous layer was purified by HP-20 (40 cc) column chromatography eluting with water/2-propanol (9:1) and lyophilized to give (S)-1-[1-hydroxy-4-phenyl-2 butyl]imidazole-4-carbonylguanidine (55.4 mg) 20 mp: 111-113C IR (KBr): 3700-2700, 1639, 1592, 1517, 1405 cm' NMR (DMSO-d 6 1 &) 1.90-2.60 (4H, m), 3.62 (2H, d, J=5.0), 4.07 (1H, m), 5.02 (1H, brs), 7.00-8.00 (11H, m) MASS: 302 (M+H)* 25 Example 9 To an ice cooled solution of 1-[1-(tert butyldimethylsilyloxy)-4-(4-methylphenyl)-2-butyl]imidazole-4 carboxamide (obtained in Example 3(4))(194 mg, 0.50 mmol) in THF (5 30 ml) was added dropwise 1. OM Bu 4 NF in THF (1.0 ml) . After the addition was completed, the reaction mixture was stirred at ice-bath temperature for lh. 25% AcONH 4 (4 ml) was added, and the resulting WO 00/05217 PCT/JP99/03939 50 mixture was stirred for several minutes and then extracted with chloroform. The organic layer was washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by silica gel (5g) column chromatography eluting with 5 chloroform/methabol (20:1) to give 1-[1-hydroxy-4-(4 methylphenyl)-2-butyl]imidazole-4-carboxamide (44.9mg, 32.9%) as a white solid. mp: 138-141*C IR (KBr): 3320, 3193, 2852, 1693, 1668, 1606 cm-' 10 NMR (DMSO-d,, a5): 1.90-2.15 (2H, m), 2.20-2.50 (5H, m), 3.61 (2H, t, J=5.4Hz), 4.08 (1H, m), 5.00 (1H, t, J=5.3Hz), 6.90-7.15 (5H, m), 7.27 (1H, br s), 7.69 (1H, s), 7.74 (1H, S) MASS: 274 (M+H)* 15 Example 10 The following compound was prepared by a similar procedure to that of Example 9. 20 (1) 1-{l-Hydroxy-4-[3-(ethoxycarbonyl)phenyl]-2-butyl} imidazole-4-carboxamide was prepared from the compound obtained in Example 3(5). mp: 92-95'C IR (KBr): 3322, 3193, 2954, 1720, 1662, 1604, 1278 cm-' 25 NMR (DMSO-d,, 6): 1.32 (3H, t, J=7.lHz), 2.00-2.20 (2H, m), 2.35-2.55 (2H, m), 3.64 (2H, br), 4.31 (2H, q, J=7.lHz), 5.03 (1H, br s), 7.03 (1H, br s), 7.26 (1H, br s), 7.40-7.50 (2H, m), 7.65-7.85 (4H, m) MASS: 332 (M+H)* 30 (2) 1-{l-Hydroxy-4-[3-(methoxycarbonylmethyl)phenyl]-2 butyl}imidazole-4-carboxamide was prepared from the compound WO 00/05217 PCT/JP99/03939 51 obtained in Example 3(6). mp: 138.5-141.0*C IR (KBr): 3600-3000, 2951, 1738, 1651, 1583, 1267 cm-1 NMR (DMSO-d,, 5 ): 1.90-2.20 (2H, m), 2.20-2.50 (2H, M), 5 3.50-3.75 (7H, m), 4.10 (1H, m), 5.01 (1H, t, J=5.3Hz), 6.90-7.35 (6H, m), 7.70 (1H, s), 7.75 (1H, S) MASS: 332 (M+H)* (3) 1-[ ( 2
S,
3
R)-
2 -hydroxy-5-(2-benzyloxyphenyl)-3-pentyl] 10 imidazole-4-carboxamide was prepared from the compound obtained in Example 3 (17). NMR (CDCl 3 , (5): 1.02 (3H, d, J=6Hz), 1.9-2.8 (5H, m), 3.8 4.0 (2H, m), 5.07 (2H, s), 5.38 (1H, s), 6.8-7.4 (11H, m), 7.66 (1H, d, J=lHz) 15 MS: 380 (M+H)* [a ] 27 = +16.20 (c 1.0, EtOH) Example 11 Sodium methoxide (39 mg, 0.72 mmol) was added to a stirred 20 solution of 1-{l-hydroxy-4-[3-(ethoxycarbonyl)phenyl]-2-butyl} imidazole-4-carboxamide (obtained in Example 10(1))(60 mg, 0.18 mmol) in formamide (1. 5ml), and the reaction mixture was stirred at 110 0 C for 3 h. After cooling, the reaction mixture was poured into water (5 ml). The residue was purified by HP-20 (16 cc) column 25 chromatography eluting with water/2-propanol (9:1) and lyophilized to give 1-[ 4
-(
3 -carbamoylphenyl)--hydroxy-2-butyl]imidazole-4 carboxamide (39.2 mg, 71.6%) as an amorphous solid. IR (KBr): 3700-2800, 1660, 1592, 1402 cm' NMR (DMSO-d 6 , (5): 2.09 (2H, m), 2.30-2.65 (2H, m), 3.64 (2H, 30 t, J=5.4Hz), 4.14 (1H, m), 5.04 (1H, t, J=5.3Hz), 7.05 (1H, br s), 7.20-7.50 (4H, m), 7.65-7.85 (4H, m), 7.93 (1H, br WO 00/05217 PCT/JP99/03939 52 S) MASS: 332 (M+H)* Example 12 5 The following compound was prepared by a similar procedure to that of Example 1. (1) 1-{l-hydroxy-4-[3-(2-hydroxyethyl)phenyl]-2-butyl} imidazole-4-carboxamide was prepared from the compound obtained in 10 Example 10(2). IR (KBr): 3700-3000, 2927, 2861, 1658, 1595, 1414, 1055 cm NMR (DMSO-d, 6 ): 1.90-2.20 (2H, m), 2.20-2.50 (2H, m), 2.68 (2H, t, J=7.lHz), 3.50-3.70 (4H, m), 4.10 (1H, m), 4.61 (1H, t, J=5.2Hz), 5.01 (1H, t, J=5.4Hz), 6.90-7.35 (6H, 15 m), 7.70 (1H, s), 7.74 (1H, s) MASS: 304 (M+H)* (2) 1-[1-Hydroxy-4-phenyl-2-butyl]imidazole-4-carbonitrile was prepared from the compound obtained in Preparation 23. 20 mp: 111-115*C IR (KBr): 3500-3000, 2943, 2867, 2237, 1078 cm' NMR (DMSO-d, 6 ): 1.95-2.60 (4H, m), 3.55-3.70 (2H, m), 4.18 (1H, m), 5.06 (1H, t, J=5.4Hz), 7.05-7.35 (5H, m), 7.93 (1H, s), 8.25 (lH, s) 25 MASS: 242 (M+H)* Example 13 A mixture of methyl (S)-1-[1-(tert-butyldimethylsilyloxy) 4-phenyl-2-butyl]imidazole-4-carboxylate (obtained in Example 6) 30 (300 mg, 0.77 mmol) and hydrazine monohydrate (5 ml) in DMF (3 ml) was stirred at 100 0 C for 2 h. Aftercooling, the reaction mixture was poured into water (10ml) WO 00/05217 PCT/JP99/03939 53 and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel (10 g) column chromatography eluting with chloroform/methanol (100:1) to give (S)-1-[1-(tert 5 butyldimethylsilyloxy)-4-phenyl-2-butyl]imidazole-4 carbohydrazide (274 mg, 91.5%). IR (neat): 3700-3000, 2933, 2858, 1646, 1568, 1466, 1252, 1120 cm-1 NMR (CDCl, c5): -0.07 (3H, s), -0.05 (3H, s), 0.83 (9H, s), 10 2.05-2.75 (4H, m), 3.65-4.10 (5H, m), 7.00-7.40 (5H, m), 7.43 (lH, s), 7.63 (1H, s) MASS: 389 (M+H)* Example 14 15 A powder of NaOMe (417mg, 7.72mmol) was added to an ice cooled solution of hydroxylamine hydrochloride (536 mg, 7.72 mmol) in methanol (5 ml). After 30 minutes, methyl (S)-1-[1-(tert butyldimethylsilyloxy)-4-phenyl-2-butyl]imidazole-4-carboxylate (obtained in Example 6) (389 mg, 1.0 mmol) in methanol (2 ml) was added 20 to the mixture and the resulting mixture was stirred at reflux for 3 day. After cooling, the insoluble material was removed and then the filtrate was evaporated. The residue was diluted with water and the solution was acidified to pH 4 with 1N HClaq. The resulting mixture was washed with CHC1 3 . The aqueous layer was purified by HP-20 25 (40 cc) column chromatography eluting with water/2-propanol (9:1) and lyophilized to give (S)-1-[1-hydroxy-4-phenyl-2-butyl] imidazole-4-carbohydroxamic acid (92.5 mg, 43.5%) as an amorphous solid. IR (neat): 3700-2700, 1645, 1566, 1238, 1141 cm-1 30 NMR (DMSO-d,, 6): 1.90-2.60 (4H, m), 3.63 (2H, m), 4.10 (1H, m), 5.01 (1H, br), 7.05-7.40 (5H, m), 7.70 (1H, s), 7.76 (1H, s), 8.72 (1H, br), 10.62 (1H, br s) WO 00/05217 PCT/JP99/03939 54 MASS: 276 (M+H)* Example 15 A powder of NaOMe (67.2 mg, 1.24 mmol) was added to a solution 5 of hydroxylamine hydrochloride (86.4 mg, 1.24 mmol) in methanol (2 ml) at room temperature. After 30 minutes, 1-(1-hydroxy-4 phenyl-2-butyl)imidazole-4-carbonitrile (obtained in Example 12(2)) (100 mg, 0.41 mmol) was added to the mixture and the resulting mixture was stirred at reflux for 2 h. After cooling, the insoluble 10 material was removed and then the filtrate was evaporated. The residue was purified by silica gel (5 g) column chromatography eluting with chloroform/methanol (20:1) and concentrated in vacuo. The residue was triturated with isopropyl ether to give N-hydroxy-1 [1-hydroxy-4-phenyl-2-butyl imidazole-4-carboximidamide (86.3 mg, 15 76.0%) as an amorphous solid. IR (KBr): 3700-2800, 1649, 1604, 1496 cm- 1 NMR (DMSO-d 6 , a): 1.90-2.60 (4H, m), 3.62 (2H, t, J=4.9Hz), 4.09 (1H, m), 5.04 (1H, t, J=5.2Hz), 6.06 (2H, br s), 7.10-7.40 (5H, m), 7.58 (1H, s), 7.75 (1H, s), 9.41 (1H, 20 br s) MASS: 275 (M+H)* Example 16 A mixture of 1-(l-hydroxy-4-phenyl-2-butyl)imidazole-4 25 carbonitrile (obtained in Example 12 (2) ) (100 mg, 0.41 mmol) , ammonium chloride (111 mg, 2.07 mmol) and sodium azide (135 mg, 2.07 mmol) in DMF (4 ml) was stirred at 100 0 C for 8 h. After cooling, the reaction mixture was poured into water (30 ml) and the solution was washed with CHC1 3 . The aqueous layer was 30 purified by HP-20 (16 cc) column chromatography eluting with water/2-propanol (9:1) and lyophilized to give 1-(1-hydroxy-4 phenyl-2-butyl)-4-(5-tetrazolyl)imidazole (63.3 mg, 53.8%) as an WO 00/05217 PCT/JP99/03939 55 amorphous solid. IR (KBr): 3700-2700, 1651, 1612, 1496, 1458, 1250 cm-1 NMR (DMSO-d 6 , (5): 1.95-2.60 (4H, m), 3.66 (2H, m), 4.09 (1H, m), 5.03 (1H, br), 7.05-7.35 (5H, m), 7.55 (1H, s), 7.68 5 (1H, s), 9.41 (1H, br s) MASS: 285 (M+H)* Example 17 A suspension of imidazole-4-carboxamide (obtained in 10 Preparation 1) (207 mg) in DMF (3 ml) was treated with sodium hydride (60% in mineral oil, 87 mg) at ice-bath temperature and the mixture was stirred at room temperature for 20 min. A solution of (2S,3S)-2-benzyloxy-5-(1-nephthyl)-3-pentyl methanesulfonate (obtained in Preparation 27)(0.62 mg) in DMF (5 ml) was added and 15 the mixture was stirred at 80 0 C for 48 h. After cooling, the mixture was filtered to remove the insoluble material. The filtrate was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated in vacuo. Flash chromatography (dichloromethane:methanol = 50:1) gave 1 20 [( 2
S,
3
R)-
2 -benzyloxy-5-(1-naphthyl)-3-pentyl]imidazole-4 carboxamide (221 mg, 34.4%) as an oil. IR (neat): 3458, 3332, 3184, 1666, 1593 cm-1 NMR (CDCl,, d): 1.04 (3H, d, J=6.3Hz), 2.15-2.60 (2H, m), 2.80-3.10 (2H, m), 3.64 (1H, m), 3.98 (1H, m), 4.53 (1H, 25 d, J=11.6Hz), 4.55 (1H, d, J=11.6Hz), 5.49 (1H, bs), 7.00 (1H, bs), 7.15-7.90 (14H, m) MASS (APCI, m/z): 414 (M+H)* [a'] 27 +23.70 (c 0.5, EtOH) 30 Example 18 The following compounds were obtained according to the procedure of Example 17.
WO 00/05217 PCT/JP99/03939 56 (1) 1-[( 2
S,
3 S)-2-benzyloxy-5-(1-naphthyl)-3-pentyl]imidazole 4-carboxamide was prepared from (2S,3R)-2-benzyloxy-5-(1 naphthyl)-3-pentyl) methanesulfonate (obtained in Preparation 5 29(1))(1.99 g) and imidazole-4-carboxamide (0.67 g). IR (neat): 3460, 3330, 3182, 1668, 1593 cm-1 NMR (CDCl 3 , d): 1.03 (3H, d, J=6.2Hz), 2.15-2.55 (2H, m), 2.74-3.03 (2H, m), 3.66 (1H, m), 3.86 (1H, m), 4.26 (1H, d, J=11.6Hz), 4.56 (1H, d, J=11.6Hz), 5.52 (1H, bs), 7.02 10 (1H, bs), 7.12-7.50 (10H, m), 7.71-7.88 (4H, m) MASS (APCI, m/z): 414 (M+H)* [a] 2 1" -21.10 (c 0.5, EtOH) (2) 1-[( 2
S,
3 R)-2-(tert-butyldimethyllyyloxy)-5-phenyl-3 15 pentyl]imidazole-4-carboxamide was prepared from (2S,3S)-4 (tert-butyldimethylsilyloxy)-5-phenyl-3-pentyl methanesulfonate (obtained in Preparation 29(2)) and imidazole-4-carboxamide (obtained in Preparation 1) according to the procedure of Example 17. 20 IR (neat): 3465, 3332, 3188, 2935, 1672, 1599 cm-' NMR (CDCl 3 , d): -0.24 (3H, s), 0.10 (3H, s), 0.88 (9H, s), 0.98 (3H, d, J=6.lHz), 2.09 (1H, m), 2.20-2.45 (2H, m), 2.62 (1H, m), 3.77 (1H, m), 3.88 (1H, m), 5.47 (1H, bs), 6.98 (1H, bs), 7.06 (2H, d, J=6.4Hz), 7.20-7.33(3H, m), 7.38(1H, 25 d, J=1.lHz), 7.62(1H, d, J=1.lHz) MS (APCI, m/z): 388 (M+H)+ [a]D 27 +29.30 (c 0.5, EtOH) Example 19 30 The following compound was prepared by a similar procedure to that of Example 9.
WO 00/05217 PCT/JP99/03939 57 (1) (S)-1-[l-hydroxy-4-phenyl-2-butyl]imidazole-4-carbohydrazide was prepared as an amorphous solid from the compound obtained in Example 13. NMR (DMSO-d, (5): 2.00-2.55 (4H, m), 3.63 (2H, t, J=5.2Hz), 5 4.10 (1H, m), 4.33 (2H, br), 5.01 (1H, t, J=5.3Hz), 7.10-7.35 (5H, m), 7.70 (1H, s), 7.77 (1H, s), 8.97 (1H, br s) MASS: 275 (M+H)* 10 (2) 1-[ ( 2
S,
3
R)-
2 -hydroxy-5-phenyl-3-pentyl]imidazole-4 carboxamide was prepared from the compound obtained in Example 18 (2). IR (KBr): 3336, 1658, 1593 cm-' NMR (DMSO-d,, d): 0.87 (3H, d, J=6.OHz), 2.00-2.40 (4H, m), 3.75-3.95 (2H, m), 5.08 (1H, d, J=4.8Hz), 7.07 (1H, bs), 15 7.10-7.30 (6H, m), 7.72 (1H, s), 7.74 (1H, s) MS (APCI, m/z): 274(M+H)* [a ] 26 +43.50 (c 0.4, EtOH) Example 20 20 A mixture of methyl 1-[(2S,3R)-2-benzyloxy-5-(-naphthyl) 3 -pentyl]imidazole-4-carboxylate (obtained in Example 3(20)) (160 mg) in ammonium hydroxide (10 ml) and DMF (5 ml) was heated at 100 *C for 8 h in a sealed tube and then concentrated in vacuo. Flash chromatography (dichloromethane:methanol = 20:1) gave 1 25 [(2S,3R)-2-benzyloxy-5-( 1-naphthyl)-3-pentyl]imidazole-4 carboxamide (144 mg, 93.3%) as an oil. Example 21 1-[(2S,3R)-2-benzyloxy-5-(1-naphthyl)-3-pentyl]imidazole 30 4-carboxamide (obtained in Example 17 or 20) (5.07 g) was dissolved in a mixture of ethanol (300 ml) and cyclohexene (150 ml) and then palladium hydroxide (20% on carbon, 5.0 g) was added. The mixture WO 00/05217 PCT/JP99/03939 58 was heated under ref lux for 3 days. After cooling, the catalyst was filtered and washed with ethanol. The combined filtrate and washings were concentrated in vacuo. Flash chromatography (dichloromethane : methanol = 10 : 1) gave 1-[(2S,3R)-2-hydroxy-5-(1-naphthyl)-3 5 pentyl]imidazole-4-carboxamide (2.71 g, 68.4%) as a foam. IR (KBr): 3334, 1666, 1593 cm 1 NMR (DMSO-d 6 , d): 0.88 (3H, d, J=6.2Hz), 2.10-2.40 (2H, m), 2.60-2.95 (2H, m), 3.83 (1H, m), 4.05 (1H, m), 5.09 (1H, d, J=4.9Hz), 7.10 (1H, bs), 7.25 (1H, d, J=6.3Hz), 7.34 10 (1H, bs), 7.42 (1H, t, J=7.6Hz), 7.49-7.54 (2H, m), 7.76-7.94 (5H, m) MASS (APCI, m/z): 324 (M+H)* [a] D 2 +29.20 (c 0.5, EtOH) 15 Example 22 1-[( 2
S,
3
S)-
2 -hydroxy-5-(1-naphthyl)-3-pentyl]-imidazole-4 carboxamide was prepared from the compound obtained in Example 18 (1) according to a similar procedure to Example 21. IR (KBr): 3334, 1658, 1593 cm- 1 20 NMR (DMSO-d 6 , d): 0.91 (3H, d, J=6.3Hz), 2.10-2.30 (2H, m), 2.60-3.05 (2H, m), 3.95 (1H, m), 4.13 (1H, m), 5.05 (1H, d, J=4.lHz), 7.06 (1H, bs), 7.25-7.55 (5H, m), 7.75-7.95 (5H, m) MASS (APCI, m/z): 324 (M+H)* 25 [a]D 2 7 -22.40 (c 0.25, EtOH) Example 23 The following compound was prepared by a similar procedure to that of Example 4. 30 (1) 1-[ ( 2
S,
3
R)-
2 -hydroxy-5-(2-methylphenyl) -3-pentyl]imidazole 4-carboxamide was prepared from the compound obtained in Example WO 00/05217 PCT/JP99/03939 59 3(8). mp: 60-62 0 C NMR (CDCl 3 , ):1.11 (3H,d,J=6Hz), 2.0-2.6 (5H,m), 2.
2 0
(
3 H,s) 3.8-4.1 (2H,m), 5.47 (1H,s), 6.9-7.2 (5H,m), 7.46 5 (lH,d,J=lHz), 7.73 (lH,d,J=lHz) MASS: 288 (M+H)* [ a]D 2 5 = +110.50 (c 0.50, EtOH) (2) 1-[( 2
S,
3
R)-
2 -hydroxy-5-(2-methoxyphenyl)-3-pentyl} 10 imidazole-4-carboxamide was prepared from the compound obtained in Exampoe 3(10). NMR (CDCl 3 , t5): 1.09 (3H,d,J=6Hz), 2.0-2.7 (5H,m), 3.81 (3H,s), 3.9-4.0 (2H,m), 5.40 (1H,s), 6.8-7.3 (5H,m), 7.46 (lH,d,J=lHz), 7.72 (lH,d,J=lHz) 15 MASS: 304 (M+H)* a ]D25 +110.00 (c 0.50, EtOH) (3) 1-[ ( 2
S,
3
R)-
2 -hydroxy-5-(2-hexyloxyphenyl)-3-pentyl
]
imidazole-4-carboxamide was prepared from the compound obtained in 20 Example 3(11). NMR (CDCl 3 , 6): 0.8-1.0 (3H,m), 1.09 (3H,d,J=6Hz), 1.2-1.5 (6H,m), 1.7-1.9 (3H,m), 2.0-2.7 (4H,m), 3.8-4.0 (4H,m), 5.35 (1H,s), 6.8-7.3 (5H,m), 7.45 (1H,s), 7.69 (1H,s) MASS: 374 (M+H)* 25 [ a ] 2 = +22.9* (c 0.50, EtOH) (4) 1-[( 2
S,
3
R)-
2 -hydroxy-5-(2-hydroxyphenyl)-3-pentyl] imidazole-4-carboxamide was prepared from the compound obtained in Example 3(13). 30 NMR (DMSO-d,, 6): 0.87 (3H,d,J=6Hz), 1.9-2.4 (4H,m), 3.7-4.0 (2H,m), 5.05 (lH,d,J=5Hz), 6.6-7.3 (6H,m), 7.71 (2H,s), WO 00/05217 PCT/JP99/03939 60 9.29 (1H,s) MASS: 290 (M+H)* (5) 1-[( 2
S,
3
R)-
2 -hydroxy-5-(2,3-dimethylphenyl)-3-pentyl] 5 imidazole-4-carboxamide was prepared from the compound obtained in Example 3(14). NMR(CDCl 3 , (5): 1.10 (3H,d,J=6Hz), 2.0-2.6 (5H,m), 2.1 1
(
3 Hs), 2.26 (3H,s), 3.9-4.0 (2H,m), 5.43 (1H,s), 6.8-7.1 (4H,m), 7.47 (lH,d,J=lHz), 7.72 (lH,d,J=lHz) 10 MASS: 302 (M+H)* [a] 26 = +26.70 (c 0.50, EtOH) (6) 1-[( 2
S,
3
R)-
2 -hydroxy-5-[2-(trifluoromethyl)phenyl]-3 pentyl]imidazole-4-carboxamide was prepared from the compound 15 obtained in Example 3(15). NMR (CDCl 3 , (5): 1.13 (3H,d,J=6Hz), 2.0-2.4 (3H,m), 2.5-2.8 (2H,m), 3.9-4.1 (2H,m), 5.42 (1H,s), 6.9-7.8 (7H,m) MASS: 342 (M+H)* [a]D 2 5 = -0.700 (c 0.50, EtOH) 20 (7) Methyl 1-[( 2
S,
3 R)-2-hydroxy-5-(-naphthyl)-3-pentyl] imidazole-4-carboxylate was prepared from the compound obtained in Example 3(20). NMR (CDCl 3 , 6): 1.09 (3H,d,J=6Hz), 1.9-2.6 (3H,m), 2.8-3.2 25 (2H,m), 3.92 (3H,s), 3.9-4.1 (2H,m), 7.1-7.9 (9H,m) MASS: 339 (M+H)* (8) 1-{( 2
S,
3
R)-
2 -hydroxy-5-[2,3-(methylenedioxy)phenyl]-3 pentyl}imidazole-4-carboxamide was prepared from the compound 30 obtained in Example 3(16). NMR (CDCl 3 , 6): 1.11 (3H, d, J=6Hz), 2.1-2.7 (5H, m), 3.8- WO 00/05217 PCT/JP99/03939 61 4.1 (2H, m), 5.44 (1H, S), 5.92 (2H, s), 6.5-6.8 (3H, m), 6.99 (1H, S), 7.44 (1H, d, J=lHz), 7.70 (1H, d, J=lHz) MS: 318 (M+H)* [a]D 2 7 = +29.30 (C 0.50, EtOH) 5 (9) 1-[ ( 2
S,
3 R)-2-hydroxy-5-(2-naphthyl)-3-pentyl]imidazole-4 carboxamide was prepared from the compound obtained in Example 3 (18). IR (KBr): 3340, 1658 cm-' NMR (CDCl 3 , 6): 1.10 (3H, d, J=6Hz), 2.1-2.4 (3H, m), 2.4 10 2.7 (1H, m), 2.7-2.9 (1H, m), 3.8-4.1 (2H, m), 5.46 (lH, s), 7.00 (1H, s), 7.2-7.9 (9H, m) MS: 324 (M+H)* [ D = +55.40 (c 0.50, EtOH) 15 (10) 1-[(2S,3R)-2-hydroxy-6-(1-naphtyl)-3-hexyl]imidazole-4 carboxamide was prepared from the compound obtained in Example 3 (19). IR (KBr): 3340, 1658 cm-' NMR (CDCl 3 , 6): 1.08 (3H, d, J=6Hz), 1.5-2.2 (5H, m), 3.06 (2H, t, J=8Hz), 3.8-4.0 (2H, m), 5.48 (1H, s), 6.98 (1H, s), 20 7.2-8.0 (9H, m) MS: 338 (M+H)* Example 24 A mixture of 1-[ ( 2
S,
3 R)-2-(benzyloxy) -5- (2-chlorophenyl) 25 3 -pentyl]imidazole-4-carboxamide (obtained in Example 3(9))(40 mg) and iodotrimethylsilane (0.02 ml) in chloroform (1 ml) was stirred at room temperature for 2 hours. The mixture was poured into methanol and the whole was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with water, aqueous sodium bisulfite and sodium 30 bicarbonate, successively, and dried. The residue left after evaporation of solvent was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol WO 00/05217 PCT/JP99/03939 62 (20 :1) to give a white powder of 1-[(2S,3R)-2-hydroxy-5-(2 chlorophenyl)- 3 -pentyl]imidazole-4-carboxamide (6.1 mg). NMR (CDCl 3 , ( ): 1.12 (3H,d,J=6Hz), 1.9-2.4 (3H,m), 2.5-2.7 (2H,m), 3.9-4.1 (2H,m), 5.40 (1H,s), 6.9-7.4 (5H,m), 7.49 5 (lH,d,J=lHz), 7.72 (lH,d,J=lHz) MASS: 308 (M+H)* [a]D +17.9 (c 0.50, EtOH) Example 25 10 1-[( 2
S,
3
R)-
2 -Hydroxy-5-(2,3-dichlorophenyl)-3-pentyl] imidazole-4-carboxamide was prepared by a similar procedure to that of Example 24 from the compound obtained in Example 3(12). mp: 70-75C NMR (CDCl 3 , 0 ): 1.13 (3H,d,J=6Hz), 1.98 (lH,d,J=5Hz), 2.1 15 2.4 (2H,m), 2.6-2.8 (2H,m), 3.9-4.1 (2H,m), 5.39 (1H,s), 6.9-7.4 (4H,m), 7.49 (lH,d,J=lHz), 7.72 (lH,d,J=lHz) MASS: 342 (M+H)* [a]D 2 " = +9.30' (c 0.50, EtOH) 20 Example 26 Methyl 1-[( 2 S,3R)-2-(benzyloxy)-5-(1-naphthyl)-3 pentyl]imidazole-4-carboxylate was prepared by a similar procedure to that of Example 6 from methyl 4-imidazolecarboxylate and the compound obtained in Preparation 27. 25 NMR (CDCl 3 , 5 ): 1.06 (3H,d,J=6Hz), 2.1-2.6 (2H,m), 2.7-3.1
(
2 H,m), 3 .6-3.7 (H,m), 3.97 (3Hs), 3.9-4.1 (H,m), 4.33 (lH,d,J=llHz), 4.56 (lH,d,J=llHz), 7.1-7.9 (14H,m) MASS: 429 (M+H)* 30 Example 27 1-[( 2
S,
3
R)-
2 -hydroxy-5-(1-naphthyl)-3-pentyl]imidazole-4- WO 00/05217 PCT/JP99/03939 63 carbonylguanidine acetic acid salt was prepared by a similar procedure to that of Example 8 from the compound obtained in Example 23(7). NMR(DMSO-d, 5): 0.90 (3H,d,J=6Hz), 1.88 (3H,s), 2.1-2.5 (2H,m), 5 2.6-3.0 (2H,m), 3.8-4.2 (2H,m), 5.15 (lH,br s), 7.2-8.0 (9H,m) MASS: 366 (M+H)* [a] D = +17.5 (c 0.50, EtOH) 10 Example 28 A mixture of 1-[ (2S,3R)-2-hydroxy-5-(2-hydroxyphenyl)-3 pentyl]imidazole-4-carboxamide (obtained in Example 23 (4)) (4.1 mg), 1-bromo-3-phenylpropane (7 mg), and potassium carbonate (4 mg) in N,N-dimethylformamide (0.5 ml) was stirred overnight at room 15 temperature. The mixture was taken up in ethyl acetate, washed twice with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (20:1) to give a colorless gummy oil of 1-{( 2
S,
3
R)-
2 -hydroxy-5-[2-(3-phenylpropoxy)phenyl]-3 20 pentyl}imidazole-4-carboxamide (4.9 mg). NMR (CDCl 3 , 5 ): 1.08 (3H, d, J=6Hz), 2.0-2.9 (9H, m), 3.9 4.0 (4H, m), 5.39 (1H, s), 6.7-7.4 (10H, m), 7.45 (1H, s), 7.71 (1H, s) MS: 408 (M+H)* 25 Example 29 A mixture of methyl 1-[(2S,3R)-2-hydroxy-5-(1-naphthyl)-3 pentyl]imidazole-4-carboxylate (obtained in Example 23(7))(25 mg) and methylamine (40 % in water; 1 ml) in tetrahydrofuran (3 ml) was 30 heated in a steel sealed tube at 120 0 C overnight. The mixture was taken up in dichloromethane, washed with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, WO 00/05217 PCT/JP99/03939 64 eluting with a mixture of dichloromethane and methanol (30:1) to give a white powder of N-methyl-1-[(2S,3R)-2-hydroxy-5-(1-naphthyl) 3 -pentyl]imidazole-4-carboxamide (18.6 mg). NMR (CDCl 3 , (5): 1.07 (3H, d, J=6Hz), 2.1-2.5 (3H, m), 2.7 5 3.1 (2H, m), 3.01 (3H, d, J=7Hz), 3.8-4.0 (2H, m), 7.0-7.9 (10H, m) MS: 338 (M+H)* [a ]D 27 = +24.70 (c 0.50, EtOH ) 10 Example 30 A mixture of methyl 1-[ (2S,3R)-2-benzyloxy-5-(1-naphthyl) 3 -pentyl]imidazole-4-carboxylate (obtained in Example 3(20)) (97 mg) and sodium hydroxide (12 mg) in ethanol (2 ml) and water (0.2 ml) was stirred at room temperature overnight. The solvent was 15 evaporated and the residue was taken up in a mixture of ethyl acetate and water. The aqueous layer was separated, acidified to pH 3 with hydrochloric acid, and extracted with ethyl acetate. The extract was dried and evaporated to give a pale brown powder of 1-[(2S,3R) 2-benzyloxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxylic acid 20 (84.5 mg). NMR (CDCl 3 , 6): 1.07 (3H, d, J=6Hz), 2.2-2.6 (2H, m), 2.8 3.2 (2H, m), 3.5-3.7 (1H, m), 3.9-4.1 (1H, m), 4.34 (1H, d, J=12Hz), 4.55 (1H, d, J=12Hz), 7.1-7.9 (14H, m) MS: 415 (M+H)* 25 Example 31 A mixture of 1-[ ( 2
S,
3 R)-2-benzyloxy-5-(-naphthyl)-3 pentyl]imidazole-4-carboxylic acid (obtained in Example 30) (55 mg), methanesulfonamide (12.7 mg), 4 -dimethylaminopyridine (24.3 mg), and 30 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (51.2 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature for three days. Ethyl acetate and water were added, and WO 00/05217 PCT/JP99/03939 65 the whole was acidified to pH 3 with hydrochloric acid. The organic layer was dried and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (20:1) to give a pale yellow gummy oil 5 of N-methylsulfonyl-1-[( 2
S,
3 R)-2-benzyloxy-5-(1-naphthyl)-3 pentyl]imidazole-4-carboxamide (18 mg). NMR (CDCl 3 , 3 ): 1.05 (3H, d, J=6Hz), 2.2-2.5 (2H, m), 2.8 3.1 (2H, m), 3.40 (3H, s), 3.6-3.7 (1H, m), 3.9-4.1 (1H, m), 4.2-4.6 (2H, m), 7.0-7.9 (14H, m) 10 MS: 490 (M-H) Example 32 N-methylsulfonyl-1-[( 2
S,
3 R)-2-hydroxy-5-(1-naphthyl)-3 pentyl]imidazole-4-carboxamide was prepared from the compound 15 obtained in Example 31 according to the procedure of Example 4. NMR (CDCl 3
+CD
3 0D, 6): 0.97 (3H, d, J=6Hz), 2.0-2.3 (2H, m), 2.7-3.1 (2H, m), 3.06 (3H, s), 3.8-4.1 (2H, m), 7.1-7.9 (9H, m) MS: 402 (M+H)* 20 Industrial Applicability The imidazole compounds of the present invention have ADA inhibitory activity and can thus elevate Ado concentration. Since Ado is effective for immunomodulation, especially immunosuppression, 25 antiinflammation and treatment and prevention of various diseases, the imidazole compounds of the present invention are useful for treating or preventing diseases for which Ado is effective.

Claims (11)

1. A compound of the formula 5 R4N ,,, N 10 Ri-A R3 (R) 2 wherein R is hydrogen, hydroxy, protected hydroxy, or aryl optionally substituted with suitable substituent(s); 15 R 2 is hydrogen or lower alkyl; R 3 is hydroxy or protected hydroxy; R 4 is cyano, (hydroxy)iminoamino(lower)alkyl, carboxy, protected carboxy, heterocyclic group optionally substituted with amino, or carbamoyl optionally substituted with suitable 20 substituent(s); and - A - is - Q - or -O-Q-, wherein Q is single bond or lower alkylene, provided that when R 2 is lower alkyl, then R 1 is hydroxy, protected hydroxy, or aryl optionally substituted with suitable substituent (s), 25 its prodrug, or their salt.
2. The compound according to claim 1, wherein R 1 is hydrogen, hydroxy, protected hydroxy, or aryl optionally substituted with suitable substituent(s) selected from 30 the group consisting of halo(lower)alkyl, halogen, hydroxy, protected carboxy, carbamoyl, lower alkylenedioxy, lower alkoxy WO 00/05217 PCT/JP99/03939 67 optionally substituted with aryl, and lower alkyl optionally substituted with hydroxy or protected carboxy; and R 4 is cyano, (hydroxy)iminoamino(lower)alkyl, carboxy, protected carboxy, heterocyclic group optionally substituted with amino, or 5 carbamoyl optionally substituted with suitable substituent(s) selected from the group consisting of amino, hydroxy, lower alkyl, lower alkylsulfonyl and aminoimino(lower)alkyl optionally substituted with hydroxy. 10
3. The compound according to claim 2, wherein R 1 is aryl optionally substituted with suitable substituent(s) selected from the group consisting of halo(lower)alkyl, halogen, hydroxy, protected carboxy, carbamoyl, lower alkylenedioxy, lower alkoxy optionally substituted with aryl, 15 and lower alkyl optionally substituted with hydroxy or protected carboxy; R 4 is carbamoyl optionally substituted with suitable substituent(s) selected from the group consisting of amino, hydroxy, lower alkyl, lower alkylsulfonyl and aminoimino(lower)alkyl optionally 20 substituted with hydroxy; and - A - is lower alkylene.
4. The compound according to claim 3, wherein R 1 is phenyl or naphthyl, each of which are optionally 25 substituted with suitable substituent(s) selected from the group consistingof halo(lower)alkyl, halogen, hydroxy, protected carboxy, carbamoyl, lower alkylenedioxy, lower alkoxy optionally substituted with aryl, and lower alkyl optionally substituted with hydroxy or protected carboxy; and 30 R 4 is carbamoyl. WO 00/05217 PCT/JP99/03939 68
5. The compound according to claim 2, which is a compound selected from the group consisting of: (1) 1-(l-hydroxy- 4 -phenyl-2-butyl)imidazole-4-carboxamide; (2) 1-[ ( 2 S)- 2 -hydroxy-5-phenyl-3-pentyl]imidazole-4-carboxamide; 5 (3) 1-[ ( 2 S, 3 R)-2-hydroxy-5-(2-benzyloxyphenyl) -3-pentyl]} imidazole-4-carboxamide; ( 4) 1-[ (2S, 3R )-2-hydroxy-5- (1-naphthyl )-3-pentyl ]imidazole-4 carboxamide; (5) 1-[ ( 2 S, 3 R)- 2 -hydroxy-5-(2-hexyloxyphenyl)-3-pentyl] 10 imidazole-4-carboxamide; (6) 1-[ (2S,3R)-2-hydroxy-5-(2-naphthyl)-3-pentyl]imidazole-4 carboxamide; (7) 1-[( 2 S, 3 R)- 2 -hydroxy-5-(2-chlorophenyl)-3-pentylimidazole 4-carboxamide; 15 (8) 1-[( 2 S, 3 R)-2-hydroxy-5-(2,3-dichlorophenyl)-3-pentyl] imidazole-4-carboxamide; (9) 1-[ ( 2 S, 3 R)- 2 -hydroxy-5-(l-naphthyl) -3-pentyl]imidazole-4 carbonylguanidine; and (10) 1-{( 2 S, 3 R)- 2 -hydroxy-5-[2-(3-phenylpropoxy)phenyl]-3 20 pentyl}imidazole-4-carboxamide.
6. A pharmaceutical composition comprising the compound of claim 1 as an active ingredient and a pharmaceutically acceptable, substantially non-toxic carrier or excipient. 25
7. A pharmaceutical composition having an adenosine deaminase inhibiting activity, which comprises the compound of claim 1 as an active ingredient and a pharmaceutically acceptable, substantially non-toxic carrier or excipient. 30
8. A method for inhibiting adenosine deaminase, which comprises administering the compound of claim 1 to a mammal in need of the WO 00/05217 PCT/JP99/03939 69 compound.
9. A process for producing the compound of claim 1, comprising reacting a compound of formula (III) 5 R4 N -]C (III) 10 wherein R 4 is as defined above, with a compound of formula (IV) Ri-A R3 (IV) 15 2 wherein R 1 , R 2 , R 3 , and A are as defined above, and X is hydroxy or a leaving group, provided that R 3 is not hydroxy. 20
10. A process for producing the compound of claim 1, comprising reacting a compound of the formula (II) R4 25 Ri-A OR' 30 wherein Rl and R 4 are as defined above and R' is a hydroxy protective group, with a reducing agent. 35
11. Use of the compound of claim 1 for preparing a medicament for treating and/or preventing autoimmune diseases; inflammatory WO 00/05217 PCT/JP99/03939 70 conditions; organ or tissue allo-or xeno-transplant rejection; various leukemias; or diseases that arise from, or are aggravated by, insufficient blood flow through a particular organ or portion thereof.
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AUPP4840A AUPP484098A0 (en) 1998-07-23 1998-07-23 Novel imidazole compounds
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AUPP7355A AUPP735598A0 (en) 1998-11-27 1998-11-27 Novel imidazole compounds
PCT/JP1999/003939 WO2000005217A1 (en) 1998-07-23 1999-07-22 Imidazole compounds and their use as adenosine deaminase inhibitors
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