WO2005030709A1 - Novel sulfone amide derivatives capable of inhibiting bace - Google Patents

Novel sulfone amide derivatives capable of inhibiting bace Download PDF

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Publication number
WO2005030709A1
WO2005030709A1 PCT/KR2004/002523 KR2004002523W WO2005030709A1 WO 2005030709 A1 WO2005030709 A1 WO 2005030709A1 KR 2004002523 W KR2004002523 W KR 2004002523W WO 2005030709 A1 WO2005030709 A1 WO 2005030709A1
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WIPO (PCT)
Prior art keywords
amino
methyl
hydroxy
benzamide
benzylsulfonyl
Prior art date
Application number
PCT/KR2004/002523
Other languages
French (fr)
Inventor
Yeong Soo Oh
Deog-Young Choi
Young Lag Cho
Sook Kyung Yoon
Sang Won Seo
Dongchul Lim
Kyeongsik Min
Tae-Soo Lee
Sun Hwa Lee
Kyung Ha Chung
Byeong Moon Kim
Sung Jin Bae
Jong Sun Lee
Dae-Won Lee
Moses Jeong
Original Assignee
Lg Life Sciences Ltd.
Promeditech, Inc.
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Application filed by Lg Life Sciences Ltd., Promeditech, Inc. filed Critical Lg Life Sciences Ltd.
Publication of WO2005030709A1 publication Critical patent/WO2005030709A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07C311/31—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
    • C07C311/35—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
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    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/44—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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Definitions

  • the present invention relates to sulfone amide derivatives of novel structure, having inhibitory activity versus ⁇ -amyloid precursor protein cleaving enzyme (BACE) or ⁇ -secretase.
  • Sulfone amide derivatives according to the present invention can be used for the treatment and prevention of Alzheimer's disease and related diseases caused by increased BACE function.
  • Alzheimer's disease is a neuronal disease which gradually progresses with age and accounts for 50 ⁇ 70% of all dementia patients.
  • the major symptoms of Alzheimer's disease include memory loss, decline in reasoning abilities and judgment, emotional outbursts and the like. Most Alzheimer's cases occur around age 65 and progress for about 9 years to result in the death of the patient.
  • the number of patients suffering from Alzheimer's disease is increasing as society develops and ages, so that it is estimated that there will be approximately 6 million patients in the U.S.A. within 10 years, and this number will further increase beyond that.
  • the proportion of elderly persons is increasing in developed societies, and thus social problems associated with increased prevalence of senile dementia are becoming more serious.
  • the disease characteristics require the drug to be administered continually over a long period, but these therapeutic agents accompany various undesirable side effects, including renal toxicity. Therefore, it is required to develop a new therapeutic agent which can halt and reverse progression of this Alzheimer's and related diseases. Therefore, many pharmaceutical companies have been investing heavily in research in this field, especially in the area of beta-secretase inhibitors being able to inhibit production of 42-amino acid beta-amyloid protein fragments, which form plaques assumed to be an essential pathological cause of Alzheimer's disease.
  • AD Alzheimer's disease
  • beta-amyloid and angiopathy are seen in the brain and cerebral blood vessels, respectively, and lesions such as a neurofibrillar tangles appear in brain cells. It is known that such lesions are commonly found in the brain of Alzheimer's patients exhibiting impaired memory and cognitive function, whereas a small amount thereof are found in the brain of healthy elderly people, not showing symptoms of Alzheimer's disease.
  • beta-amyloid deposits and angiopathy are also found in the brain of patients suffering from beta amyloidosis-related diseases such as Down's syndrome (Trisomy 21) and Hereditary Cerebral Hemorrhage, aside from Alzheimer's disease patients.
  • Beta-amyloid deposits are a representative symptom of Alzheimer's disease and are generally regarded as a major causative factor of the disease. Beta-amyloid peptide is a major component of the plaque deposits.
  • Various types of beta-amyloid precursor proteins (hereinafter, referred to as "APP") are known: for example, APP 695, APP 751 and APP 770, consisting of 695, 751 and 770 amino acids, respectively. Mutation of APP genes is known to cause the familial early onset AD.
  • Beta-amyloid proteins of 39 ⁇ 42 amino acids are produced from high molecular weight Amyloid Precursor Protein (APP) found in neuronal cells through serial cleavage by 3 types of protein secretases. This process occurs at the Golgi bodies of neuronal cells, wherein APP and secretase are anchored in the Golgi membrane.
  • APP Amyloid Precursor Protein
  • the N-terminus of beta-amyloid corresponds to the 99 th amino acid from C-terminus of APP, and this site is cleaved by beta-secretase.
  • the C-terminus of beta-amyloid buried inside the membrane is cleaved by the gamma secretase to produce the beta-amyloid protein which is then secreted from neuronal cells.
  • APP precursor may be cleaved at other sites via different routes; for example, where the middle site of beta-amyloid (between 16 th and 17 th amino acids from N-terminus) is cleaved by alpha-secretase, sAPP alpha having a high molecular weight is produced and secreted, and thus no beta-amyloids are produced.
  • Beta-amyloid proteins of a variety of lengths, mainly consisting of 40 and 42 amino acid residues may be produced by BACE and gamma-secretase. The beta- amyloid proteins of 40 and 42 amino acid residues are produced at a ratio of about 9 : 1 under normal conditions.
  • beta-amyloid protein fragment of 42 amino acid residues is produced from cultured neuronal cells and then secreted to the culture media, and this beta-amyloid can be differentially measured in the cerebrospinal fluid of normal and diseased brain (Seubert et al., Nature 359:325-327 (1992)).
  • the 42 beta-amyloid tends to easily aggregate and accelerates the generation of amyloid plaques in the brains of diseased patients, thereby gradually necrotizing the surrounding neuronal cells. This is assumed to be a major causative mechanism of Alzheimer's disease.
  • beta- and gamma-secretases are known as aspartic proteases and are anchored in membranes.
  • beta-secretase the gene thereof was identified through various methods and the in vivo activity of beta-secretase was reported in 1999 (Sinha et al. Nature 402:537-554). Furthermore, the X-ray crystal structure of beta- secretase has already been determined and a peptide inhibitor having strong affinity to beta-secretase is known. As well, it was reported that a gene knockout animal from which the gene has been removed exhibits normal characteristics, thereby suggesting that beta-secretase specific inhibitor can be developed as a more stable and efficient therapeutic agent.
  • an object of the present invention is to provide novel sulfone amide derivatives as represented by Formula 1 having high inhibitory activity versus BACE.
  • a further object of the present invention is to provide processes for preparation of these sulfone amide derivatives.
  • Another object of the present invention is to provide pharmaceutical compositions for inhibiting BACE activity comprising a therapeutically effective amount of these sulfone amide derivatives as an active agent.
  • Still another object of the present invention is to provide methods for treating and preventing Alzheimer's disease and related diseases caused by production of beta- amyloid, by the use of these sulfone amide derivatives of Formula 1 as an active agent.
  • alkyl group a group consisting of 1 to 10 carbon atoms, including linear or branched forms, being a saturated or unsaturated hydrocarbon group.
  • substituents include, for example, acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano, halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy, guanido, etc.
  • cycloalkyl group a ring structure including saturated or partially unsaturated hydrocarbon, and optionally including heteroatoms such as 0 to 5 of oxygen, sulfur, nitrogen.
  • Said ring has from triangle to dodecagon structures, and is a compound of a single ring or fused ring form.
  • One or more hydrogens can be substituted with substituents defined in the following, at all possible substitution positions without limitation to the order and kinds thereof.
  • Substituents include, for example, acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano, halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy, guanido, etc.
  • cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, morpholinyl, homomorpholinyl, thiomorpholinyl, homothiomorpholinyl, S- oxide(thiomorpholinyl S-oxide), S,S-dioxide(thiomorpholinyl S,S-dioxide), piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl
  • aryl group a group including all aromatic and heteroaromatic groups.
  • Said aromatic group is single ring or fused ring, and said ring is unsaturated hydrocarbons consisting of pentagon to 15-gon in form.
  • One or more hydrogens can be substituted with a group selected from the following: acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano, halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy, guanido.
  • Said heteroaromatic group is an aromatic group having heteroatoms such as 1 to 5 of oxygen, sulfur, nitrogen.
  • one or more hydrogens can be substituted with the group selected from among the following: acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano, halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy, guanido group.
  • aryl group are phenyl, 1- naphthyl, 2-naphthyl, pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolinyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, cinnolinyl, carbazolyl, is
  • N-methylmorpholine NMM - N,N-dimethyl formamide: DMF ⁇ 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide ⁇ :
  • EDC 1-hydroxybenzotriazole hydrate: HOBt - trifluoroacetic acid: TFA - t-butoxycarbonyl: Boc - benzyloxycarbonyl: Cbz - methyl: Me - ethyl: Et - equivalent: Eq
  • the present invention provides novel sulfone amide derivatives as represented by Formula 1 below having inhibitory activity versus BACE.
  • A means a substituent of the benzene ring, and is hydrogen, halogen, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted ester, substituted or unsubstituted amide, substituted or unsubstituted amine, substituted or unsubstituted alkoxy group.
  • Said substituted alkyl, ester, amide, amine and alkoxy group preferably includes ones substituted with halogen.
  • a preferable example of alkyl group substituted with halogen is trifluoromethyl group (-CF3).
  • Preferable examples of unsubstituted ester group are methyl ester group (-CO2-CH3) and benzyl ester group (- CO2-CH2-C6H5).
  • Preferable examples of said A itself or halogens as substituents of alkyl and the like are fluorine, chlorine and bromine.
  • "Ri” is a simple alkyl (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl (-SAC-Ar) substituted with aromatic, or hydrogen, and is preferably alkyl substituted with aromatic.
  • Rj and R 2 may form a ring structure of simple alkyl group form.
  • R 2 is a simple alkyl (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl (-SAC-Ar) substituted with aromatic, or hydrogen, and is preferably a simple alkyl group. As mentioned above, R ⁇ and R 2 may form a ring structure with simple alkyl group form.
  • R 3 is -SAC, alkyl substituted with double bond including allyl, -SCAC, -Ar, -SAC-Ar, hydrogen, or one of side chain residues of all native amino acids.
  • R 3 comprises carboxylie acid or base being side chain residues of amino acids, it also includes the case where a protective group such as a simple ester group is bonded thereto, and the case where it is in the form of pharmaceutically acceptable salts.
  • "X" is any one of substituents as represented by Formulas 2 to 4 below:
  • R 4 is each independently -SAC, alkyl substituted with double bond including allyl, -SCAC, -Ar, -SAC-Ar, hydrogen, or one of side chain residues of all native amino acids. Where the adjacent position becomes a chiral center depending upon the kind of t , both kinds of stereo isomers are included in the scope of R 4 definition, in which distereomeric compounds are also included.
  • R 4 comprises carboxylie acid or base being side chain residues of amino acids, it also includes the case where a protective group such as a simple ester group is bonded thereto, and the case where it is in the form of pharmaceutically acceptable salts.
  • Rt also includes specific cases as below.
  • R 5 is a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar), hydrogen, or one of side chain residues of all native amino acids.
  • R is a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar), or hydrogen.
  • R ⁇ may be groups as represented by Formula 5 or 6.
  • R is each independently a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar), hydrogen, or one of side chain residues of all native amino acids.
  • -SAC simple alkyl group
  • -SCAC cycloalkyl
  • -Ar aromatic alkyl substituted with aromatic
  • hydrogen or one of side chain residues of all native amino acids.
  • R 7 comprises carboxylie acid or base being side chain residues of amino acids, it also includes the case where a protective group such as a simple ester group is bonded thereto, and the case where it is in the form of pharmaceutically acceptable salts.
  • R 8 and R 9 are each independently a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar), alkyl substituted with aromatic which is substituted with carboxylie acid, or hydrogen.
  • Rio is each independently a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (- Ar), alkyl substituted with aromatic (-SAC-Ar), or hydrogen, and is preferably a simple alkyl group.
  • R ⁇ is each independently a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (- Ar), aromatic substituted with alkyl or alkoxy, heteroaromatic substituted with alkyl or alkoxy, or heterocycloalkyl substituted with alkoxy. Therefore, in the definition of the present disclosure (including claims) for sulfone amide derivatives of Formula 1, according to the present invention, salts and isomers thereof are all included. According to the definition of Formula 1 , sulfone amide derivatives according to the present invention can be any one of Formulas 7 to 9 below.
  • n, A, R ls R 2 , R 3 , Rt, R 5 , R ⁇ , Rio and R ⁇ are the same as in Formula 1.
  • the most preferable examples of sulfone amide derivatives according to the present invention include the compounds below:
  • the present invention also provides a process for the preparation of the sulfone amide derivatives of Formula 1.
  • Skilled persons having knowledge about synthesis of compounds in the art to which the present invention pertains could readily prepare the sulfone amide derivatives of Formula 1 according to the present invention, using known compounds, or readily preparable compounds therefrom. Therefore, the below description associated with preparation processes is provided only to disclose exemplary ones, and the order of preparation steps may be changed if necessary. As such, the scope of the present invention is not limited to only such preparation processes as described herein.
  • the process for preparation of the sulfone amide derivative (derivative of Formula 7) in which X in Formula 1 is the substituent of Formula 2 is described referring to Reaction Scheme 1 below.
  • the lactone compound (1) in which amino group is protected (BocNH-) is prepared using an amino acid according to the known method (J. Am. Chem. Soc. 2000, 122, 3522-3523).
  • the compound is reacted with lithium bis(trimethylsilyl)amide (preferably, 1.0 M) and iodomethane in anhydrous tetrahydrofurane solution to synthesize the alkyl-substituted lactone compound (2).
  • the lactone compound (2) is treated with lithium hydroxide solution (preferably 1.0 N)
  • O-protected carboxyl compound (3) can be obtained using imidazole and t- butyldimethylsilyl chloride.
  • Compound (3) is coupled with an amine to produce a compound (4), of which the protective group is then removed and coupled with a sulfone amide-substituted benzoic acid to synthesize the compound (5).
  • the O-protective group is removed to synthesize the desired compound (6).
  • the above benzoic acid substituted with sulfone amide (sulfone amide- substituted benzoic acid) can be prepared by the below procedure.
  • the sulfone amide-substituted benzoic acid for preparation of cyclic sulfone amide derivative can be synthesized by Reaction Scheme 2 below.
  • a commercially available ethyl-3-aminobenzoate (7) is reacted with 3- chloropropanesulfonyl chloride to synthesize ethyl- ⁇ bis [(3- chloropropyl)sulfonyl]amino ⁇ benzoate (8).
  • the compound (8) thus synthesized is reacted with sodium hydroxide solution (preferably 1 N) in N,N-dimethylformamide solvent to synthesize a cyclic compound (9) which is then reacted with lithium hydroxide solution (preferably 1 N) in a mixed solvent of tetrahydrofurane and methanol to produce a compound (10).
  • a sulfone amide-substituted benzoic acid for preparation of non- cyclic sulfone amide derivatives can be prepared by the process wherein an alkylsulfonylamino benzoate is synthesized using the compound (7) and alkyl sulfonyl chloride and then hydrolyzed with lithium hydroxide solution. Further, the process for preparation of the sulfone amide derivatives (derivatives of Formulas 8 and 9) in which X in Formula 1 is the substituent of Formula 3 or 4 is described referring to Reaction Scheme 3 below.
  • an epoxide compound (11) in which an amino group is protected (BocNH-) is prepared using an amino acid according to the known method Tetrahedron Letters 1999, 36, 5453-5456).
  • the compound (11) is reacted with the corresponding amine in isopropanol solution to synthesize a compound (12).
  • the protective group of the compound (12) is removed and then coupled with an alkylsulfonylamino benzoic acid to synthesize a compound (14) (compound of Formula 8).
  • the present invention provides a pharmaceutical composition for inhibiting BACE activity, more specifically, a composition for inhibiting beta-amyloid production, comprising a physiologically acceptable carrier and a therapeutically effective amount of sulfone amide derivatives of Formula 1.
  • the sulfone amide derivatives of Formula 1 can be formulated in various forms for pharmaceutical administration according to intended purposes.
  • an active agent specifically the sulfone amide derivative of Formula 1 is mixed with various physiologically acceptable carriers which can be selected according to desired formulation.
  • the active agent can be formulated into dosage forms suitable for injection, intradermal administration or oral administration, and preferably formulated into unit dosage form in aspect of ease of administration and uniformity of dosage amount.
  • conventional physiological carriers can be used for preparation of the formulation for oral administration.
  • water, glycol, oil and alcohol can be used as a carrier in case of oral aqueous formulations such as suspension, syrup, elixir solution; and starch, sugar, kaoline, lubricant, coupling agent and disintegrants can be used in case of solid formulations such as powder, pills, capsules and tablets.
  • the tablet and capsules are the most convenient administration manner due to the ease of administration, and preferably, tablets and pills are formulated in enteric coating form.
  • sterilized water is conventionally used as a carrier and may contain other components such as aqueous adjuvant.
  • water-in-oil or oil-in-water suspensions can be formulated using dispersion agent, wetting agent or suspension agent, according to known methods.
  • a solvent that can be used herein is water, Ringer's solution, isotonic NaCl solution and the like, and sterilized fixation oil solvent is conventionally used as a solvent or suspension medium. Any non-stimulative fixation oil, including mono- and di-glycerides, can be used for this purpose, and also fatty acid such as aleic acid can be used for the formulation for injection administration.
  • transdermal formulation for transdermal administration, penetration- facilitating agent and/or proper wetting agent as a carrier can be used together with suitable additives being non-irritating to skin.
  • suitable additives compounds facilitating administration via skin and/or facilitating the preparation of a desired composition are selected.
  • the transdermal formulation is administered in various manners such as transdermal patch, cream or ointments.
  • the composition in accordance with the present invention can be made in a sustained release form, and carriers therefor include implant, microencapsulated delivery system, biodegradable/biocompatible polymers and the like which are known in the art.
  • Said "therapeutically effective amount” means the amount of active agents effective for relieving or reducing symptoms and clinical markers for disease requiring prevention or treatment, and delaying the onset of symptoms.
  • Therapeutically effective amounts can be determined empirically using known in vivo and in vitro model systems for the disease requiring treatment.
  • the active agent specifically the sulfone amide derivative of Formula 1
  • the total 1-day amount administered via single or multiple doses is preferably in the range of 0.1 ⁇ 100 mg per 1 kg by weight; however, the level of specific amount administered to a specific patient can be altered depending upon the kind of compound used, weight of patient, sex, health condition, food, administration time, method of administration, rate of excretion, mixture of pharmaceuticals and seriousness of disease.
  • the sulfone amide derivative of Formula 1 can be used in formulation of pharmaceutical compositions in which the derivative is present in the form of a prodrug thereof.
  • pharmaceutically acceptable salts are included in the sulfone amide derivatives as represented by Formula 1, wherein said salts are not particularly limited so long as the salt can maintain the activity of the therapeutic compound in vivo and the salt does not cause undesirable effects.
  • salts include inorganic salts and organic salts, and preferably include, for example, acetic, nitric, aspartic, sulfonic, sulfuric, maleic, glutamic, formic, succinic, phosphoric, phthalic, tannic, tartaric, hydrobromic, propionic, benzenesulfonic, benzoic, stearic, esyl, lactic, bicarbonic, bisulfuric, bitartaric, oxalic, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, toluenesulfonic, edisylic, esylic, fumaric, gluceptic, pamoic, gluconic, glycollylarsanilic, methylnitric, polygalactouronic, hexylresorcinoic, malonic, hydrabamic, hydrochloric, hydroiodic, hydroxyn
  • the BACE-inhibiting composition according to the present invention may further contain any other components which do not inhibit the function of the active agent or which support the function of active agent, and also the composition may be formulated in various manners well known in the art.
  • the present invention provides a method for treatment or prevention of diseases caused by production of beta-amyloid using the sulfone amide derivative of Formula 1 as an active agent.
  • a representative example of diseases caused by production of said beta-amyloid is Alzheimer's disease as mentioned previously, but is not limited thereto, and also includes diseases associated with Alzheimer's disease such as Down's syndrome, and Hereditary Cerebral Hemorrhage and the like.
  • the sulfone amide derivative of Formula 1 in accordance with the present invention when administered to human patients in an effective amount, it inhibits the function of BACE (or beta-secretase) to inhibit the production of beta-amyloid caused by the enzymatic function of BACE, whereby it is effective for the treatment or prevention of Alzheimer's disease and related diseases.
  • Said “treatment” means halting or slowing of disease progression when it is used for treatment of patients showing disease symptoms; and said “prevention” means prevention of the development of disease symptoms when used to treat a patient not showing symptoms but having a high possibility of developing such symptoms.
  • FIG. 1 is a graph showing the relation between drug concentration versus time after oral administration of the compounds obtained in EXAMPLES 88 and 89 (Compounds 1 and 2) and the known compound (Compound 3) to mice.
  • the mixture was diluted with water, and acidified using 25% citric acid, then eluted by ethyl acetate, followed by washing with sodium chloride solution. After removing solvent by distillation under reduced pressure below room temperature, the residue was dissolved in 10 ml of N,N-dimethylformamide, and 1.32 g (19.34 mmol) of imidazole and 1.46 g (9.67 mmol) of t-butyldimethylsilyl chloride were added thereto, followed by stirring overnight.
  • the compound obtained by distillation under reduced pressure was dissolved in 50 ml of N,N-dimethylformamide, and 1.0 N of sodium hydroxide solution was added thereto, followed by stirring for 2 hours. After removing solvent by distillation under reduced pressure, the residue was acidified using 1.0 N of hydrochloride solution and eluted by ethyl acetate, then washed with sodium chloride solution. After removing solvent by distillation under reduced pressure, the residue was purified by column chromatography using a 1 :3 mixture of ethyl acetate and hexane to obtain 2.5 g of the title compound at 92% yield.
  • Preparation Example 16 Preparation of N- lS)-3-methyl-l-rr2i?.4i?V4-methyl-5-oxotetrahvdro-2- furanv ⁇ butylj-S-ffpropylsulfony ⁇ aminolbenzamide A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 15 instead of the compound obtained in Preparation Example 4, whereby 0.38 g of the title compound was obtained at 93% yield.
  • a compound obtained after removing solvent by distillation under reduced pressure was dissolved in 35 ml of tetrahydrofurane, 7 ml of methanol and 21 ml of 1.0 N lithium hydroxide solution, then stirred for 5 hours. After removing solvent by distillation under reduced pressure, the residue was diluted with water, and the solid produced by acidification using 1.0 N hydrochloride solution was filtered to obtain 1.74 g of the title compound at 99% yield.
  • Preparation Example 34 Preparation of 3-rethylfpropylsulfonvnaminol-N-lf lS -3 -methyl- 1 -r(2fl,4i?)-4-methyl- 5-oxotetrahvdro-2-furanvHbutyl ⁇ benzamide A process was conducted in the same manner as in Preparation Example 5 except for using the compound obtained in Preparation Example 33 instead of the compound obtained in Preparation Example 4, whereby 0.18 g of the title compound was obtained at 83% yield.
  • Preparation Example 42 Preparation of 3-rbenzylfpropylsulfonvnaminol-N-((lS)-3-methyl-l-rf2i?.4i?V4- methyl-5-oxotetrahvdro-2-furanyl1butvUbenzamide A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 41 instead of the compound obtained in Preparation Example 4, whereby 0.21 g of the title compound was obtained at 85% yield.
  • Preparation Example 50 Preparation of ethyl 3-[(butylsulfonyl aminolbenzoate A process was conducted in the same manner as in Preparation Example 19, except for using 1-butanesulfonylchloride instead of benzenesulfonylchloride, whereby 1.08 g of the title compound was obtained at 76% yield.
  • Preparation Example 57 Preparation of S-rrbenzylsulfonvnfmethvnaminol-N-i ⁇ -S-methyl-l- ⁇ i? ⁇ /? ⁇ - methyl-5-oxotetrahvdro-2-furanyllbutyl ⁇ benzamide A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 56 instead of the compound obtained in Preparation Example 4, whereby 0.2 g of the title compound was obtained at 83 % yield.
  • Preparation Example 70 Preparation of 3-[methyl(2-naphthylsulfonyDamino]benzoic acid A process was conducted in the same manner as in Preparation Example 29, except for using the compound obtained in Preparation Example 69 instead of the compound obtained in Preparation Example 14, whereby 0.17 g of the title compound was obtained at 99% yield.
  • IH NMR 400 MHz, CDC1 3 ); 8.21 (IH, s), 8.01 (IH, d), 7.90 (3H, t), 7.76 (IH, s), 7.68-
  • Preparation Example 74 Preparation of 3-[ ⁇ [2-(acetylamino)-4-methyl-l,3-thiazol-5- yl] sulfonyl ⁇ (methvPamino]benzoic acid A process was conducted in the same manner as in Preparation Example 29, except for using the compound obtained in Preparation Example 73 instead of the compound obtained in Preparation Example 14, whereby 0.12 g of the title compound was obtained at 75% yield.
  • the reaction was terminated using saturated ammonium chloride solution, then the solvent was removed by distillation under reduced pressure, followed by eluting with ethylacetate and washing with sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 1 :2 mixture of ethyl acetate and hexane to obtain 0.72 g of the title compound at 13% yield.
  • Preparation Example 85 Preparation of tert-butyl (lS,2S.4S)-4-r( ⁇ (lS)-l-r(benzylamino')carbonyll-2- methylpropyl ⁇ amino)carbonyll-2-hydroxy-l-isobutyl-5-methylhexylcarbamate A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 84 instead of the compound obtained in Preparation Example 12, whereby 63 mg of the title compound was obtained at 79% yield.
  • Example 25 whereby 10 mg of the title compound was obtained at 100% yield.
  • Example 32 Preparation of N-l(lS.2S.4 ⁇ V5-(((lS)-l-r(benzylamino)carbonyl1-2- methylpropyl ⁇ amino)-2-hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[methyl(2- thienylsulfonyPaminolbenzamide
  • a process was conducted in the same manner as in Example 21, except for using the compound obtained in Preparation Example 65 instead of the compound obtained in Preparation Example 56, whereby 38 mg of the title compound was obtained at 57% yield.
  • Example 34 Preparation of N-r(lS,2S.4igV5-( S)-l-r(ber ⁇ zylaminofcarbonyll-2- methylpropyl)amino -2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyl1-3- rmethyl(propylsulfonvPamino]benzamide
  • a process was conducted in the same manner as in Example 21, except for using the compound obtained in Preparation Example 29 instead of the compound obtained in Preparation Example 56, whereby 45 mg of the title compound was obtained at 71% yield.
  • Example 36 Preparation of . N- ⁇ (l S.2SAR)-5-(i (1S)-1- Kbenzylaminolcarbonyll -2- methylpropyl ⁇ amino -2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonyP(methvPamino1-5-(trifluoromethvPbenzamide A process was conducted in the same manner as in Example 21, except for using 3-[(benzylsulfonyl)(methyl)amino]-5-(trifluoromethyl)benzoic acid instead of the compound obtained in Preparation Example 56, whereby 17 mg of the title compound was obtained at 55% yield.
  • Example 51 Preparation of 3-rr(2-aminobenzyPsulfonyll(methvPaminol-N-r(lS.2S.4i?)-5-( ⁇ (lS)-l - [(benzylamino)carbonyll -2-methylpropyl I amino -2-hydroxy- 1 -isobutyl-4-methyl-5- oxopentyllbenzamide
  • a process was conducted in the same manner as in Example 39, except for using the compound obtained in Example 50 instead of the compound obtained in Example 38, whereby 8 mg of the title compound was obtained at 80% yield.
  • Preparation Example 100 Preparation of tert-butyl dS)-l-((2i?)-4-r(E)ethylidenel-5-oxotetrahvdro-2-furanyll-3- methylbutylcarbamate A process was conducted in the same manner as in Preparation Example 79, except for using the compound obtained in Preparation Example 99 instead of the compound obtained in Preparation Example 78, whereby 0.33 g of the title compound was obtained at 25% yield.
  • Example 62 whereby 20 mg of the title compound was obtained at 63% yield.
  • IH ⁇ MR 400 MHz, CD 3 OD
  • 7.77 IH, s
  • 7.71 IH, m
  • 7.45-7.18 (12H, m)
  • 4.45 2H, s
  • 4.35 2H, dd
  • 4.23-4.12 2H, m
  • 3.61 IH, m
  • 3.25 3H, s
  • 2.75 (IH, m) 1.90-1.58
  • Example 59 whereby 60 mg of the title compound was obtained at 91% yield.
  • Preparation Example 113 Preparation of tert-butyl 1 -f (benzylamino carbonyllcyclopentylcarbamate A process was conducted in the same manner as in Preparation Example 75, except for using l-[(t-butoxycarbonyl)amino]cyclopentancarboxylic acid instead of t- butoxycarbonyl (S)-valine, whereby 133 mg of the title compound was obtained at 48% yield.
  • Example 75 Preparation of 4-( ⁇ [(2J?.4S,5S -5-( ⁇ 3-[(benzylsulfonvP(methyPamino1benzoyl ⁇ amino)- 4-hvdroxy-2,7-dimethyloctanoyl]amino ⁇ methvPcvclohexanecarboxylic acid
  • a process was conducted in the same manner as in Example 60, except for using the compound obtained in Example 74 instead of the compound obtained in Example 59, whereby 36 mg of the title compound was obtained at 80%> yield.
  • Example 59 whereby 61 mg of the title compound was obtained at 87%) yield.
  • Preparation Example 122 Preparation of methyl 3-[(tert-butoxycarbonvPamino]cvclohexanecarboxylate A process was conducted in the same manner as in Preparation Example 118, except for using 3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid instead of trans-4- ⁇ [(tert-butoxycarbonyl)amino]methyl ⁇ cyclohexanecarboxylic acid, whereby 0.44 g of the title compound was obtained at 90%) yield.
  • Example 79 Preparation of 3- ⁇ [(2i-,4S,5S)-5-( ⁇ 3-[(benzylsulfonvP(methypamino]benzoyl ⁇ amino)- 4-hydroxy-2 ,7-dimethyloctano yll amino ) cyclohexanecarboxylic acid A process was conducted in the same manner as in Example 60, except for using the compound obtained in Example 78 instead of the compound obtained in Example 59, whereby 60 mg of the title compound was obtained at 86% yield.
  • Example 59 whereby 49 mg of the title compound was obtained at 96%> yield.

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Abstract

The present invention relates to novel derivatives of sulfone amide of Formula 1 as defined in this disclosure which inhibit the activity of BACE (or beta-secretase). These sulfone amide derivatives are useful for the treatment and prevention of Alzheimer's disease and related diseases caused by production of beta-amyloid, by inhibiting the activity of BACE.

Description

Novel Sulfone Amide Derivatives Capable Of Inhibiting
BACE
FIELD OF THE INVENTION The present invention relates to sulfone amide derivatives of novel structure, having inhibitory activity versus β -amyloid precursor protein cleaving enzyme (BACE) or β-secretase. Sulfone amide derivatives according to the present invention can be used for the treatment and prevention of Alzheimer's disease and related diseases caused by increased BACE function.
BACKGROUND OF THE INVENTION
Alzheimer's disease (Senile dementia) is a neuronal disease which gradually progresses with age and accounts for 50 ~ 70% of all dementia patients. The major symptoms of Alzheimer's disease include memory loss, decline in reasoning abilities and judgment, emotional outbursts and the like. Most Alzheimer's cases occur around age 65 and progress for about 9 years to result in the death of the patient. The number of patients suffering from Alzheimer's disease is increasing as society develops and ages, so that it is estimated that there will be approximately 6 million patients in the U.S.A. within 10 years, and this number will further increase beyond that. Likewise, the proportion of elderly persons is increasing in developed societies, and thus social problems associated with increased prevalence of senile dementia are becoming more serious. However, no therapeutic agent that can treat the essential pathogenic cause of Alzheimer's disease has yet been developed. Until now, acetylcholine esterase inhibitors have been used as a general therapeutic agent. Aricept (trade name) from Pfizer, Exelon (trade name) from Novartis, and Reminyl (trade name) from Janssen are known as representative examples of acetylcholine esterase inhibitors. However, these drugs cannot be strictly defined as therapeutic agents of Alzheimer's disease, because they do not treat the essential pathogenic cause thereof and result in only partial recovery from the disease in some patients (about 40 ~ 50%), and their efficacy is seen for a limited time period only. In addition, the disease characteristics require the drug to be administered continually over a long period, but these therapeutic agents accompany various undesirable side effects, including renal toxicity. Therefore, it is required to develop a new therapeutic agent which can halt and reverse progression of this Alzheimer's and related diseases. Therefore, many pharmaceutical companies have been investing heavily in research in this field, especially in the area of beta-secretase inhibitors being able to inhibit production of 42-amino acid beta-amyloid protein fragments, which form plaques assumed to be an essential pathological cause of Alzheimer's disease. In patients suffering from Alzheimer's disease (hereinafter, sometimes referred to as "AD"), abnormal deposits of beta-amyloid and angiopathy are seen in the brain and cerebral blood vessels, respectively, and lesions such as a neurofibrillar tangles appear in brain cells. It is known that such lesions are commonly found in the brain of Alzheimer's patients exhibiting impaired memory and cognitive function, whereas a small amount thereof are found in the brain of healthy elderly people, not showing symptoms of Alzheimer's disease. Such beta-amyloid deposits and angiopathy are also found in the brain of patients suffering from beta amyloidosis-related diseases such as Down's syndrome (Trisomy 21) and Hereditary Cerebral Hemorrhage, aside from Alzheimer's disease patients. Beta-amyloid deposits are a representative symptom of Alzheimer's disease and are generally regarded as a major causative factor of the disease. Beta-amyloid peptide is a major component of the plaque deposits. Various types of beta-amyloid precursor proteins (hereinafter, referred to as "APP") are known: for example, APP 695, APP 751 and APP 770, consisting of 695, 751 and 770 amino acids, respectively. Mutation of APP genes is known to cause the familial early onset AD. For instance, there is Swedish (SW) mutation in which the 595th amino acid, Lys, and the 596th amino acid, Met, are th substituted with Asp and Leu, respectively, and the 717 amino acid, Val, is substituted with Gly, He, Phe and the like. Beta-amyloid proteins of 39 ~ 42 amino acids are produced from high molecular weight Amyloid Precursor Protein (APP) found in neuronal cells through serial cleavage by 3 types of protein secretases. This process occurs at the Golgi bodies of neuronal cells, wherein APP and secretase are anchored in the Golgi membrane. The N-terminus of beta-amyloid corresponds to the 99th amino acid from C-terminus of APP, and this site is cleaved by beta-secretase. The C-terminus of beta-amyloid buried inside the membrane is cleaved by the gamma secretase to produce the beta-amyloid protein which is then secreted from neuronal cells. APP precursor may be cleaved at other sites via different routes; for example, where the middle site of beta-amyloid (between 16th and 17th amino acids from N-terminus) is cleaved by alpha-secretase, sAPP alpha having a high molecular weight is produced and secreted, and thus no beta-amyloids are produced. Beta-amyloid proteins of a variety of lengths, mainly consisting of 40 and 42 amino acid residues, may be produced by BACE and gamma-secretase. The beta- amyloid proteins of 40 and 42 amino acid residues are produced at a ratio of about 9 : 1 under normal conditions. It was found that the beta-amyloid protein fragment of 42 amino acid residues is produced from cultured neuronal cells and then secreted to the culture media, and this beta-amyloid can be differentially measured in the cerebrospinal fluid of normal and diseased brain (Seubert et al., Nature 359:325-327 (1992)). In comparison with the 40 beta-amyloid, the 42 beta-amyloid tends to easily aggregate and accelerates the generation of amyloid plaques in the brains of diseased patients, thereby gradually necrotizing the surrounding neuronal cells. This is assumed to be a major causative mechanism of Alzheimer's disease. It is also known that where levels of 40 and 42 beta-amyloid proteins are increased or where levels of 42 beta-amyloid are selectively increased by the mutation of Presenilin 1 & 2 genes, onset of Alzheimer's disease is further accelerated and the symptoms of the disease are more severe (Selkoe et al., Neuron 6:487 (1991)). Therefore, it is assumed that the treatment of Alzheimer's disease may be possible by decreasing the production of 42 beta-amyloid, and beta- or gamma-secretase inhibitors may be prospective candidates as therapeutic agents for treatment of Alzheimer's disease. The beta- and gamma-secretases are known as aspartic proteases and are anchored in membranes. However, no gene coding for a gamma-secretase inhibitor has yet been identified. Further, it is known that substrates for gamma-secretase are not limited to APP, but that the enzyme also participates in the cleavage of Notch protein, which is known to play a key role in cell-cycle control. In particular, gene knockout animals from which the gamma-secretase gene has been removed die in utero, and recent clinical tests of gamma-secretase inhibitors showed considerable toxicity; thus gamma-secretase inhibitors are not promising drug candidates. As a result, it has not yet been confirmed whether gamma-secretase inhibitors can be developed as safe therapeutic agents against Alzheimer's disease. On the other hand, in case of beta-secretase, the gene thereof was identified through various methods and the in vivo activity of beta-secretase was reported in 1999 (Sinha et al. Nature 402:537-554). Furthermore, the X-ray crystal structure of beta- secretase has already been determined and a peptide inhibitor having strong affinity to beta-secretase is known. As well, it was reported that a gene knockout animal from which the gene has been removed exhibits normal characteristics, thereby suggesting that beta-secretase specific inhibitor can be developed as a more stable and efficient therapeutic agent. Attempts to treat Alzheimer's disease by inhibiting beta-secretase are recent, and in this connection, most such inhibitors consist of peptide linkage elements using native amino acids (Ghosh et al. J. Am. Chem. Soc. 122:3522-3523, Ghosh et al. J. Med. Chem. 44:2865-2868, Tung et. al. J. Med. Chem. 45:259-262). However, an advanced inhibitor in which the N-terminus and C-terminus differ from those of native amino acids was reported by Elan Pharmaceutical Company in the U.S. More specifically, the N-terminus consists of a peptide bond using isophthalic acid, and the C-terminus consists of a non-peptide bond using benzylamine.
SUMMARY OF THE INVENTION
The inventors of the present invention synthesized novel compounds different from known inhibitor compounds and measured the binding strength thereof to BACE, in which the chemical structures thereof were designed to allow the compounds to have a high selectivity to specific enzymes, and found that the compounds as represented by Formula 1 below are suitable for the requirements desired in the present invention. The present invention was accomplished on the basis of such finding. Therefore, an object of the present invention is to provide novel sulfone amide derivatives as represented by Formula 1 having high inhibitory activity versus BACE. A further object of the present invention is to provide processes for preparation of these sulfone amide derivatives. Another object of the present invention is to provide pharmaceutical compositions for inhibiting BACE activity comprising a therapeutically effective amount of these sulfone amide derivatives as an active agent. Still another object of the present invention is to provide methods for treating and preventing Alzheimer's disease and related diseases caused by production of beta- amyloid, by the use of these sulfone amide derivatives of Formula 1 as an active agent.
DETAILED DESCRIPTION OF THE INVENTION
Before providing the detailed description of the present invention, some terms used in the present disclosure are briefly explained below. a) alkyl group: a group consisting of 1 to 10 carbon atoms, including linear or branched forms, being a saturated or unsaturated hydrocarbon group. One or several hydrogens can be substituted with substituents as described hereinafter, at all possible substitution positions without limitation to the order and kinds thereof. Said substituents include, for example, acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano, halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy, guanido, etc. b) cycloalkyl group: a ring structure including saturated or partially unsaturated hydrocarbon, and optionally including heteroatoms such as 0 to 5 of oxygen, sulfur, nitrogen. Said ring has from triangle to dodecagon structures, and is a compound of a single ring or fused ring form. One or more hydrogens can be substituted with substituents defined in the following, at all possible substitution positions without limitation to the order and kinds thereof. Substituents include, for example, acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano, halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy, guanido, etc. The concrete examples of said cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, morpholinyl, homomorpholinyl, thiomorpholinyl, homothiomorpholinyl, S- oxide(thiomorpholinyl S-oxide), S,S-dioxide(thiomorpholinyl S,S-dioxide), piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, etc. c) aryl group : a group including all aromatic and heteroaromatic groups. Said aromatic group is single ring or fused ring, and said ring is unsaturated hydrocarbons consisting of pentagon to 15-gon in form. One or more hydrogens can be substituted with a group selected from the following: acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano, halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy, guanido. Said heteroaromatic group is an aromatic group having heteroatoms such as 1 to 5 of oxygen, sulfur, nitrogen. Also, one or more hydrogens can be substituted with the group selected from among the following: acyl, amino, carboalkoxy, carboxy, carboxyamino, cyano, halo, hydroxy, nitro, thio, alkyl, cycloalkyl, alkoxy, aryloxy, sulfoxy, guanido group. The examples of said aryl group are phenyl, 1- naphthyl, 2-naphthyl, pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolinyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, cinnolinyl, carbazolyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiopyranyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl-N- oxide, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyrazinyl-N-oxide, quinolinyl-N-oxide, indolyl-N-oxide, indolinyl-N-oxide, pyrazinyl-N-oxide, isoquinolyl-N-oxide, qunazolinyl-N-oxide, quinoxalinyl-N-oxide, N-phthalazinyl-N- oxide, imidazolinyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide, thiazolyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N- oxide, pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide . For the convenience of explanation, some terms freqeuntly used in present disclosure are abbrieviated as the below. - N-methylmorpholine: NMM - N,N-dimethyl formamide: DMF { 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide} : EDC - 1-hydroxybenzotriazole hydrate: HOBt - trifluoroacetic acid: TFA - t-butoxycarbonyl: Boc - benzyloxycarbonyl: Cbz - methyl: Me - ethyl: Et - equivalent: Eq
The present invention provides novel sulfone amide derivatives as represented by Formula 1 below having inhibitory activity versus BACE.
Formula 1
Figure imgf000011_0001
wherein, the detailed definitions of substituents are described below. (I) "A" means a substituent of the benzene ring, and is hydrogen, halogen, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted ester, substituted or unsubstituted amide, substituted or unsubstituted amine, substituted or unsubstituted alkoxy group. Said substituted alkyl, ester, amide, amine and alkoxy group preferably includes ones substituted with halogen. A preferable example of alkyl group substituted with halogen is trifluoromethyl group (-CF3). Preferable examples of unsubstituted ester group are methyl ester group (-CO2-CH3) and benzyl ester group (- CO2-CH2-C6H5). Preferable examples of said A itself or halogens as substituents of alkyl and the like are fluorine, chlorine and bromine. (II) "Ri" is a simple alkyl (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl (-SAC-Ar) substituted with aromatic, or hydrogen, and is preferably alkyl substituted with aromatic. In addition, Rj and R2 may form a ring structure of simple alkyl group form. (III) "R2" is a simple alkyl (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl (-SAC-Ar) substituted with aromatic, or hydrogen, and is preferably a simple alkyl group. As mentioned above, R\ and R2 may form a ring structure with simple alkyl group form. (IV) "R3" is -SAC, alkyl substituted with double bond including allyl, -SCAC, -Ar, -SAC-Ar, hydrogen, or one of side chain residues of all native amino acids. Where the adjacent position becomes a chiral center depending upon the kind of R3, both kinds of stereo isomers are included in the scope of R3 definition, in which distereomeric compounds are also included. Where R3 comprises carboxylie acid or base being side chain residues of amino acids, it also includes the case where a protective group such as a simple ester group is bonded thereto, and the case where it is in the form of pharmaceutically acceptable salts. (V) "X" is any one of substituents as represented by Formulas 2 to 4 below: Formula 2
Figure imgf000013_0001
Formula 3
Figure imgf000013_0002
Formula 4
Figure imgf000013_0003
wherein, n is 0 or 1. R4 is each independently -SAC, alkyl substituted with double bond including allyl, -SCAC, -Ar, -SAC-Ar, hydrogen, or one of side chain residues of all native amino acids. Where the adjacent position becomes a chiral center depending upon the kind of t, both kinds of stereo isomers are included in the scope of R4 definition, in which distereomeric compounds are also included. Where R4 comprises carboxylie acid or base being side chain residues of amino acids, it also includes the case where a protective group such as a simple ester group is bonded thereto, and the case where it is in the form of pharmaceutically acceptable salts. Rt also includes specific cases as below. That is, -(CH2)nOR (R = -SAC, -SCAC, -Ar, -SAC-Ar: n = 1, 2) and - (CH2)nOC(=O)R (R = -SAC, -SCAC, -Ar, -SAC-Ar: n = 1, 2). R5 is a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar), hydrogen, or one of side chain residues of all native amino acids. R is a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar), or hydrogen. In addition, Rβ may be groups as represented by Formula 5 or 6.
Formula 5
Figure imgf000014_0001
wherein, R is each independently a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar), hydrogen, or one of side chain residues of all native amino acids. Where the adjacent position becomes a chiral center depending upon the kind of R7, both kinds of stereo isomers are included in the scope of R7 definition, in which distereomeric compounds are also included. Where R comprises carboxylie acid or base being side chain residues of amino acids, it also includes the case where a protective group such as a simple ester group is bonded thereto, and the case where it is in the form of pharmaceutically acceptable salts. R8 and R9 are each independently a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar), alkyl substituted with aromatic which is substituted with carboxylie acid, or hydrogen. Rio is each independently a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (- Ar), alkyl substituted with aromatic (-SAC-Ar), or hydrogen, and is preferably a simple alkyl group. Rπ is each independently a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (- Ar), aromatic substituted with alkyl or alkoxy, heteroaromatic substituted with alkyl or alkoxy, or heterocycloalkyl substituted with alkoxy. Therefore, in the definition of the present disclosure (including claims) for sulfone amide derivatives of Formula 1, according to the present invention, salts and isomers thereof are all included. According to the definition of Formula 1 , sulfone amide derivatives according to the present invention can be any one of Formulas 7 to 9 below.
Formula 7
Figure imgf000016_0001
Formula 8
Figure imgf000016_0002
Formula 9
Figure imgf000016_0003
wherein, n, A, Rls R2, R3, Rt, R5, R^, Rio and Rπ are the same as in Formula 1. The most preferable examples of sulfone amide derivatives according to the present invention include the compounds below:
(1) 4-[({(2S)-2-[((2i?,4S,5S)-5-{[3-(l,l-dioxo-116-isothiazolidin-2- yl)benzoyl] amino} -4-hydroxy-2,7- dimethyloctanoyl)amino]propanoyl } amino)methyl]benzoic acid
(2) N-(( 1 S,2S,4J?)-5- { [( 1 S)-2-(benzylamino)- 1 -methyl-2-oxoethyl] amino } -2- hydroxy- 1 -isobutyl -4-methyl-5-oxopentyl)- 1 -methyl-2,2,4-trioxo- 1 ,2,3 ,4-tetrahydro- 2λ6, 1 -benzothiazine-7-carboxamide. (3) 4-{[((2S)-2-{[(2i-,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3-
[(propylsulfonyl)amino]benzoyl } amino)octanoyl] amino } propanoyl)amino] methyl } benz oic acid
(4) 4-{[((2S)-2-{[(2i-,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3-
[(phenylsulfonyl)amino]benzoyl}amino)octanoyl]amino}propanoyl)amino]methyl}benz oic acid.
(5) 4-{[((2S)-2-{[(2i?,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3-[(2- thienylsulfony l)amino]benzoyl } amino)octanoyl] amino } propanoy l)amino] methyl } benzo ic acid (6) 4-{[((2S)-2-{[(2i?,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3-
[methyl(propylsulfony l)amino]benzoyl } amino)octanoyl] amino } propanoy l)amino] meth yl} benzoic acid
(7) 4-{[((2S)-2-{[(2i?,4S,5S)-5-({3-[ethyl(propylsulfonyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}propanoyl)amino]methyl}benzoic acid (8) 4-{[((2S)-2-{[(2i?,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3-
[propyl(propylsulfonyl)amino] benzoyl } amino)octanoyl] amino } propanoyl)amino] methy
1} benzoic acid.
(9) 4-{[((2S)-2-{[(2i-,4S,5S)-5-({3-[benzyl(propylsulfonyl)amino]benzoyl}amino)-
4-hydroxy-2,7-dimethyloctanoyl] amino } propanoy l)amino] methyl } benzoic acid (10) 4-{[((2S)-2-{[(2i?,4S,5S)-5-({3-[(ethylsulfonyl)(methyl)amino]benzoyl}amino)-
4-hydroxy-2,7-dimethyloctanoyl]amino}propanoyl)amino]methyl}benzoic acid
(11) 4-{[((2S)-2-{[(2i?,4S,5S)-5-({3-
[(butylsulfonyl)(methyl)amino]benzoyl } amino)-4-hydroxy-2,7- dimethyloctanoyl] amino } propanoyl)amino] methyl } benzoic acid (12) 4-{[((2S)-2-{[(2i?,4S,5S)-5-({3-
[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7- dimethyloctanoyl] amino } propanoyl)amino]methyl } benzoic acid
(13) 4-[({(2S)-2-[((2i?,4S,5S)-4-hydroxy-2,7-dimethyl-5-{[3-(methyl{[2-(l- naphthyl)ethyl] sulfonyl } amino)benzoyl] amino } octanoyl)amino]propanoyl } amino)meth yfjbenzoic acid
(14) N-(( 1 S,2S,4i?)-5 - { [( 1 S)-2-(benzylamino)- 1 -methyl-2-oxoethyl] amino } -2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl)-3-[methyl(2- thienylsulfonyl)amino] benzamide (15) N-(( 1 S,2S,4i?)-5- { [( 1 S)-2-(benzylamino)- 1 -methyl-2-oxoethyl] amino } -2-hydroxy- l-isobutyl-4-methyl-5-oxopentyl)-3-[methyl(phenylsulfonyl)amino]benzamide
(16) N-((lS,2S,4i?)-5-{[(lS)-2-(benzylamino)-l-methyl-2-oxoethyl]amino}-2-hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl)-3 - [methyl( 1 -naphthylsulfonyl)amino]benzamide
(17) N-(( 1 S,2S,4i?)-5- { [( 1 S)-2-(benzylamino)- 1 -methyl-2-oxoethyl] amino } -2-hydroxy- l-isobutyl-4-methyl-5-oxopentyl)-3-[methyl(2-naphthylsulfonyl)amino]benzamide
(18) N-((lS,2S,4Λ)-5-{[(lS)-2-(benzylamino)-l-methyl-2-oxoethyl]amino}-2-hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl)-3-[ { [5-(dimethylamino)- 1 - naphthyl]sulfonyl}(methyl)amino]benzamide
(19) 3- [ { [2-(acetylamino)-4-methyl- 1 ,3 -thiazol-5-yl] sulfonyl } (methyl)amino] -N- ((1 S,2S,4R)-5 - { [( 1 S)-2-(benzylamino)- 1 -methyl-2-oxoethyl] amino } -2-hydroxy- 1 - isobutyl-4-methyl-5-oxopentyl)benzamide
(20) N-((lS,2S,4i?)-5-{[(lS)-2-(benzylamino)-l-methyl-2-oxoethyl]amino}-2- hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl)-3- [(benzylsulfonyl)(methyl)amino]benzamide (21) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonyl)(methyl)amino]benzamide (22) N-[(lS,2S,4S)-4-({[(lS)-2-(benzylamino)-l-methyl-2- oxoethyl]amino}carbonyl)-2-hydroxy-l-isobutyl-5-methylhexyl]-3- [(benzylsulfonyl)(methyl)amino]benzamide
(23) N-{(lS,2S,4S)-4-[({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl } amino)carbonyl] -2-hydroxy- 1 -isobutyl-5-methylhexyl } -3 -
[(benzylsulfonyl)(methyl)amino]benzamide (24) N-[(lS,2S,4i?)-4-({[(lS)-2-(benzylamino)-l-methyl-2- oxoethyl] amino } carbonyl)-2 -hydroxy- 1 -isobutyl-6-heptenyl] -3 -
[(benzylsulfonyl)(methyl)amino]benzamide
(25)N-{(lS,2S,4i?)-4-[({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl } amino)carbony 1] -2-hydroxy- 1 -isobuty 1-6-heptenyl } -3 - [(benzylsulfonyl)(methyl)amino]benzamide
(26) 4-({[(25)-2-({(2Λ)-2-[(2S,3S)-3-({3-
[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-2-hydroxy-5-methylhexyl]-4- pentenoyl } amino)propanoyl] amino } methy l)benzoic acid
(27) 4-({[(25)-2-({(2i?)-2-[(2S,3S)-3-({3- [(benzylsulfonyl)(methyl)amino]benzoyl} amino)-2-hydroxy-5-methylhexyl]-4- pentenoyl } amino)propanoyl] amino } methy l)benzoic acid
(28) 4-{[((2S)-2-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)- 4-hydroxy-2,7-dimethyloctanoyl]amino}-3-methylbutanoyl)amino]methyl}benzoic acid
(29) 4-{[((2S)-2-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)- 4-hydroxy-7-methyl-2-propyloctanoyl]amino } propanoyl)amino]methyl } benzoic acid
(30) N-{(lS,2S,4i?)-4-[({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl } amino)carbonyl] -2-hydroxy- 1 -isobuty lheptyl } -3 - [(benzylsulfonyl)(methyl)amino]benzamide
(31) 4-{[((2S)-2-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)- 4-hydroxy-7-methyl-2-propyloctanoyl]amino}-3- methylbutanoyl)amino] methyl } benzoic acid
(32) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl]-3-[methyl(2- thienylsulfonyl)amino]benzamide
(33) N-(( 1 S,2S,4R)-5- { [( 1 S)-2-(benzylamino)- 1 -methyl-2-oxoethyl] amino } -2-hydroxy- l-isobutyl-4-methyl-5-oxopentyl)-3-[methyl(propylsulfonyl)amino]benzamide
(34) N-[(lS,2S,4R)-5-({(lS)-l- [(benzylamino)carbonyl] -2-methylpropyl } amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[methyl(propylsulfonyl)amino]benzamide (35) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-5-[(benzylsulfonyl)(methyl)amino]-2- chlorobenzamide
(36) N-[(lS,2S,4Λ)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5- (trifluoromethyl)benzamide
(37) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5- bromobenzamide
(38) N-[(lS,2S,4/?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5- nitrobenzamide
(39) 3-amino-N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl}amino)-2-hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-5- [(benzylsulfonyl)(methyl)amino]benzamide (40) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5- cyanobenzamide
(41) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5- methylbenzamide
(42) N- [( 1 S,2S,4i?)-5-( { ( 1 S)- 1 - [(benzylamino)carbonyl]-2-methylproρyl } amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5- chlorobenzamide (43) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylproρyl}amino)-2- hydroxy- 1 -isobutyl -4-methyl-5-oxopentyl]-5- [(benzylsulfonyl)(methyl)amino]isophthalamide
(44) methyl 3-({[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl}amino)-2-hydroxy-l-isobutyl-4-methyl-5-oxopentyl]amino}carbonyl)-5- [(benzylsulfonyl)(methyl)amino]benzoate
(45) benzyl 3-({[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2- methy Ipropyl } amino)-2-hydroxy- 1 -isobutyl-4-methyl-5 -oxopentyl] amino } carbonyl)-5 - [(benzylsulfonyl)(methyl)amino]benzoate
(46) N-[(lS,2S,4i-)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylproρyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-4- methoxybenzamide
(47) N-[(lS,2S,4Λ)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylproρyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-4- fluorobenzamide (48) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-4- chlorobenzamide
(49) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl]-5-[(benzylsulfonyl)(methyl)amino]-2- methoxybenzamide
(50) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-{methyl[(2- nitrobenzyl)sulfonyl]amino}benzamide (51) 3-[[(2-aminobenzyl)sulfonyl](methyl)amino]-N-[(lS,2S,4i?)-5-({(lS)-l-
[(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-l-isobutyl-4-methyl-5- oxopentyljbenzamide
(52) N-[(lS,2S,4i-)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-{methyl[(2- methy lbenzyl)sulfonyl] amino } benzamide
(53) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-{methyl[(3- methy lbenzyl)sulfonyl] amino } benzamide
(54) N-[(lS,2S,4Λ)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-{methyl[(4- methylbenzyl)sulfonyl] amino } benzamide
(55) N-{(lS,2S,4i-)-4-[({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl } amino)carbonyl]-2 -hydroxy- 1 -isobutyl-6-heptynyl } -3 - [(benzylsulfonyl)(methyl)amino]benzamide (56) N-{(lS,2S,4Z)-4-[({(lS)-l-[(benzylamino)carbonyl]-2- methy Ipropyl } amino)carbonyl] -2-hydroxy- 1 -isobutyl-4-hexenyl } -3 - [(benzylsulfonyl)(methyl)amino]benzamide
(57) N-{(lS,2S,4i? or 4S)-4-[({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl } amino)carbonyl] -2-hydroxy- 1 -isobuty lhexyl } -3 -
[(benzylsulfonyl)(methyl)amino]benzamide
(58) N-{(lS,2S,4i? or 4S)-4-[({(lS)-l-[(benzylamino)carbonyl]-2- methy Ipropyl } amino)carbonyl] -2-hydroxy- 1 -isobuty lhexyl } -3 - [(benzylsulfonyl)(methyl)amino]benzamide (59) methyl (2S)-2-{[(2i?,4S,5S)-5-({3-
[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7- dimethyloctanoyl]amino}-3-methylbutanoate.
(60) (2S)-2-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}-3-methylbutanoic acid (61) N-(( 1 S,2S,4i?)-5 - { [( 1 S)- 1 -(aminocarbonyl)-2-methylpropyl]amino } -2-hydroxy-
1 -isobutyl-4-methyl-5 -oxopentyl)-3 - [(benzylsulfonyl)(methyl)amino]benzamide
(62) (2S)-2-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}butanoic acid
(63) N-[(lS,2S,4i-)-5-({(lS)-l -[(benzylamino)carbonyl]propyl}amino)-2-hydroxy-l - isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide
(64) (2S,3i?)-2-{[(2i?,4S,5S)-5-({3-
[(benzylsulfonyl)(methyl)amino]benzoyl } amino)-4-hydroxy-2,7- dimethyloctanoyl] amino} -3-methylpentanoic acid
(65) N-[(lS,2S,4i-)-5-({(lS,2i?)-l-[(benzylamino)carbonyl]-2-methylbutyl}amino)- 2-hydroxy- 1 -isobutyl-4-methyl-5 -oxopentyl] -3 - [(benzylsulfonyl)(methyl)amino]benzamide
(66) methyl (2S)-2-{[(2i?,4S,5S)-5-({3- [(benzylsulfonyl)(methyl)amino]benzoyl } amino)-4-hydroxy-2,7- dimethyloctanoyl] amino } -3 ,3 -dimethylbutanoate
(67) (2S)-2-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}-3,3-dimethylbutanoic acid
(68) N-[(lS,2S,47?)-5-({(lS)-l-[(benzylamino)carbonyl]-2,2- dimethy Ipropyl} amino)-2-hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonyl)(methyl)amino]benzamide
(69) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2,2- dimethylpropyl}amino)-2-hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonyl)(methyl)amino]benzamide
(70) N- [( 1 S,2S,4i?)-5 -( { 1 - [(benzylamino)carbonyl] cyclopentyl } amino)-2-hydroxy- 1 - isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide
(71) (2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7- dimethyloctanoic acid
(72) 3 - [(benzylsulfonyiχmethyl)amino] -N-(( 1 S,2S,4i?)-2-hydroxy- 1 -isobutyl-4- methyl-5-oxo-5-{[(3i? or 3S)-2-oxopiperidinyl]amino}pentyl)benzamide (73) 3 - [(benzylsulfonyl)(methyl)amino] -N-(( 1 S,2S,4i?)-2-hydroxy- 1 -isobutyl-4- methyl-5-oxo-5-{[(3i? or 3S)-2-oxopiperidinyl]amino}pentyl)benzamide (74) methyl 4-({[(2i?,4S,5S)-5-({3-
[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7- dimethyloctanoyl]amino}methyl)cyclohexanecarboxylate (75) 4-({[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl] amino } methyl)cyclohexanecarboxylic acid
(76) methyl 4-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)- 4-hydroxy-2,7-dimethyloctanoyl]amino}cyclohexanecarboxylate (77) 4-{[(27?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}cyclohexanecarboxylic acid
(78) methyl 3-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)- 4-hydroxy-2,7-dimethyloctanoyl] amino } cyclohexanecarboxylate
(79) 3-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}cyclohexanecarboxylic acid
(80) methyl 5-{[(27?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)- 4-hydroxy-2,7-dimethyloctanoyl]amino}pentanoate
(81) 5-{[(2i-,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}pentanoic acid (82) ethyl 3-((lS)-l-{[(2#,4S,5S)-5-({3-
[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7- dimethyloctanoyl]amino}-2-methylpropyl)-4,5-dihydro-5-isoxazolecarboxylate (83) 3-[(benzylsulfonyl)(methyl)amino]-N-((lS,2S,4i?)-5-{[(lS)-l-cyano-2- methylpropyl]amino}-2-hydroxy-l-isobutyl-4-methyl-5-oxopentyl)benzamide (84) methyl (2S)-2-{[(3S,4S)-4-({3-
[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-3-hydroxy-6- methylheptanoyl] amino } -3 -methy lbutanoate
(85) (2S)-2-{[(3S,4S)-4-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-3- hydroxy-6-methylheptanoyl] amino } -3 -methy lbutanoic acid (86) N- [( 1 S,2S)-4-( { ( 1 S)- 1 - [(benzylamino)carbonyl] -2-methylproρyl } amino)-2- hydroxy-l-isobutyl-4-oxobutyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide
(87) 4-{[((25)-2-{[(3S,4S)-4-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)- 3 -hydroxy-6-methylheptanoyl] amino } -3 -methy lbutanoyl)amino]methyl } benzoic acid (88) N-{(lS,2i?)-l-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3- [methyl(propylsulfonyl)amino]benzamide
(89) N-{(lS)-l-[(5i?)-3-(3-methoxybenzyl)-l,3-oxazolidin-5-yl]-2-phenylethyl}-3- [methyl(propylsulfonyl)amino]benzamide
(90) N-{(lS,2i-)-l-benzyl-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-3- [methyl(propylsulfonyl)amino]benzamide
(91) N-{(lS)-l-[(5i-)-3-(3-methylbenzyl)-l,3-oxazolidin-5-yl]-2-phenylethyl}-3- [methyl(propylsulfonyl)amino]benzamide
(92) N-{(lS,2i?)-l-benzyl-2-hydroxy-3-[(2-pyridinylmethyl)amino]propyl}-3- [methyl(propylsulfonyl)amino]benzamide (93) N-{(lS,2i?)-l-benzyl-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3- [methyl(propylsulfonyl)amino]benzamide
(94) N-{(lS)-l-[(5i?)-3-(3-ethylbenzyl)-l,3-oxazolidin-5-yl]-2-phenylethyl}-3- [methyl(propylsulfonyl)amino]benzamide
(95) N-[( 1 S,2R)- 1 -benzyl-3 -(benzylamino)-2-hydroxypropyl]-3 - [methyl(propylsulfonyl)amino]benzamide
(96) N-{(lS)-l-[(5Λ)-3-benzyl-l,3-oxazolidin-5-yl]-2-phenylethyl}-3- [methyl(propylsulfonyl)amino]benzamide
(97) N-((lS,2i?)-l-benzyl-2-hydroxy-3-{[(li?)-l-phenylpropyl]amino}propyl)-3- [methyl(propylsulfonyl)amino]benzamide (98) 3-[methyl(propylsulfonyl)amino]-N-((lS)-2-phenyl-l-{(5/?)-3-[(li?)-l- phenylpropyl]-l,3-oxazolidin-5-yl}ethyl)benzamide
(99) N-(( 1 S,2R)- 1 -benzyl-2-hydroxy-3- { [( 1 S)- 1 -pheny Ipropyl] amino }propyl)-3 - [methyl(propylsulfonyl)amino]benzamide (100) 3-[methyl(propylsulfonyl)amino]-N-((lS)-2-phenyl-l-{(57?)-3-[(lS)-l- phenylpropyl]-l,3-oxazolidin-5-yl}ethyl)benzamide
(101) N-((lS,2i?)-l-benzyl-2-hydroxy-3-{[(li?)-l-(3- methoxyphenyl)ethyl]amino}propyl)-3-[methyl(propylsulfonyl)amino]benzamide
(102) N-((lS)-l-{(5i?)-3-[(l^)-l-(3-methoxyphenyl)ethyl]-l,3-oxazolidin-5-yl}-2- phenylethyl)-3 - [methyl(propylsulfonyl)amino]benzamide
(103) N-((lS,2i?)-l-benzyl-2-hydroxy-3-{[(lS)-l-(3- methoxyphenyl)ethyl]amino}propyl)-3-[methyl(propylsulfonyl)amino]benzamide
(104) N-((lS)-l-{(5 ?)-3-[(lS)-l-(3-methoxyphenyl)ethyl]-l,3-oxazolidin-5-yl}-2- phenylethyl)-3-[methyl(propylsulfonyl)amino]benzamide (105) N- {( 1 S,2R)- 1 -benzyl-2-hydroxy-3 -[(3-methoxybenzyl)amino]ρropyl } -3 - [(benzylsulfonyl)(methyl)amino]benzamide
(106) 3-[(benzylsulfonyl)(methyl)amino]-N-{(lS)-l-[(5i-)-3-(3-methoxybenzyl)-l,3- oxazolidin-5-yl] -2-phenylethyl } benzamide
(107) 3-[(butylsulfonyl)(methyl)amino]-N-{(lS)-l-[(5i-)-3-(3-methoxybenzyl)-l,3- oxazolidin-5-yl]-2-phenylethyl}benzamide
(108) 3-[(ethylsulfonyl)(methyl)amino]-N-{(lS)-l-[(5i-)-3-(3-methoxybenzyl)-l,3- oxazolidin-5 -yl] -2-phenylethyl } benzamide
(109) N-{(lS)-l-[(5i-)-3-(3-methoxybenzyl)-l,3-oxazolidin-5-yl]-2-phenylethyl}-3- [methyl(methylsulfonyl)amino]benzamide (110) N- {( 1 S,2R)- 1 -benzyl-2-hydroxy-3-[(3-methoxybenzoyl)amino]propyl} -3- [(benzylsulfonyl)(methyl)amino]benzamide
(111) N-{(lS,2Λ)-l-benzyl-2-hydroxy-3-[(phenylsulfonyl)amino]propyl}-3- [(benzylsulfonyl)(methyl)amino]benzamide (112) N-((lS,2i?)-l-benzyl-2-hydroxy-3-{[2-(trifluoromethyl)benzyl]amino}propyl)-3- [(benzylsulfonyl)(methyl)amino]benzamide
(113) N-(( 1 S,2R)- 1 -benzyl-2-hydroxy-3 - { [3 -(trifluoromethyl)benzyl] amino } propyl)-3 - [(benzylsulfonyl)(methyl)amino]benzamide
(114) N- {( 1 S,2R)- 1 -benzyl-3-[(3-bromobenzyl)amino]-2-hydroxypropyl} -3- [(benzylsulfonyl)(methyl)amino]benzamide
(115) N-((lS,2i?)-l-benzyl-2-hydroxy-3-{[3-
(trifluoromethoxy)benzyl] amino } propyl)-3 - [methyl (propylsulfony l)amino] benzamide
(116) N- { ( 1 S,2i?)- 1 -benzyl-2-hydroxy-3-[(3 -phenoxybenzyl)amino]propyl } -3- [methyl(propylsulfonyl)amino]benzamide (117) N- { ( 1 S,2R)- 1 -benzyl-2-hydroxy-3 - [(3 -hydroxybenzyl)amino]propyl } -3 - [methyl(propylsulfonyl)amino]benzamide
(118) N-{(lS,2i?)-l-benzyl-2-hydroxy-3-[(4-methoxybenzyl)amino]propyl}-3- [methyl(propylsulfonyl)amino]benzamide
(119) N- { ( 1 S,2i?)- 1 -benzyl-2-hydroxy-3 -[(2-methoxybenzyl)amino]propyl} -3 - [methyl(propylsulfonyl)amino]benzamide
(120) N- { ( 1 S,2R)- 1 -benzyl-3 - [(3 -ethoxybenzyl)amino] -2-hydroxypropyl } -3 - [methyl(propylsulfonyl)amino]benzamide
(121) N-((lS,2i?)-3-{[3-(allyloxy)benzyl]amino}-l-benzyl-2-hydroxypropyl)-3- [methyl(propylsulfonyl)amino]benzamide ( 122) N-(( 1 S,2R)- 1 -benzyl-3- { [3-(benzyloxy)benzyl] amino } -2-hydroxypropyl)-3 - [methyl(propylsulfonyl)amino]benzamide
(123) 3-({[(2i?,3S)-2-hydroxy-3-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)- 4-phenylbutyl]amino } methyl)phenyl benzoate (124) N-((lS,2i?)-l-benzyl-3-{[3-(dimethylamino)benzyl]amino}-2-hydroxypropyl)- 3-[methyl(propylsulfonyl)amino]benzamide
(125) N- [( 1 S,2R)- 1 -benzyl-2-hydroxy-3 -(phenethylamino)propyl] -3- [methyl(propylsulfonyl)amino]benzamide
(126) N-((lS,2i?)-l-benzyl-3-{[(5-ethyl-2-furyl)methyl]amino}-2-hydroxypropyl)-3- [methyl(propylsulfonyl)amino] benzamide
(127) N-(( 1 S,2R)- 1 -benzyl-3 - { [(5-ethyl-2-thienyl)methyl]amino} -2-hydroxypropyl)- 3-[methyl(propylsulfonyl)amino]benzamide
(128) N-[(lS,2i?)-l-benzyl-2-hydroxy-3-({[5-(hydroxymethyl)-2- furyl]methyl}amino)propyl]-3-[methyl(propylsulfonyl)amino]benzamide ( 129) N-(( 1S,2R)- 1 -benzyl-3 - { [(5-bromo-2-thienyl)methyl]amino } -2-hydroxypropyl)- 3 - [methyl(propylsulfonyl)amino] benzamide
(130) N- { ( 1 S,2R)- 1 -benzyl-3 - [(3 -chlorobenzyl)amino] -2-hydroxypropyl } -3 - [methyl(propylsulfonyl)amino]benzamide
(131) N-{(lS,2^)-l-benzyl-3-[(3-bromobenzyl)amino]-2-hydroxypropyl}-3- [methyl(propylsulfonyl)amino] benzamide
(132) N-{(lS,2#)-l-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3- [methyl(propylsulfonyl)amino]benzamide
(133) N-((IS,2R)-1 -benzyl-2-hydroxy-3-{ [3-(trifluoromethyl)benzyl]amino}propyl)- 3-[methyl(propylsulfonyl)amino]benzamide (134) N-{(lS,2i?)-l-benzyl-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-3- [methyl(propylsulfonyl)amino]benzamide
(135) N-{(lS,2i?)-3-[(l,3-benzodioxol-5-ylmethyl)amino]-l-benzyl-2- hydroxypropyl } -3 - [methyl(propylsulfonyl)amino] benzamide (136) N-{(1 S,2R)- 1 -benzyl-3 - [(3 ,5-dimethoxybenzyl)amino] -2-hydroxypropyl } -3 - [methyl(propylsulfonyl)amino]benzamide
(137) N-{(lS,2£)-l-benzyl-2-hydroxy-3-[(2-hydroxy-3- methoxybenzyl)amino]propyl } -3 - [methyl (propylsulfonyl)amino]benzamide
(138) N- { ( 1 S,2R)- 1 -benzyl-3 - [(2,3 -dimethoxybenzyl)amino] -2-hydroxypropyl } -3 - [methyl(propylsulfonyl)amino]benzamide
(139) N-{(lS,2i?)-l-benzyl-2-hydroxy-3-[(2-hydroxy-5- methoxybenzyl)amino]propyl } -3 - [methyl (propylsulfonyl)amino]benzamide
(140) N- { ( 1 S,2i?)- 1 -benzyl-3 - [(2,5 -dimethoxybenzyl)amino] -2-hydroxypropyl } -3 - [methyl(propylsulfonyl)amino]benzamide (141) N- { ( 1 S,2R)- 1 -benzyl-2-hydroxy-3- [( 1 -naphthylmethyl)amino]propyl } -3- [methyl(propylsulfonyl)amino]benzamide
( 142) N- {( 1 S,2R)-3-[( 1 ,3-benzodioxol-4-ylmethyl)amino]- 1 -benzyl-2- hydroxypropyl } -3 - [methy l(propylsulfonyl)amino] benzamide
(143) N-[(lS,2i?)-l-benzyl-2-hydroxy-3-(lH-pyrazol-l-yl)propyl]-3- [methyl(propylsulfonyl)amino]benzamide
(144) N-[(lS,2Λ)-l-benzyl-3-(3-benzyl-lH-pyrazol-l-yl)-2-hydroxypropyl]-3- [methyl(propylsulfonyl)amino]benzamide
(145) N-[( 1 S,2R)- 1 -benzyl-2-hydroxy-3 -(3 -isopropyl- 1 H-pyrazol- 1 -yl)propyl] -3 - [methyl(propylsulfonyl)amino]benzamide (146) N-((lS,2i?)-l-benzyl-2-hydroxy-3-{3-[(E)-2-phenylethenyl]-lH-pyrazol-l- yl } propyl)-3- [methyl(propylsulfonyl)amino]benzamide
(147) N-[( 1 S,2R)- 1 -benzyl-2-hydroxy-3-(3 -phenethyl- 1 H-pyrazol- 1 -yl)propyl] -3 - [methyl(propylsulfonyl)amino]benzamide (148) N- {( 1 S,2R)- 1 -benzyl-2-hydroxy-3 -[(3 -methoxybenzyl)(methyl)amino]propyl } - 3-[methyl(propylsulfonyl)amino]benzamide
(149) N- { ( 1 S,2i?)-3 - [acetyl(3 -methoxybenzyl)amino] - 1 -benzy 1-2-hydroxypropyl } -3 - [methyl(propylsulfonyl)amino]benzamide
(150) N-((lS)-l-{(li?)-l-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-methylbutyl)- 3-[methyl(propylsulfonyl)amino]benzamide
(151) N-{(1 S,2S)- 1 -benzyl-2-hydroxy-3 - [(3 -methoxybenzyl)amino]propyl } -3- [methyl(propylsulfonyl)amino]benzamide
(152) N-{(15)-l-[(5S)-3-(3-methoxybenzyl)-l,3-oxazolidin-5-yl]-2-phenylethyl}-3- [methyl(propylsulfonyl)amino]benzamide (153) N-{(lS,2S)-l-benzyl-2-hydroxy-3-[(3-methoxybenzyl)(methyl)amino]propyl}- 3-[methyl(propylsulfonyl)amino]benzamide
The present invention also provides a process for the preparation of the sulfone amide derivatives of Formula 1. Skilled persons having knowledge about synthesis of compounds in the art to which the present invention pertains could readily prepare the sulfone amide derivatives of Formula 1 according to the present invention, using known compounds, or readily preparable compounds therefrom. Therefore, the below description associated with preparation processes is provided only to disclose exemplary ones, and the order of preparation steps may be changed if necessary. As such, the scope of the present invention is not limited to only such preparation processes as described herein. First, the process for preparation of the sulfone amide derivative (derivative of Formula 7) in which X in Formula 1 is the substituent of Formula 2 is described referring to Reaction Scheme 1 below.
Reaction Scheme 1
Figure imgf000032_0001
5
Figure imgf000032_0002
6 Formula 7
As the first step, the lactone compound (1) in which amino group is protected (BocNH-) is prepared using an amino acid according to the known method (J. Am. Chem. Soc. 2000, 122, 3522-3523). The compound is reacted with lithium bis(trimethylsilyl)amide (preferably, 1.0 M) and iodomethane in anhydrous tetrahydrofurane solution to synthesize the alkyl-substituted lactone compound (2). After the lactone compound (2) is treated with lithium hydroxide solution (preferably 1.0 N), O-protected carboxyl compound (3) can be obtained using imidazole and t- butyldimethylsilyl chloride. Compound (3) is coupled with an amine to produce a compound (4), of which the protective group is then removed and coupled with a sulfone amide-substituted benzoic acid to synthesize the compound (5). As the last step, the O-protective group is removed to synthesize the desired compound (6). The above benzoic acid substituted with sulfone amide (sulfone amide- substituted benzoic acid) can be prepared by the below procedure. First, the sulfone amide-substituted benzoic acid for preparation of cyclic sulfone amide derivative can be synthesized by Reaction Scheme 2 below.
Reaction Scheme 2
Figure imgf000033_0001
Figure imgf000033_0002
9 10 A commercially available ethyl-3-aminobenzoate (7) is reacted with 3- chloropropanesulfonyl chloride to synthesize ethyl- {bis [(3- chloropropyl)sulfonyl]amino}benzoate (8). The compound (8) thus synthesized is reacted with sodium hydroxide solution (preferably 1 N) in N,N-dimethylformamide solvent to synthesize a cyclic compound (9) which is then reacted with lithium hydroxide solution (preferably 1 N) in a mixed solvent of tetrahydrofurane and methanol to produce a compound (10). Likewise, a sulfone amide-substituted benzoic acid for preparation of non- cyclic sulfone amide derivatives can be prepared by the process wherein an alkylsulfonylamino benzoate is synthesized using the compound (7) and alkyl sulfonyl chloride and then hydrolyzed with lithium hydroxide solution. Further, the process for preparation of the sulfone amide derivatives (derivatives of Formulas 8 and 9) in which X in Formula 1 is the substituent of Formula 3 or 4 is described referring to Reaction Scheme 3 below.
Reaction Scheme 3 1
Figure imgf000034_0001
12 11
Figure imgf000034_0002
13 14 Formula 8
Figure imgf000034_0003
15 Formula 9
First, an epoxide compound (11) in which an amino group is protected (BocNH-) is prepared using an amino acid according to the known method Tetrahedron Letters 1999, 36, 5453-5456). The compound (11) is reacted with the corresponding amine in isopropanol solution to synthesize a compound (12). The protective group of the compound (12) is removed and then coupled with an alkylsulfonylamino benzoic acid to synthesize a compound (14) (compound of Formula 8). At this step, where cyclization of some substituents (between -OH and =N-R4) in the compound (14) is desired, it is stirred with formaline in tetrahydrofurane solvent to synthesize a compound (15) (compound of Formula 9).
The compounds of Formula 1 according to the present invention, as will be seen later in the experimental results, have BACE-inhibitory activity, thereby exhibiting the effect of preventing beta-amyloid production. Therefore, the present invention provides a pharmaceutical composition for inhibiting BACE activity, more specifically, a composition for inhibiting beta-amyloid production, comprising a physiologically acceptable carrier and a therapeutically effective amount of sulfone amide derivatives of Formula 1. The sulfone amide derivatives of Formula 1 can be formulated in various forms for pharmaceutical administration according to intended purposes. In preparation of pharmaceutical compositions according to the present invention, an active agent, specifically the sulfone amide derivative of Formula 1, is mixed with various physiologically acceptable carriers which can be selected according to desired formulation. The active agent, according to desired purposes, can be formulated into dosage forms suitable for injection, intradermal administration or oral administration, and preferably formulated into unit dosage form in aspect of ease of administration and uniformity of dosage amount. For preparation of the formulation for oral administration, conventional physiological carriers can be used. For example, water, glycol, oil and alcohol can be used as a carrier in case of oral aqueous formulations such as suspension, syrup, elixir solution; and starch, sugar, kaoline, lubricant, coupling agent and disintegrants can be used in case of solid formulations such as powder, pills, capsules and tablets. The tablet and capsules are the most convenient administration manner due to the ease of administration, and preferably, tablets and pills are formulated in enteric coating form. In case of the formulation for parenteral administration, sterilized water is conventionally used as a carrier and may contain other components such as aqueous adjuvant. As the formulation for injection administration, for example, water-in-oil or oil-in-water suspensions can be formulated using dispersion agent, wetting agent or suspension agent, according to known methods. A solvent that can be used herein is water, Ringer's solution, isotonic NaCl solution and the like, and sterilized fixation oil solvent is conventionally used as a solvent or suspension medium. Any non-stimulative fixation oil, including mono- and di-glycerides, can be used for this purpose, and also fatty acid such as aleic acid can be used for the formulation for injection administration. In case of the formulation for transdermal administration, penetration- facilitating agent and/or proper wetting agent as a carrier can be used together with suitable additives being non-irritating to skin. As the additives, compounds facilitating administration via skin and/or facilitating the preparation of a desired composition are selected. The transdermal formulation is administered in various manners such as transdermal patch, cream or ointments. For prevention of rapid clearance of active agents in vivo, the composition in accordance with the present invention can be made in a sustained release form, and carriers therefor include implant, microencapsulated delivery system, biodegradable/biocompatible polymers and the like which are known in the art. Said "therapeutically effective amount" means the amount of active agents effective for relieving or reducing symptoms and clinical markers for disease requiring prevention or treatment, and delaying the onset of symptoms. Therapeutically effective amounts can be determined empirically using known in vivo and in vitro model systems for the disease requiring treatment. When the active agent, specifically the sulfone amide derivative of Formula 1, is administered for clinical purposes, the total 1-day amount administered via single or multiple doses is preferably in the range of 0.1 ~ 100 mg per 1 kg by weight; however, the level of specific amount administered to a specific patient can be altered depending upon the kind of compound used, weight of patient, sex, health condition, food, administration time, method of administration, rate of excretion, mixture of pharmaceuticals and seriousness of disease. In some cases, the sulfone amide derivative of Formula 1 can be used in formulation of pharmaceutical compositions in which the derivative is present in the form of a prodrug thereof. As described previously, pharmaceutically acceptable salts are included in the sulfone amide derivatives as represented by Formula 1, wherein said salts are not particularly limited so long as the salt can maintain the activity of the therapeutic compound in vivo and the salt does not cause undesirable effects. These salts include inorganic salts and organic salts, and preferably include, for example, acetic, nitric, aspartic, sulfonic, sulfuric, maleic, glutamic, formic, succinic, phosphoric, phthalic, tannic, tartaric, hydrobromic, propionic, benzenesulfonic, benzoic, stearic, esyl, lactic, bicarbonic, bisulfuric, bitartaric, oxalic, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, toluenesulfonic, edisylic, esylic, fumaric, gluceptic, pamoic, gluconic, glycollylarsanilic, methylnitric, polygalactouronic, hexylresorcinoic, malonic, hydrabamic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactobionic, mandelic, estolic, methylsulfuric, mucic, napsylic, muconic, p-nitromethanesulfonic, hexamic, pantothenic, monohydrogen phosphoric, dihydrogen phosphoric, salicylic, sulfamic, sulfanilic, methanesulfonic, teoclic, acid, etc. The BACE-inhibiting composition according to the present invention may further contain any other components which do not inhibit the function of the active agent or which support the function of active agent, and also the composition may be formulated in various manners well known in the art. In addition, the present invention provides a method for treatment or prevention of diseases caused by production of beta-amyloid using the sulfone amide derivative of Formula 1 as an active agent. A representative example of diseases caused by production of said beta-amyloid is Alzheimer's disease as mentioned previously, but is not limited thereto, and also includes diseases associated with Alzheimer's disease such as Down's syndrome, and Hereditary Cerebral Hemorrhage and the like. Therefore, when the sulfone amide derivative of Formula 1 in accordance with the present invention is administered to human patients in an effective amount, it inhibits the function of BACE (or beta-secretase) to inhibit the production of beta-amyloid caused by the enzymatic function of BACE, whereby it is effective for the treatment or prevention of Alzheimer's disease and related diseases. Said "treatment" means halting or slowing of disease progression when it is used for treatment of patients showing disease symptoms; and said "prevention" means prevention of the development of disease symptoms when used to treat a patient not showing symptoms but having a high possibility of developing such symptoms.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the relation between drug concentration versus time after oral administration of the compounds obtained in EXAMPLES 88 and 89 (Compounds 1 and 2) and the known compound (Compound 3) to mice.
DESCRIPTION OF THE PREFERRED EMBODIMENTS The detailed description of the present invention illustrated in below with reference to the embodiments below is provided only to aid the understanding of persons skilled in the art, and is not intended to limit the scope of the present invention.
[Preparation Example 1] Preparation of. tert-butyl ( 1 S)-3 -methyl- 1 - r(2i?V5-oxotetrahvdro-2- furanyl] butylcarbamate According to the known method (J Am. Chem. Soc. 2000, 122, 3522-3523), the title compound was synthesized from t-butoxycarbonyl-(S)-leucine.
IH NMR (500 MHz, CDC13); 4.50 (IH, t), 4.41 (IH, d), 3.84 (IH, m), 2.52 (2H, t), 2.22 (IH, m), 2.11 (IH, m), 1.65 (IH, m), 1.55 (IH, m), 1.43 (9H, s), 1.33 (IH, m), 0.93 (3H, d), 0.92 (3H, d)
[Preparation Example 2]
Preparation of tert-butyl dS)-3-methyl-l-rr2i?.4i?V4-methyl-5-oxotetrahvdro-2- furanyl] butylcarbamate 20.67 g (76.17 mmol) of the compound from Preparation Example 1 was dissolved in 350 ml of anhydrous tetrahydrofurane, and cooled to -78°C, then 152 ml (167.57 mmol, tetrahydrofurane solution) of 1.0 M lithium bis(trimethylsylyl)amide was added thereto. After stirring for 30 minutes, 10.4 ml (167.57 mmol) of iodomethane was added and stirred for 1 hour. After the reaction was terminated using saturated ammonium chloride solution, the solvent was removed by distillation under reduced pressure, then the product was eluted with ethyl acetate and washed with sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 1 :5 mixture of ethyl acetate and hexane, and 15.35 g of the title compound was obtained at 71% yield. IH NMR (500 MHz, CDC13); 4.47 (IH, s), 4.37 (IH, d), 3.82 (IH, m), 2.66 (IH, m), 2.39 (IH, m), 1.91 (IH, m), 1.63 (IH, m), 1.53 (IH, m), 1.41 (9H, s), 1.32 (IH, m), 1.25 (3H, d), 0.92 (3H, d), 0.90 (3H, d).
[Preparation Example 3]
Preparation of ethyl 3-{bis[f3-chloropropyl)sulfonyl]amino}benzoate 0.83 g (5 mmol) of ethyl-3-aminobenzoate and 1.52 ml (12.5 mmol) of 3- chloropropanesulfonyl chloride were dissolved in 25 ml of dichloromethane, and cooled to 0°C. 2.09 ml (15 mmol) of trimethylamine was added thereto and heated to room temperature, followed by stirring for 2 hours. The solvent was removed by distillation under reduced pressure, and eluted with ethyl acetate, then washed with saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, precipitates were settled using diethylether and filtered to obtain 1.02 g of the title compound at 46% yield.
IH NMR (500 MHz, CDC13); 8.17 (IH, m), 8.03 (IH, s), 7.56 (2H, d), 4.40 (2H, q), 3.76 (4H, t), 3.67 (4H, t), 2.42-2.37 (4H, m), 1.40 (3H, t). [Preparation Example 4]
Preparation of 3-(l,l-dioxo-l,6-isothiazolidin-2-yl benzoic acid 1.0 g (2.24 mmol) of the compound obtained in Preparation Example 3 was added in 4 ml of N,N-dimethylformamide and 4.5 ml of 1.0 N sodium hydroxide, and stirred for 2 hours. After removing solvent by distillation under reduced pressure, the residue was eluted with ethyl acetate and washed with sodium chloride solution. The compound obtained by distillation under reduced pressure was dissolved in 10 ml of tetrahydrofurane, 2 ml of methanol and 6 ml of 1.0 N lithium hydroxide solution, and stirred for 5 hours. After removing solvent by distillation under reduced pressure, the residue was diluted with water, and the solid produced by acidification with 1.0 N hydrochloride solution was filtered to obtain 0.35 g of the title compound at 64% yield. IH NMR (500 MHz, CD3OD); 7.88 (IH, s), 7.78 (IH, d), 7.52-7.43 (2H, m), 3.83 (2H, t), 3.46 (2H, t), 2.56-2.50 (2H, m)
[Preparation Example 5]
Preparation of 3 -( 1 , 1 -dioxo- 1.6-isothiazolidin-2-vn-N- { ( 1 S)-3-methyl- 1 -\(2RAR)-4- methyl-5-oxotetrahvdro-2-furanyl1butvU benzamide 0.29 g (1.0 mmol) of the compound obtained in Preparation Example 2 was dissolved in 5 ml of 4.0 Ν hydrochloride solution diluted with ethyl acetate, and stirred for 1 hour. After solvent distillation under reduced pressure and concentration, the resulting mixture was cooled to 0°C and 0.29 g (1.2 mmol) of the compound from Preparation Example 4, 0.23 g (1.2 mmol) of EDC and 0.2 g (1.5 mmol) of HOBT were added thereto. 1.05 ml (6.0 mmol) of Ν,Ν-diisopropylamine was further added and the mixture was heated to room temperature, then stirred overnight. After removing solvent by distillation under reduced pressure, the mixture was dissolved in ethyl acetate and washed with water, 1.0 N of hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the residue was purified by column chromatography to obtain 0.4 g of the title compound at 97% yield.
IH NMR (500 MHz, CDC13); 7.57 (IH, d), 7.52 (IH, s),7.45-7.38 (2H, m), 6.02 (IH, d), 4.62 (IH, m), 4.47 (IH, m), 3.82 (2H, t), 3.40 (2H, t), 2.66-2.52 (3H, m), 2.43 (IH, m), 1.99 (IH, m), 1.73 (IH, m), 1.62 (IH, m), 1.47 (IH, m), 1.25 (3H, d), 0.95 (6H, d)
[Preparation Example 6]
Preparation of (2RAS.5S)-4- { rtert-butylf dimethynsilylloxy} -5- ( B-fl .1 -dioxo- 1.6- isothiazolidin-2-v0benzoyl]amino}-2 -dimethyloctanoic acid 0.4 g (0.97 mmol) of the compound obtained in Preparation Example 5 was dissolved in 5 ml of tetrahydrofurane, and 5 ml of 1.0 N lithium hydroxide solution was added thereto, followed by stirring for 1 hour. After removing solvent by distillation under reduced pressure, the mixture was diluted with water, and acidified using 25% citric acid, then eluted by ethyl acetate, followed by washing with sodium chloride solution. After removing solvent by distillation under reduced pressure below room temperature, the residue was dissolved in 10 ml of N,N-dimethylformamide, and 1.32 g (19.34 mmol) of imidazole and 1.46 g (9.67 mmol) of t-butyldimethylsilyl chloride were added thereto, followed by stirring overnight. After 4 ml of methanol was added and stirred for 2 hours, 25% citric acid was added and the mixture was eluted using ethyl acetate, followed by washing with water and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using the mixture of 5:95 methanol and dichloromethane to obtain 0.45 g of the title compound at 86% yield.
IH NMR (500 MHz, CDC13); 7.56 (IH, m), 7.53 (IH, s), 7.41 (2H, d), 6.33 (IH, d), 4.27 (IH, m), 3.84-3.77 (3H, m), 3.39 (2H, t), 2.65 (IH, m), 2.57-2.52 (2H, m), 1.87 (IH, m), 1.64 (IH, m), 1.56-1.36 (3H, m), 1.20 (3H, d), 0.96 (3H, d), 0.95 (3H, d), 0.91 (9H, s), 0.12 (3H, s), 0.10 (3H, s)
[Preparation Example 7]
Preparation of benzyl 4- { [(tert-butoxycarbonvDaminolmethyl } benzoate 5.03 g (20 mmol) of 4-(t-butoxycarbonylamino-methyl)-benzoic acid and 4.15 g (30 mmol) of potassium carbonate were dissolved in 100 ml of N,N- dimethylformamide, then 2.85 ml of benzyl bromide was added, and stirred for 5 hours.
After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 1 :3 mixture of ethyl acetate and hexane to obtain 6.5 g of the title compound at 99% yield.
IH NMR (500 MHz, CDC13); 8.03 (2H, d), 7.44 (2H, d), 7.38 (2H, t), 7.35-7.32 (3H, m),
5.35 (2H, s), 4.91 (IH, br), 4.36 (2H, d), 1.45 (9H, s)
[Preparation Example 8]
Preparation of; benzyl 4-IT{f2S)-2-lϊtert- butoxycarbonyDamino] propanoyl I amino)methyl1 benzoate 1.71 g (5.0 mmol) of the compound obtained in Preparation Example 7 was dissolved in 15 ml of 4.0 N hydrochloride solution diluted with ethyl acetate, and stirred for 3 hours. After solvent distillation under reduced pressure and concentration, the residue was dissolved in 24 ml of N,N-dimethylformamide and cooled to 0°C, then 1.04 g(5.5 mmol) of t-butoxycarbonyl-(s)-alanine, 1.15 g (6.0 mmol) of EDC and 1.01 g (7.5 mmol) of HOBT were added. Hereto, 5.23 ml (30.0 mmol) of N,N- diisopropylethylamine was added, and heated to room temperature, followed by stirring overnight. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride. After removing solvent by distillation under reduced pressure, the product was precipitated using diethyl ether to obtain 1.78 g of the title compound at 86% yield.
IH NMR (500 MHz, CDC13); 8.01 (2H, d), 7.43 (2H, d), 7.38 (2H, t), 7.34 (IH, d), 7.31 (2H, d), 6.68 (IH, br), 5.35 (2H, s), 4.94 (IH, br), 4.49 (2H, br), 4.18 (IH, br), 1.41 (9H, s), 1.38 (3H, d).
[Preparation Example 9]
Preparation of benzyl 4-rr4S.7i?.9S)-9-rπS)-l-(r3-(l.l-dioxo-116-isothiazolidin-2- vDbenzoyl] amino } -3 -methylbutyl -4.7, 11,11,12,12-hexamethyl-3 ,6-dioxo- 10-oxa-2.5- diaza- 11 -silatridec- 1 -yl benzoate 59 mg (0.144 mmol) of the compound obtained in Preparation Example 8 was dissolved in 3 ml of 4.0 N hydrochloride solution diluted with ethyl acetate, and stirred for 2 hours. After solvent distillation under reduced pressure and concentration, the residue was dissolved in N,N-dimethylformamide and cooled to 0°C, then 65 mg (0.12 mmol) of the compound obtained in Preparation Example 6 and 55 mg (0.144 mmol) of HATU were added thereto. 0.5 ml (excess amount) of N,N-diisopropylethylamine was further added, and heated to room temperature, followed by stirring for 4 hours. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 71 mg of the title compound at 71% yield. IH NMR (500 MHz, CDC13); 8.00 (2H, d), 7.59 (IH, s), 7.55 (IH, d), 7.45-7.32 (7H, m), 7.30 (2H, d), 7.03 (IH, t), 6.97 (IH, d), 6.28 (IH, d), 5.35 (2H, s), 4.52-4.28 (4H, m), 3.80-3.70 (3H, m), 3.36 (2H, t), 2.58-2.48 (3H, m), 1.68-1.54 (3H, m), 1.48 (IH, m), 1.34 (IH, m), 1.15 (3H, d), 1.11 (3H, d), 0.95 (3H, d), 0.94 (3H, d), 0.91 (9H, s), 0.10 (3H, s), 0.09 (3H, s)
[Example 1]
Preparation of 4-rr( S)-2-r(r2i?.4S.5S)-5-{r3-π.l-dioxo-116-isothiazolidin-2- yl)benzoyl1amino)-4-hvdroxy-2,7- dimethyloctanoyl)amino]propanoyl } amino methyl]benzoic acid After dissolving 68 mg (0.081 mmol) of the compound obtained in Preparation Example 9 in 3 ml of methanol, active carbon supported palladium (10%) was added and stirred overnight under hydrogen atmosphere. After removing solids by filtration under reduced pressure using Cellite, the residue obtained by removing solvent by distillation under reduced pressure was dissolved in 3 ml of tetrahydrofurane. 0.24 ml (0.24 mmol, tetrahydrofurane solution) of 1.0 M tetrabutylammoniumfluoride was added and stirred overnight. After removing solvent by distillation under reduced pressure, the residue was purified by column chromatography using a 15:85 mixture of methanol and dichloromethane and precipitated using diethylether to obtain 46 mg of the title compound at 90% yield.
IH NMR (500 MHz, CD3OD); 7.92 (2H, d), 7.65 (IH, s), 7.57 (IH, d), 7.50-7.41 (2H, m), 7.30 (2H, d), 4.41 (2H, q), 4.33 (IH, q), 4.17 (IH, m), 3.84 (2H, t), 3.59 (IH, m), 3.44 (2H, t), 2.68 (IH, m), 2.50 (2H, m), 1.83 (IH, m), 1.68-1.62 (2H, m), 1.48-1.36 (2H, m), 1.32 (3H, d), 1.13 (3H, d), 0.96 (3H, d), 0.94 (3H, d) ESI MS (m/e) = 631 [M+H]+
[Preparation Example 10]
Preparation of (2i?,4S.5S)-5-r(tert-butoxycarbonyl)aminol-4-(rtert- butyl(dimethy0silyl1oxy}-2,7-dimethyloctanoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 2 instead of the compound obtained in Preparation Example 5, whereby 9.1 g of the title compound was obtained at 90% yield.
IH NMR (500 MHz, DMSO, d6); 6.57 (IH, d), 3.63 (IH, m), 3.47 (IH, m), 2.42 (IH, br), 1.77 (IH, m), 1.53 (IH, m), 1.36 (9H, s), 1.30-1.15 (3H, m), 1.07 (3H, d), 0.86 (9H, s), 0.84 (3H, d), 0.79 (3H, d), 0.09 (3H, s), 0.03 (3H, s)
[Preparation Example 11]
Preparation of tert-butyl ( 1 S)-2-("benzylamino)- 1 -methyl-2-oxoethylcarbamate 3.78 g (20 mmol) of t-butoxycarbonyl-(S)-alanine was dissolved in 100 ml of N,N- dimethylfomiamide, and cooled to 0°C, and 4.37 ml (40 mmol) of benzylamine, 4.6 g (24 mmol) EDC, and 3.24 g (24 mmol) of HOBT were added thereto. 20.9 ml (120 mmol) of N,N-diisopropylethylamine was further added, and heated to room temperature, followed by stirring overnight. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water and sodium chloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the residue was purified by column chromatography using a 1 :2 mixture of methylacetate and hexane, and 3.88 g of the title compound was obtained at 70% yield. IH NMR (500 MHz, CDC13); 7.33-7.23 (5H, m), 6.56 (IH, br), 5.02 (IH, br), 4.42 (2H, d), 4.18 (IH, br), 1.40 (9H, s), 1.37 (3H, d).
[Preparation Example 12]
Preparation of tert-butyl (lS.2S.4i?V5-(rflS)-2-rbenzylamino)-l-methyl-2- oxoethyl]amino) -2- { [tert-butyl(dimethyl silyl]oxy } - 1 -isobutyl-4-methyl-5- oxopentylcarbamate 1.34 g (4.8 mmol) of the compound obtained in Preparation Example 11 was dissolved in 20 ml of 4.0 N hydrochloride solution diluted with ethyl acetate, and stirred for 2 hours. After solvent distillation under reduced pressure and concentration, the residue was dissolved in 20 ml of N,N-dimethylformamide and cooled to 0°C, then 1.67 g (4.0 mmol) of the compound obtained in Preparation Example 10, EDC 0.92 g (4.8 mmol) and HOBT 0.81 g (6.0 mmol) were added thereto. 4.18 ml (24.0 mmol) of N,N- diisopropylethylamine was further added, and heated to room temperature, followed by stirring overnight. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 2:98 mixture of methanol and dichloromethane to obtain 2.06 g of the title compound at 89% yield.
IH NMR (400 MHz, CDC13); 7.28-7.16 (5H, m), 6.66 (IH, br), 6.45 (IH, d), 4.46 (IH, d), 4.41 (IH, d), 4.36 (2H, dd), 3.64 (IH, m), 3.56 (IH, dd), 2.43 (IH, m), 1.69-1.52 (2H, m), 1.43-1.35 (2H, m), 1.38 (9H, s), 1.31 (3H, d), 1.14 (IH, m), 1.01 (3H, d), 0.87 (3H, d), 0.85 (3H, d), 0.83 (9H, s), 0.01 (6H, s).
[Preparation Example 13]
Preparation of tert-butyl πS.2S.4i? -5-UαS)-2-(benzylaminoVl-methyl-2- oxoethyl]amino}-2-hvdroxy-l-isobutyl-4-methyl-5-oxopentylcarbamate 2.06 g (3.56 mmol) of the compound obtained in Preparation Example 12 was dissolved in 20 ml of tetrahydrofurane, and 7.12 ml (7.12 mmol tetrahydrofurane solution) of 1.0 N tetrabutylammoniumfluoride was added thereto, followed by stirring overnight. After removing solvent by distillation under reduced pressure, the residue was purified by column chromatography using ethyl acetate and solidified using hexane to obtain 1.56 g of the title compound at 95% yield. IH NMR (500 MHz, CDC13); 7.33-7.21 (5H, m), 6.69 (IH, br), 6.56 (IH, d), 4.62 (IH, d), 4.48 (IH, dd), 4.40 (2H, d), 3.53 (2H, br), 2.60 (IH, m), 1.76-1.58 (4H, m), 1.42 (9H, s), 1.38 (3H, d), 1.25 (IH, m), 1.12 (3H, d), 0.90 (6H, d).
[Example 2] Preparation of N-((lS,2S,4i?)-5-{[(lS)-2-(benzylamino)-l-methyl-2-oxoethyl]amino}-2- hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl)- 1 -methyl-2,2,4-trioxo- 1 ,2,3 ,4-tetrahydro- 2λ6, 1 -benzothiazine-7-carboxamide 93 mg (0.2 mmol) of the compound obtained in Preparation Example 13 was dissolved in 2.5 ml of 20% trifluoroacetic acid, and stirred for 30 minutes. After distillation under reduced pressure below room temperature to perform concentration, the mixture was dissolved in 50 ml Ν,Ν-dimethylformamide, and cooled at 0°C, then 77 mg (0.3 mmol) of l-methyl-2,2,4-trioxo-tetrahydro-2,6,l-benzothiazine-7-carboxylic acid and 114 mg (0.3 mmol) of HATU were added thereto. 0.5 ml (excess amount) of N,N-diisopropylethylamine was further added and heated to room temperature, followed by stirring for 4 hours. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 3:1 mixture of ethyl acetate and hexane to obtain 53 mg of the title compound at 44% yield.
IH NMR (400 MHz, CD3OD); 8.15 (IH, d), 7.77 (IH, s), 7.66 (IH, d), 7.33-7.21 (5H, m), 4.91 (2H, s), 4.43-4.31 (3H, m), 4.20 (IH, m), 3.60 (IH, m), 3.51 (3H,s), 2.71 (IH, m), 1.86 (IH, m), 1.70-1.62 (2H, m), 1.49-1.42 (2H, m), 1.32 (3H, d), 1.15 (3H, d), 0.97 (3H, d), 0.96 (3H, d)
ESI MS (m/e) = 601 [M+H]+
[Preparation Example 14]
Preparation of ethyl 3 - (propylsulfonyl)aminol benzoate 1.65 g (10 mmol) of ethyl 3-aminobenzoate and 2.81 ml (25 mmol) of propanesulfonylchloride were dissolved in 50 ml of dichloromethane and cooled to 0°C. 4.18 ml (30 mmol) of trimethylamine was added and heated to room temperature, followed by stirring for 2 hours. After solvent was removed by distillation under reduced pressure and eluted using ethylacetate, the residue was washed with saturated sodium bicarbonate solution and sodium chloride solution. The compound obtained by distillation under reduced pressure was dissolved in 50 ml of N,N-dimethylformamide, and 1.0 N of sodium hydroxide solution was added thereto, followed by stirring for 2 hours. After removing solvent by distillation under reduced pressure, the residue was acidified using 1.0 N of hydrochloride solution and eluted by ethyl acetate, then washed with sodium chloride solution. After removing solvent by distillation under reduced pressure, the residue was purified by column chromatography using a 1 :3 mixture of ethyl acetate and hexane to obtain 2.5 g of the title compound at 92% yield. 1H NMR (500 MHz, CDC13); 7.84 (IH, d), 7.80 (IH, s), 7.51 (IH, d), 7.43 (IH, t), 6.59 (IH, s), 4.39 (2H, q), 3.09 (2H, t), 1.87 (2H, m), 1.40 (3H, t), 1.03 (3H, t).
[Preparation Example 15]
Preparation of 3-[("propylsulfonyl)amino]benzoic acid 0.41 g (1.52 mmol) of the compound obtained in Preparation Example 14 was dissolved in 10 ml of tetrahydrofurane, 2 ml of methanol and 6 ml of 1.0 N lithium hydroxide, followed by stirring for 5 hours. After removing solvent by distillation under reduced pressure, the residue was diluted with water, and the solid produced by acidification using 1.0 N hydrochloride was filtered to obtain 0.33 g of the title preparation formulation at 89% yield. IH NMR (500 MHz, CD3OD); 7.89 (IH, s), 7.76 (IH, d), 7.47 (IH, d), 7.42 (IH, t), 3.07 (2H, t), 1.80 (2H, m), 1.00 (3H, t).
[Preparation Example 16] Preparation of N- lS)-3-methyl-l-rr2i?.4i?V4-methyl-5-oxotetrahvdro-2- furanv^butylj-S-ffpropylsulfonyπaminolbenzamide A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 15 instead of the compound obtained in Preparation Example 4, whereby 0.38 g of the title compound was obtained at 93% yield.
IH ΝMR (500 MHz, CDC13); 7.80 (IH, s), 7.72 (IH, s), 7.59 (IH, m), 7.41 (2H, d),
6.22 (IH, d), 4.66 (IH, m), 4.57 (IH, m), 3.09 (2H, t), 2.62 (IH, m), 2.42 (IH, m), 2.04
(IH, m), 1.92-1.82 (2H, m), 1.78-1.63 (2H, m), 1.50 (IH, m), 1.25 (3H, d), 1.01 (3H, t),
0.95 (6H, d).
[Preparation Example 17]
Preparation of (2RAS,5S)-4- i rtert-butyl(dimethyl silyl]oxyl -2.7-dimethyl-5-f ( 3-
[(propylsulfonyl aminolbenzoyl } amino octanoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 16 instead of the compound obtained in Preparation Example 5, whereby 0.45 g of the title compound was obtained at 91% yield.
IH ΝMR (500 MHz, CDC13); 8.56 (IH, s), 7.87 (IH, s), 7.64 (IH, d), 7.37 (IH, t), 7.29
(IH, d), 6.20 (IH, d), 4.36 (IH, m), 3.86 (IH, t), 3.06-2.94 (2H, m), 2.75 (IH, m), 1.90 (IH, m), 1.80-1.66 (3H, m), 1.56-1.46 (2H, m), 1.39 (IH, m), 1.21 (3H, d), 1.00 (3H, d), 0.99 (3H, d), 0.91 (9H, s), 0.82 (3H, t), 0.15 (3H, s), 0.09 (3H, s).
[Preparation Example 18] Preparation of benzyl 4-{(4S.7i?.9S)-4.7.11.11.12.12-hexamethyl-9-r(TSV3 -methyl- 1- ( { 3 -[(prop ylsulfonvPaminol benzoyl } amino)butyl] -3 ,6-dioxo- 10-oxa-2,5-diaza- 11 - silatridec- 1 -yl } benzoate A process was conducted in the same manner as in Preparation Example 9, except for using the compound obtained in Preparation Example 17 instead of the compound obtained in Preparation Example 6, whereby 91 mg of the title compound was obtained at 83% yield.
IH NMR (500 MHz, CDC13); 7.81 (2H, d), 7.43-7.28 (7H, m), 7.23 (IH, d), 7.16-7.10 (3H, m), 6.58 (2H, br), 5.31 (2H, s), 4.68 (IH, m), 4.42 (IH, dd), 4.25 (IH, m), 4.00 (IH, m), 3.67 (IH, m), 2.96-2.84 (2H, m), 2.47 (IH, m), 1.98 (IH, m), 1.80-1.64 (3H, m), 1.52-1.40 (2H, m), 1.47 (IH, m), 1.36 (3H, d), 1.27 (IH, m), 1.11 (3H, d), 0.96 (3H, d), 0.90 (9H, s), 0.90 (3H, d), 0.85 (3H, d), 0.11 (3H, s), 0.09 (3H, s)
[Example 3]
Preparation of 4-([((2S)-2-(r(2i?.4S.5S)-4-hydroxy-2 -dimethyl-5-('{3- [(propylsulfonyl aminolbenzoyl } amino octano yl] amino } propanoyQamino] methyl } benz oic acid A process was conducted in the same manner as in Example 1 , except for using the compound obtained in Preparation Example 18 instead of the compound obtained in Preparation Example 9, whereby 46 mg of the title compound was obtained at 71% yield.
IH NMR (500 MHz, CD3OD); 7.94 (2H, d), 7.64 (IH, s), 7.54 (IH, s), 7.41 (2H, d), 7.33 (2H, d), 4.43 (2H, d), 4.34 (IH, m), 4.15 (IH, m), 3.59 (1H, m), 3.09 (2H, t), 2.71 (IH, m), 1.88-1.76 (3H, m), 1.70-1.62 (2H, m), 1.48-1.38 (2H, m), 1.34 (3H, d), 1.14 (3H, d), 1.00 (3H, t), 0.96 (3H, d), 0.95 (3H, d) ESI MS (m/e) = 633 [M+H]+
[Preparation Example 19]
Preparation of ethyl 3-[(phenylsulfonyl amino1benzoate 0.83 g (5 mmol) of ethyl 3-aminobenzoate and 1.32 g (7.5 mmol) of benzenesulfonylchloride were dissolved in 25 ml of N,N-dimethylformamide and cooled to 0°C. 1.65 ml (15 mmol) of N-methylmorphorine was added thereto and heated to room temperature, followed by stirring for 2 hours. After a solvent was removed by distillation under reduced pressure and eluted using ethyl acetate, the residue was washed with saturated sodium carbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 1 :3 mixture of ethyl acetate and hexane to obtain 1.0 g of the title compound at 65% yield. IH NMR (500 MHz, CDC13); 7.80-7.76 (3H, m), 7.64 (IH, s), 7.53 (IH, d), 7.44 (2H, t), 7.38 (IH, d), 7.33 (IH, t), 6.76 (IH, s), 4.34 (2H, q), 1.36 (3H, t).
[Preparation Example 20]
Preparation of 3-[(phenylsulfonyl)amino1benzoic acid A process was conducted in the same manner as in Preparation Example 15, except for using the compound obtained in Preparation Example 19 instead of the compound obtained in Preparation Example 14, whereby 0.78 mg of the title compound was obtained at 86% yield.
IH NMR (500 MHz, CD3OD); 7.79-7.73 (3H, m), 7.69 (IH, m), 7.56 (IH, t), 7.48 (2H, t), 7.34-7.30 (2H, m).
[Preparation Example 21]
Preparation of N-(qS -3-methyl-l-rf2i .Ry4-methyl-5-oxotetrahydro-2- furanyl]butyl)-3-[(phenylsulfonyl amino]benzamide A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 20 instead of the compound obtained in Preparation Example 4, whereby 0.42 g of the title compound was obtained at 94% yield.
IH ΝMR (500 MHz, CDC13); 7.81 (2H, d), 7.69 (IH, s), 7.58-7.42 (5H, m), 7.38 (IH, d), 6.06 (IH, d), 4.62 (IH, m), 4.55 (IH, m), 2.57 (IH, m), 2.40 (IH, m), 2.01 (IH, m),
1.69 (IH, m), 1.62 (IH, m), 1.47 (IH, m), 1.24 (3H, d), 0.94 (3H, d), 0.93 (3H, d)
[Preparation Example 22]
Preparation of (2i?.4S.5S)-4-{rtert-butyl(dimethyl)silyl1oxy)-2.7-dimethyl-5-r(3- [fphenylsulfonyl)amino]benzoyl } amino)octanoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 21 instead of the compound obtained in Preparation Example 5, whereby 0.47 g of the title compound was obtained at 88% yield. IH NMR (500 MHz, CDC13); 8.55 (IH, br), 7.70 (2H, d), 7.65 (IH, s), 7.48 (IH, d), 7.39 (IH, t), 7.31-7.22 (4H, m), 6.18 (IH, d), 4.33 (IH, dd), 3.85 (IH, t), 2.71 (IH, m), 1.84 (IH, m), 1.68 (IH, m), 1.54-1.44 (2H, m), 1.39 (IH, m), 1.20 (3H, d), 0.99 (6H, d), 0.90 (9H, s), 0.14 (3H, s), 0.09 (3H, s)
[Preparation Example 23]
Preparation of benzyl 4-U4S R,9S)-4 Λ lΛ lΛ2Λ2- examethγl-9-\(lS)-3-methyl-l- ( { 3 - [(phenylsulfonvDamino] benzoyl I amino butyl] -3 ,6-dioxo- 10-oxa-2, 5 -diaza- 11- silatridec- 1 -yl I benzoate A process was conducted in the same manner as in Preparation Example 9, except for using the compound obtained in Preparation Example 22 instead of the compound obtained in Preparation Example 6, whereby 97 mg of the title compound was obtained at 86% yield. IH NMR (500 MHz, CDC13); 7.73 (2H, d), 7.70 (2H, br), 7.44-7.25 (12H, m), 7.20 (IH, t), 7.10 (IH, br), 7.04 (2H, br), 6.53 (2H, br), 5.31 (2H, s), 4.66 (IH, br), 4.33 (IH, m), 4.23 (IH, br), 4.05 (IH, br), 3.71 (IH, m), 2.49 (IH, m), 1.64 (IH, m), 1.52-1.42 (2H, m), 1.38-1.28 (2H, m), 1.12 (3H, d), 0.93 (6H, d), 0.90 (9H, s), 0.83 (3H, d), 0.12 (3H, s), 0.09 (3H, s)
[Example 4]
Preparation of 4-(r((2S)-2-([('2i?.4S.5S)-4-hvdroxy-2.7-dimethyl-5-r(3-
[(phenylsulfonvπamino]benzovUamino octanoyl amino>propanoyl)amino1methvUbenz oic acid A process was conducted in the same manner as in Example 1 , except for using the compound obtained in Preparation Example 23 instead of the compound obtained in Preparation Example 9, whereby 23 mg of the title compound was obtained at 32% yield.
IH NMR (500 MHz, CD3OD); 7.95 (2H, d), 7.78 (2H, d), 7.57-7.44 (5H, m), 7.37-7.26 (4H, m), 4.43 (2H, d), 4.33 (IH, m), 4.12 (IH, m), 3.57 (IH, m), 2.68 (IH, m), 1.79 (IH, m), 1.70-1.58 (2H, m), 1.47-1.38 (2H, m), 1.31 (3H, d), 1.13 (3H, d), 0.94 (3H, d). 0.93 (3H, d) ESI MS (m/e) = 667 [M+H]+
[Preparation Example 24]
Preparation of ethyl 3-r(2-thienylsulfonyl)amino1benzoate A process was conducted in the same manner as in Preparation Example 19, except for using 2-thiophensulfonylchloride instead of benzenesulfonylchloride, whereby 1.17 g of the title compound was obtained at 75% yield. IH NMR (500 MHz, CDC13); 7.84 (IH, d), 7.70 (IH, s), 7.54 (IH, d), 7.51 (IH, d), 7.45 (IH, d), 7.38 (IH, t), 7.00 (IH, dd), 6.78 (IH, s), 4.36 (2H, q), 1.37 (3H, t)
[Preparation Example 25]
Preparation of 3-[(2-thienylsulfonyl)aminolbenzoic acid A process was conducted in the same manner as in Preparation Example 15, except for using the compound obtained in Preparation Example 24 instead of the compound obtained in Preparation Example 14, whereby 0.96 g of the title compound was obtained at 91% yield. IH NMR (500 MHz, CD3OD); 7.79 (IH, s), 7.74 (IH, d), 7.71 (IH, d), 7.51 (IH, d), 7.39-7.33 (2H, m), 7.05 (IH, dd)
[Preparation Example 26]
Preparation of N- { (1 S)-3-methyl- 1 - r i?.4i-)-4-methyl-5-oxotetrahvdro-2- furanyl]buty -3-l(2-thienylsulfonyl)amino]benzamide A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 25 instead of the compound obtained in Preparation Example 4, whereby 0.45 g of the title compound was obtained at 99% yield. IH ΝMR (500 MHz, CDC13); 8.22 (IH, s), 7.70 (IH, s), 7.57 (IH, d), 7.54 (IH, d), 7.52
(IH, d), 7.41 (IH, d), 7.36 (IH, t), 7.00 (IH, dd), 6.17 (IH, d), 4.64 (IH, m), 4.59 (IH, m), 2.58 (IH, m), 2.41 (IH, m), 2.04 (IH, m), 1.75-1.62 (2H, m), 1.49 (IH, m), 1.25
(3H, d), 0.95 (3H, d), 0.93 (3H, d)
[Preparation Example 27]
Preparation of (2i?.4S.5S)-4-(rtert-butvirdimethyl silylloxyl-2.7-dimethyl-5-r{3-r - thienylsulfonyl amino]benzoyl } amino octanoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 26 instead of the compound obtained in Preparation Example 5, whereby 0.49 g of the title compound was obtained at 87% yield.
IH ΝMR (500 MHz, CDC13); 8.85 (IH, br), 7.69 (IH, s), 7.58 (IH, d), 7.42-7.28 (4H, m), 6.84 (IH, t), 6.19 (IH, d), 4.34 (IH, dd), 3.86 (IH, t), 2.72 (IH, m), 1.84 (IH, m), 1.70 (IH, m), 1.49 (2H, t), 1.38 (IH, m), 1.20 (3H, d), 0.98 (3H, d), 0.97 (3H, d), 0.90 (9H, s), 0.14 (3H, s), 0.09 (3H, s)
[Preparation Example 28]
Preparation of benzyl 4-((4S.7i?.9Sl-4.7.11.11.12.12-hexamethyl-9-rπS)-3-methyl-l- ( { 3 - [(2-τhienylsulfonyDamino] benzoyl I amino)butyl1 -3 ,6-dioxo- 10-oxa-2.5 -diaza- 11 - silatridec- 1 -yl I benzoate A process was conducted in the same manner as in Preparation Example 9, except for using the compound obtained in Preparation Example 27 instead of the compound obtained in Preparation Example 6, whereby 79 mg of the title compound was obtained at 75% yield.
IH NMR (500 MHz, CDC13); 7.71 (2H, br), 7.46-7.33 (11H, m), 7.22 (IH, t), 7.16-7.03 (3H, m), 6.88 (IH, t), 6.54 (IH, br), 6.39 (IH, br), 5.32 (2H, s), 4.61 (IH, br), 4.40 (IH, dd), 4.21 (IH, br), 4.03 (IH, br), 3.69 (IH, m), 2.50 (IH, m), 1.64 (IH, m), 1.50-1.42 (2H, m), 1.38-1.26 (2H, m), 1.16 (3H, d), 0.94 (6H, d), 0.90 (9H, s), 0.84 (3H, d), 0.11 (3H, s), 0.09 (3H, s)
[Example 5]
Preparation of 4-(r(T2SV2-(r(2 4S.5SV4-hvdroxy-2.7-dimethyl-5- 3-r(2- thienylsulfonvDaminolbenzoyl } amino)octanoyll amino } propanovDaminolmethyl } benzo ic acid 79 mg (0.09mmol) of the compound obtained in Preparation Example 28 was dissolved in 3 ml of tetrahydrofurane, 0.5 ml of methanol and 2 ml of 1.0 N lithium hydroxide, then stirred for 5 hours. After removing solvent by distillation under reduced pressure, the residue was diluted with water, and acidified using 1.0 N of hydrochloride solution, then eluted by ethyl acetate. The compound obtained after washing with sodium chloride solution and removing solvent by distillation under reduced pressure, was dissolved in 3 ml of tetrahydrofurane. 0.27 ml of 1.0 M tetrabutylammoniumfluoride (0.27 mmol, tetrahydrofurane solution) was added thereto and stirred overnight. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 15:85 mixture of methanol and dichloromethane, then solidified and filtered to obtain 28 mg of the title compound at 46% yield. IH NMR (500 MHz, CD3OD); 7.94 (2H, d), 7.69 (IH, d), 7.55 (IH, s), 7.54-7.51 (2H, m), 7.37-7.30 (4H, m), 7.03 (IH, dd), 4.42 (2H, d), 4.33 (IH, dd), 4.13 (IH, m), 3.57 (IH, m), 2.67 (IH, m), 1.80 (IH, m), 1.70-1.58 (2H, m), 1.48-1.37 (2H, m), 1.32 (3H, d), 1.13 (3H, d), 0.95 (3H, d), 0.93 (3H, d) ESI MS (m/e) = 673 [M+H]+
[Preparation Example 29]
Preparation of 3- [methylCpropylsulfonvDaminol benzoic acid After dissolving 1.86 g (6.85 mmol) of the compound obtained in Preparation Example 14 and 1.89 g (13.7 mmol) of potassium carbonate in 20 ml of N,N- dimethylformamide, 2.13 ml (34.25 mmol) of iodomethane was added thereto and stirred for 5 hours. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water and sodium chloride. A compound obtained after removing solvent by distillation under reduced pressure was dissolved in 35 ml of tetrahydrofurane, 7 ml of methanol and 21 ml of 1.0 N lithium hydroxide solution, then stirred for 5 hours. After removing solvent by distillation under reduced pressure, the residue was diluted with water, and the solid produced by acidification using 1.0 N hydrochloride solution was filtered to obtain 1.74 g of the title compound at 99% yield.
IH NMR (500 MHz, CD3OD); 8.05 (IH, s), 7.94 (IH, d), 7.67 (IH, d), 7.50 (IH, t), 3.35 (3H, s), 3.08 (2H, t), 1.86-1.74 (2H, m), 1.02 (3H, t)
[Preparation Example 30]
Preparation of N- ( ( 1 S)-3 -methyl- 1 - r(2 ?.4i?V4-methyl-5-oxotetrahvdro-2- furanyl]butyl \ -3 - [methyl (propylsulfonyl amino]benzamide A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 29 instead of the compound obtained in Preparation Example 4, whereby 0.4 g of the title compound was obtained at 94% yield.
IH NMR (500 MHz, CDC13); 7.80 (IH, s), 7.61 (IH, d), 7.53 (IH, d), 7.45 (IH, t), 6.01 (IH, d), 4.63 (IH, m), 4.48 (IH, m), 3.37 (3H, s), 2.98 (2H, dd), 2.62 (IH, m), 2.43 (IH, m), 2.00 (IH, m), 1.90-1.82 (2H, m), 1.77-1.63 (2H, m), 1.49 (IH, m), 1.25 (3H, d),
1.03 (3H, t), 0.96 (6H, d)
[Preparation Example 31] Preparation of (2RAS.5S)-4-i [tert-butylfdimethyl silylloxyl-2,7-dimethyl-5-f (3- [methyl(propylsulfonyl amino1benzoyl}amino octanoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 30 instead of the compound obtained in Preparation Example 5, whereby 0.48 g of the title compound was obtained at 95% yield.
IH NMR (500 MHz, CDC13); 7.80 (IH, s), 7.58 (2H, d), 7.44 (IH, s), 6.36(1H, d), 4.26 (IH, m), 3.82 (IH, t), 3.35 (3H, s), 2.96 (2H, dd), 2.64 (IH, m), 1.92-1.80 (3H, m), 1.64 (IH, m), 1.54-1.39 (3H, m), 1.20 (3H, d), 1.02 (3H, t), 0.97 (3H, d), 0.94 (3H, d), 0.90 (9H, s), 0.13 (3H, s), 0.11 (3H, s).
[Preparation Example 32]
Preparation of benzyl 4- i(4SJR.9S)-4 Λ 1.11.12.12-hexamethyl-9- (1 S)-3 -methyl- 1- ( { 3- [methyKpropylsulfonvDaminolbenzoyl } amino)butyll -3.6-dioxo- 10-oxa-2,5-diaza- 11-silatridec-l-v benzoate A process was conducted in the same manner as in Preparation Example 9, except for using the compound obtained in Preparation Example 31 instead of the compound obtained in Preparation Example 6, whereby 88 mg of the title compound was obtained at 79% yield. IH NMR (500 MHz, CDC13); 8.01 (2H, d), 7.84 (IH, s), 7.58 (2H, t), 7.48-7.29 (8H, m), 6.95 (IH, t), 6.89 (IH, d), 6.27 (IH, d), 5.35 (2H, s), 4.54-4.31 (4H, m), 3.73 (IH, m), 3.34 (3H, s), 2.95 (2H, dd), 2.54 (IH, m), 1.87-1.78 (2H, m), 1.69-1.56 (3H, m), 1.49 (IH, m), 1.37 (IH, m), 1.17 (3H, d), 1.12 (3H, d), 1.01 (3H, t), 0.96 (3H, d), 0.94 (3H, d), 0.91 (9H, s), 0.11 (3H, s), 0.09 (3H, s).
[Example 6]
Preparation of 4-(rrr2S)-2-(r(2i?.4S.5S)-4-hvdroxy-2.7-dimethyl-5-((3-
[methvKpropylsulfonyDaminolbenzoyl } amino octanoyl amino } propano vOaminol meth yl) benzoic acid A process was conducted in the same manner as in Example 1 , except for using the compound obtained in preparation Example 32 instead of the compound obtained in preparation Example 9, whereby 52 mg of the title compound was obtained at 80% yield.
IH NMR (500 MHz, CD3OD); 7.96 (2H, d), 7.87 (IH, s), 7.75 (IH, d), 7.60 (IH, d), 7.48 (IH, t), 7.36 (2H, d), 4.44 (2H, s), 4.33 (IH, m), 4.19 (IH, m), 3.60 (IH, m), 3.34 (3H, s), 3.09 (2H, dd), 2.71 (IH, m), 1.88-1.76 (3H, m), 1.70-1.61 (2H, m), 1.49-1.37 (2H, m), 1.33 (3H, d), 1.14 (3H, d), 1.02 (3H, t), 0.95 (3H, d), 0.94 (3H, d) ESI MS (m/e) - 647 [M+H]+
[Preparation Example 33]
Preparation of 3-[ethyl(propylsulfonyl amino]benzoic acid A process was conducted in the same manner as in Preparation Example 29, except for using iodoethane instead of iodomethane, whereby 0.25 g of the title compound was obtained at 92% yield.
IH NMR (500 MHz, CDC13); 8.07 (IH, d), 7.04 (IH, s), 7.64 (IH, d), 7.53 (IH, t), 3.80 (2H, q), 2.98 (2H, dd), 1.92-1.83 (2H, m), 1.15 (3H, t), 1.05 (3H, t)
[Preparation Example 34] Preparation of 3-rethylfpropylsulfonvnaminol-N-lf lS -3 -methyl- 1 -r(2fl,4i?)-4-methyl- 5-oxotetrahvdro-2-furanvHbutyl}benzamide A process was conducted in the same manner as in Preparation Example 5 except for using the compound obtained in Preparation Example 33 instead of the compound obtained in Preparation Example 4, whereby 0.18 g of the title compound was obtained at 83% yield.
IH NMR (500 MHz, CDC13); 7.78 (IH, s), 7.59 (IH, d), 7.55 (IH, d), 7.47 (IH, t), 6.06 (IH, d), 4.63 (IH, m), 4.48 (IH, m), 3.78 (2H, q), 2.98 (2H, dd), 2.62 (IH, m), 2.43 (IH, m), 2.01 (IH, m), 1.92-1.82 (2H, m), 1.78-1.64 (2H, m), 1.50 (IH, m), 1.26 (3H, d), 1.14 (3H, t), 1.04 (3H, t), 0.96 (6H, d)
[Preparation Example 35]
Preparation of (2i?,4S.5S)-4-(ltert-butyl(dimethvnsilylloxyl-5-(,{3-
[ethyl('propylsulfonyπamino]benzoyl}amino)-2,7-dimethyloctanoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 34 instead of the compound obtained in Preparation Example 5, whereby 0.22 g of the title compound was obtained at 98% yield.
IH NMR (500 MHz, CDC13); 7.77 (IH, s), 7.66 (IH, d), 7.53 (IH, d), 7.48 (IH, t), 6.38 (IH, d), 4.28 (IH, m), 3.84-3.75 (3H, m), 2.97 (2H, dd), 2.65 (IH, m), 1.93-1.83 (3H, m), 1.66 (IH, m), 1.56-1.40 (3H, m), 1.21 (3H, d), 1.13 (3H, t), 1.03 (3H, t), 0.97 (3H, d), 0.95 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.09 (3H, s)
[Preparation Example 36] Preparation of benzyl 4-{(4S,7i?.9SV9-r(lS)-l-('(3-
[ethyl(propylsulfonvDamino]benzoyl } amino)-3 -methylbutyll -4,7,11,11,12,12- hexamethyl-3.6-dioxo- 10-oxa-2.5-diaza- 11 -silatridec- 1 -yllbenzoate A process was conducted in the same manner as in Preparation Example 9, except for using the compound obtained in Preparation Example 35 instead of the compound obtained in Preparation Example 6, whereby 89 mg of the title compound was obtained at 71% yield.
IH NMR (500 MHz, CDC13); 8.01 (2H, d), 7.80 (IH, s), 7.63 (IH, d), 7.54-7.29 (9H, m), 6.97 (IH, t), 6.89 (IH, d), 6.31 (IH, d), 5.35 (2H, d), 4.54-4.31 (4H, m), 3.82-3.70 (3H, m), 2.96 (2H, dd), 2.53 (IH, m), 1.89-1.81(2H, m), 1.70-1.55 (3H, m), 1.49 (IH, m), 1.38 (IH, m), 1.16 (3H, d), 1.12 (3H, t), 1.10 (3H, d), 1.02 (3H, t), 0.95 (3H, d), 0.94 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.09 (3H, s)
[Example 7] Preparation of 4-{r((2S)-2-{r(2i?.4S.5S)-5-({3-
[ethyl(propylsulfonyDaminolbenzoyl}amino -4-hvdroxy-2.7- dimethyloctanovn amino } propanoy l)amino]methyl } benzoic acid A process was conducted in the same manner as in Example 1, except for using the compound obtained in preparation Example 36 instead of the compound obtained in preparation Example 9, whereby 43 mg of the title compound was obtained at 66% yield.
IH NMR (500 MHz, CD3OD); 7.96 (2H, d), 7.84 (IH, s), 7.81 (IH, d), 7.56 (IH, d),
7.51 (IH, t), 7.37 (2H, d), 4.44 (2H, s), 4.34 (IH, m), 4.19 (IH, m), 3.79 (2H, q), 3.60
(IH, m), 3.09 (2H, dd), 2.71 (IH, m), 1.88-1.78 (2H, m), 1.72-1.63 (2H, m), 1.49-1.37 (3H, m), 1.33 (3H, d), 1.14 (3H, d), 1.10 (3H, t), 1.03 (3H, t), 0.96 (3H, d), 0.94 (3H, d)
ESI MS (m/e) = 661 [M+H]+
[Preparation Example 37]
Preparation of 3-[propyl(propylsulfonyl amino1benzoic acid A process was conducted in the same manner as in Preparation Example 29, except for using iodopropane instead of iodomethane, whereby 0.27 mg of the title compound was obtained at 93% yield.
IH NMR (500 MHz, CDC13); 8.08-8.03 (2H, m), 7.66 (IH, d), 7.52 (IH, t), 3.70 (2H, t), 2.98 (2H, dd), 1.92-1.83 (2H, m), 1.54-1.45 (2H, m), 1.04 (3H, t), 0.91 (3H, t)
[Preparation Example 38]
Preparation of N- 1 ( 1 S)-3 -methyl- 1 - l(2i-.4i? -4-methyl-5-oxotetrahvdro-2- furanyl] butyl } -3 - [prop vKpropylsulfonvPamino] benzamide A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 37 instead of the compound obtained in Preparation Example 4, whereby 0.17 g of the title compound was obtained at 75% yield.
IH NMR (500 MHz, CDC13); 7.79 (IH, s), 7.59 (IH, d), 7.55 (IH, d), 7.47 (IH, t), 6.14 (IH, d), 4.63 (IH, m), 4.48 (IH, m), 3.67 (2H, t), 2.97 (2H,dd), 2.61 (IH, m), 2.43 (IH, m), 2.00 (IH, m), 1.91-1.82 (2H, m), 1.77-1.64 (2H, m), 1.52-1.44 (3H, m), 1.26 (3H, d),
1.03 (3H, t), 0.95 (6H, d), 0.90 (3H, t)
[Preparation Example 39] Preparation of ("2i?,4S.5S)-4-{[tert-butyl(dimethyl silylloxyl-2.7-dimethyl-5-r(3- [propyl(propylsulfonyl aminolbenzoy amino octanoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 38 instead of the compound obtained in Preparation Example 5, whereby 0.2 g of the title compound was obtained at 97% yield.
IH NMR (500 MHz, CDC13); 7.78 (IH, s), 7.65 (IH, d), 7.53 (IH, d), 7.47 (IH, t), 6.39 (IH, d), 4.28 (IH, m), 3.82 (IH, dd), 3.67 (2H, t), 2.96 (2H, dd), 2.66 (IH, m), 1.96- 1.82 (3H, m), 1.66 (IH, m), 1.58-1.40 (5H, m), 1.21 (3H, d), 1.12 (3H, t), 0.97 (3H, d), 0.95 (3H, d), 0.92 (9H, s), 0.86 (3H, t), 0.13 (3H, s), 0.11 (3H, s)
[Preparation Example 40]
Preparation of benzyl 4-(r4S.7i?.9S)-4.7.11.11.12,12-hexamethyl-9-r('lS)-3-methyl-l- ({3-[propylfpropylsulfonyl)aminolbenzoyl|amino)butyll-3,6-dioxo-10-oxa-2,5-diaza- 11-silatridec-l-yl } benzoate A process was conducted in the same manner as in Preparation Example 9, except for using the compound obtained in Preparation Example 39 instead of the compound obtained in Preparation Example 6, whereby 100 mg of the title compound was obtained at 85% yield. IH NMR (500 MHz, CDC13); 8.02 (2H, d), 7.81 (IH, s), 7.63 (IH, d), 7.54 (IH, d), 7.48 (IH, d), 7.44 (2H, d), 7.39 (2H, t), 7.35 (IH, d), 7.31 (2H, d), 6.97 (IH, t), 6.91 (IH, d), 6.31 (IH, d), 5.30 (2H, s), 4.55-4.30 (4H, m), 3.77-3.60 (3H, m), 2.95 (2H, dd), 2.53 (IH, m), 1.90-1.80 (2H, m), 1.70-1.34 (7H, m), 1.17 (3H, d), 1.13 (3H, d), 1.02 (3H, t), 0.96 (3H, d), 0.95 (3H, d), 0.92 (9H, s), 0.88 (3H, t), 0.11 (3H, s), 0.10 (3H, s)
[Example 8]
Preparation of 4-(r((2S)-2-U(2i?,4S,5S -4-hvdroxy-2.7-dimethyl-5- 3-
[propyl(propylsulfonvπaminolbenzoyl}amino octanoyl]amino}propanoyl amino1methv 1} benzoic acid A process was conducted in the same manner as in Example 1 , except for using the compound obtained in Preparation Example 40 instead of the compound obtained in Preparation Example 9, whereby 53 mg of the title compound was obtained at 55% yield.
IH NMR (500 MHz, CD3OD); 7.97 (2H, d), 7.87 (IH, s), 7.82 (IH, d), 7.58 (IH, d), 7.52 (IH, t), 7.38 (2H, d), 4.45 (2H, s), 4.35 (IH, m), 4.20 (IH, m), 3.71 (2H, t), 3.61 (IH, m), 3.08 (2H, t), 2.72 (IH, m), 1.89-1.78 (2H, m), 1.72-1.62 (2H, m), 1.51-1.38 (5H, m), 1.34 (3H, d), 1.15 (3H, d), 1.04 (3H, t), 0.96 (3H, d), 0.95 (3H, d), 0.91 (3H, t) ESI MS (m/e) = 675 [M+H]+
[Preparation Example 41]
Preparation of 3- rbenzyl(propylsulfonyl)aminol benzoic acid A process was conducted in the same manner as in Preparation Example 29, except for using benzylbromide instead of iodomethane, whereby 0.3 g of the title compound was obtained at 90% yield.
IH NMR (500 MHz, CD3OD); 7.95 (IH, s), 7.88 (IH, d), 7.53 (IH, d), 7.40 (IH, t), 7.27-7.16 (5H, m), 4.92 (2H, s), 3.15 (2H, dd), 1.90-1.84 (2H, m), 1.06 (3H, t)
[Preparation Example 42] Preparation of 3-rbenzylfpropylsulfonvnaminol-N-((lS)-3-methyl-l-rf2i?.4i?V4- methyl-5-oxotetrahvdro-2-furanyl1butvUbenzamide A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 41 instead of the compound obtained in Preparation Example 4, whereby 0.21 g of the title compound was obtained at 85% yield.
IH NMR (500 MHz, CDC13); 7.60 (IH, s), 7.54 (IH, d), 7.42 (IH, d), 7.37 (IH, t), 7.29-7.21 (5H, m), 5.92 (IH, d), 4.88 (2H, d), 4.61 (IH, m), 4.44 (IH, m), 3.04 (2H, dd), 2.56 (IH, m), 2.39 (IH, m), 2.02-1.86 (3H, m), 1.70 (IH, m), 1.61 (IH, m), 1.47 (IH, m), 1.25 (3H, d), 1.06 (3H, t), 0.95 (3H, d), 0.93 (3H, d)
[Preparation Example 43]
Preparation of (2i?,4S,5S)-5-({3-[benzyl('propylsulfonyl)aminolbenzoyl}amino')-4-
{ [tert-butyl(dimethyl)silyl]oxy}-2,7-dimethyloctanoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 42 instead of the compound obtained in Preparation Example 5, whereby 0.25 g of the title compound was obtained at 97% yield.
IH NMR (500 MHz, CDC13); 7.68 (IH, s), 7.57 (IH, d), 7.39 (IH, d), 7.36 (IH, t), 7.27-7.19 (5H, m), 6.25 (IH, d), 4.88 (2H, dd), 4.24 (IH, m), 3.80 (IH, t), 3.03 (2H, dd),
2.64 (IH, m), 1.96-1.80 (3H, m), 1.61 (IH, m), 1.53-1.38 (3H, m), 1.21 (3H, d), 1.05
(3H, t), 0.95 (6H, d), 0.92 (9H, s), 0.13 (3H, s), 0.10 (3H, s)
[Preparation Example 44] Preparation of benzyl 4-{f4S.7i?.9S 9-r(TS)-l-α3-
[benzyl(propylsulfonyl amino1benzoyl| amino)-3-methylbutyl1-4,7, 11,11,12.12- hexamethyl-3 ,6-dioxo- 10-oxa-2,5-diaza- 11 -silatridec- 1 -yl 1 benzoate A process was conducted in the same manner as in Preparation Example 9, except for using the compound obtained in Preparation Example 43 instead of the compound obtained in Preparation Example 6, whereby 91 mg of the title compound was obtained at 78% yield.
IH NMR (500 MHz, CDC13); 8.01 (2H, d), 7.69 (IH, s), 7.57 (IH, d), 7.46-7.18 (14H, m), 6.95 (IH, t), 6.85 (IH, d), 6.19 (IH, d), 5.35 (2H, s), 4.87 (2H, dd), 4.54-4.26 (4H, m), 3.72 (IH, dd), 3.02 (2H, dd), 2.51 (IH, m), 1.94-1.85 (2H, m), 1.64-1.24 (5H, m), 1.11 (3H, d), 1.08-1.02 (6H, m), 0.99-0.90 (15H, m), 0.11 (3H, s), 0.10 (3H, s)
[Example 9]
Preparation of 4-f r((2S)-2-(r(2 4£5S)-5-ff3- [benzyl('propylsulfonyl)aminolbenzoyl)amino -4-hydroxy-2,7- dimethyloctanoyl] amino } propano yl amino]methyl } benzoic acid A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 44 instead of the compound obtained in Preparation Example 28, whereby 39 mg of the title compound was obtained at 57% yield.
IH NMR (500 MHz, CD3OD); 7.96 (2H, d), 7.79 (IH, s), 7.70 (IH, d), 7.46 (IH, d), 7.42-7.35 (3H, m), 7.30-7.16 (5H, m), 4.92 (2H, s), 4.44 (2H, s), 4.34 (IH, m), 4.16 (IH, m), 3.60 (IH, m), 3.18 (2H, t), 2.70 (IH, m), 1.94-1.77 (3H, m), 1.72-1.56 (2H, m), 1.50-1.36 (2H, m), 1.31 (3H, d), 1.14 (3H, d), 1.06 (3H, t), 0.96 (3H, d), 0.95 (3H, d) ESI MS (m/e) = 723 [M+H]+
[Preparation Example 45]
Preparation of ethyl 3-[(ethylsulfonvDamino1benzoate A process was conducted in the same manner as in Preparation Example 14, except for using ethanesulfonylchloride instead of propanesulfonylchloride, whereby
0.65 g of the title compound was obtained at 61% yield.
IH NMR (500 MHz, CDC13); 7.86-7.82 (2H, m), 7.53 (IH, d), 7.43 (IH, t), 6.72 (IH, s),
4.39 (2H, q), 3.15 (2H, q), 1.40 (3H, t), 1.38 (3H, t)
[Preparation Example 46]
Preparation of ethyl 3-[("ethylsulfonyl)amino]benzoate A process was conducted in the same manner as in Preparation Example 29, except for using the compound obtained in Preparation Example 45 instead of the compound obtained in Preparation Example 14, whereby 0.57 g of the title compound was obtained at 92% yield.
IH NMR (500 MHz, CDC13); 8.07 (IH, s), 8.02 (IH, d), 7.72 (IH, d), 7.50 (IH, t), 3.41
(3H, s), 3.07 (2H, q), 1.38 (3H, t)
[Preparation Example 47]
Preparation of 3 -r(ethylsulfonviymethyl aminol -N- { ( 1 S)-3 -methyl- 1 -\( 2RAR V4- methyl-5-oxotetrahvdro-2-furanyl'lbutyl}benzamide A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 46 instead of the compound obtained in Preparation Example 4, whereby 0.17 g of the title compound was obtained at 81% yield.
IH ΝMR (500 MHz, CDC13); 7.82 (IH, s), 8.60 (IH, d), 7.58 (IH, d), 7.43 (IH, t), 6.26 (IH, d), 4.63 (lH,m), 4.48 (IH, m), 3.37 (3H, s), 3.05 (2H, q), 2.61 (IH, m), 2.43 (IH, m), 1.99 (IH, m), 1.78-1.62 (2H, m), 1.49 (IH, m), 1.36 (3H, t), 1.24 (3H, d), 0.95 (6H, d)
[Preparation Example 48]
Preparation of r2i?,4S,5S)-4-(rtert-butyl(dimethvnsilylloxyl-5-((3- [(ethylsulfonyπ(methyl amino]benzoyl}amino -2,7-dimethyloctanoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 47 instead of the compound obtained in Preparation Example 5, whereby 0.2 g of the title compound was obtained at 97% yield. IH NMR (500 MHz, CDC13); 7.81 (IH, s), 7.62-7.57 (2H, m), 7.45 (IH, t), 6.36 (IH, d),
4.28 (IH, m), 3.82 (IH, t), 3.37 (3H, s), 3.04 (2H, q), 2.64 (IH, m), 1.89 (IH, m), 1.64
(IH, m), 1.56-1.38 (3H, m), 1.36 (3H, t), 1.21 (3H, d), 0.97 (3H, d), 0.96 (3H, d), 0.90
(9H, s), 0.13 (3H, s), 0.11 (3H, s)
[Preparation Example 49]
Preparation of benzyl 4-((4S,7i?,9S -9-r(lS)-l-r(3-
[(ethylsulfonvD(methyl aminolbenzoyl } amino -3 -methylbutyl]-4,7, 11,11,12,12- hexamethyl-3 ,6-dioxo- 10-oxa-2 , 5 -diaza- 11 -silatridec- 1 -yl } benzoate A process was conducted in the same manner as in Preparation Example 9, except for using the compound obtained in Preparation Example 48 instead of the compound obtained in Preparation Example 6, whereby 103 mg of the title compound was obtained at 75% yield.
IH NMR (500 MHz, CDC13); 8.01 (2H, d), 7.85 (IH, s), 7.61 (IH, d), 7.57 (IH, d), 7.48-7.30 (8H, m), 6.97 (IH, t), 6.92 (IH, d), 6.29 (IH, d), 5.36 (2H, s), 4.55-4.32 (4H, m), 3.74 (IH, dd), 3.35 (3H, s), 3.03 (2H, q), 2.54 (IH, m), 1.70-1.56 (3H, m), 1.49 (IH, m), 1.39 (IH, m), 1.35 (3H, t), 1.17 (3H, d), 1.13 (3H, d), 0.90 (3H, d), 0.95 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.09 (3H, s)
[Example 10]
Preparation of 4-(rff2S -2-(r(2i?,4S,5S)-5- -
[(ethylsulfonyl)(methyl amino]benzoyl } amino -4-hydroxy-2,7- dimethyloctanoyl] amino } propanoy Damino] methyl } benzoic acid A process was conducted in the same manner as in Example 1 , except for using the compound obtained in Preparation Example 49 instead of the compound obtained in
Preparation Example 9, whereby 56 mg of the title compound was obtained at 72% yield.
IH NMR (500 MHz, CD3OD); 7.96 (2H, d), 7.88 (IH, s), 7.75 (IH, d), 7.61 (IH, d),
7.48 (IH, t), 7.37 (2H, d), 4.44 (2H,s), 4.34 (IH, m), 4.18 (IH, m), 3.60 (IH, m), 3.35 (3H, s), 3.14 (2H, q), 2.69 (IH, m), 1.84 (IH, m), 1.70-1.60 (2H, m), 1.48-1.36 (2H, m),
1.34-1.28 (6H, m), 1.14 (3H, d), 0.95 (3H, d), 0.94 (3H, d)
ESI MS (m/e) = 633 [M+H]+
[Preparation Example 50] Preparation of ethyl 3-[(butylsulfonyl aminolbenzoate A process was conducted in the same manner as in Preparation Example 19, except for using 1-butanesulfonylchloride instead of benzenesulfonylchloride, whereby 1.08 g of the title compound was obtained at 76% yield. IH NMR (500 MHz, CDC13); 7.87-7.82 (2H, m), 7.53 (IH, d), 7.42 (IH, t), 6.96 (IH, s), 4.40 (2H, q), 3.11 (2H, dd), 1.86-1.78 (2H, m), 1.46-1.36 (5H, m), 0.89 (3H, t)
[Preparation Example 51]
Preparation of 3- [(butylsulfonvDfmethyDamino] benzoic acid A process was conducted in the same manner as in Preparation Example 29, except for using the compound obtained in Preparation Example 50 instead of the compound obtained in Preparation Example 14, whereby 0.96 g of the title compound was obtained at 93% yield.
IH NMR (500 MHz, CD3OD); 8.05 (IH, s), 7.94 (IH, d), 7.66 (IH, d), 7.50 (IH, t), 3.35 (3H, s), 3.10 (2H, dd), 1.74-1.70 (2H, m), 1.46-1.42 (2H, m), 0.92 (3H, t)
[Preparation Example 52]
Preparation of 3 -KbutylsulfonylϊmethvDaminol -N- l S -3-methyl- 1 - \(2RAR)-4- methyl-5-oxotetrahvdro-2-furanyllbutyl|benzamide A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 51 instead of the compound obtained in Preparation Example 4, whereby 0.17 g of the title compound was obtained at 79% yield.
IH NMR (500 MHz, CDC13); 7.81 (IH, d), 7.59 (2H, dd), 7.42 (IH, t), 6.38 (IH, d), 4.63 (IH, dd), 4.48 (IH, m), 3.35 (3H, s), 2.99 (2H, dd), 2.61 (IH, m), 2.44 (IH, m),
1.99 (IH, m), 1.86-1.73 (3H, m), 1.66 (IH, m), 1.53-1.36 (3H, m), 1.23 (3H, d), 0.94
(6H, d), 0.90 (3H, t)
[Preparation Example 53] Preparation of. r2i?.4S.5S)-4-{ltert-butyl("dimethvnsilylloxy}-5-({3-
[('butylsulfonyl (methvπamino1benzoyl}amino)-2,7-dimethyloctanoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 52 instead of the compound obtained in Preparation Example 5, whereby 0.2 g of the title compound was obtained at 98% yield.
IH NMR (500 MHz, CDC13); 7.80 (IH, s), 7.62-7.57 (2H, m), 7.45 (IH, t), 6.36 (IH, d), 4.28 (IH, m), 3.82 (IH, dd), 3.36 (3H, s), 2.99 (2H, dd), 2.66 (IH, m), 1.88 (IH, m), 1.84-1.75 (2H, m), 1.65 (IH, m), 1.58-1.36 (5H, m), 1.21 (3H, d), 1.02-0.86 (18H, m), 0.13 (3H, s), 0.1 l (3H, s)
[Preparation Example 54]
Preparation of benzyl 4-{(4S.7i-.9S)-9-[(lS)-l-f(3-
[(butylsulfonvD(methvDaminolbenzoyl) aminoV3-methylbutyl"[-4,7, 11,11,12,12- hexamethyl-3 ,6-dioxo- 10-oxa-2 , 5 -diaza- 11 -silatridec- 1 - yl } benzoate A process was conducted in the same manner as in Preparation Example 9, except for using the compound obtained in Preparation Example 53 instead of the compound obtained in Preparation Example 6, whereby 113 mg of the title compound was obtained at 80%) yield. IH NMR (500 MHz, CDC13); 8.01 (2H, d), 7.84 (IH, s), 7.58 (2H, m), 7.49-7.29 (8H, m), 6.96 (IH, t), 6.90 (IH, d), 6.29 (IH, d), 5.35 (2H, s), 4.54-4.30 (4H, m), 3.74 (IH, dd), 3.34 (3H, s), 2.97 (2H, dd), 2.53 (IH, m), 1.82-1.74 (2H, m), 1.72-1.56 (3H, m), 1.54-1.34 (4H, m), 1.17 (3H, d), 1.12 (3H, d), 1.02-0.86 (18H, m), 0.11 (3H, s), 0.09 (3H, s) [Example 11]
Preparation of 4-{r(T2SV2-(l(2i?,4S,5SV5- 3-
[(butylsulfonyl)(methyl)amino]benzoyl}amino)-4-hvdroxy-2,7- dimethyloctano yl] amino } propano vDamino] methyl ) benzoic acid A process was conducted in the same manner as in Example 1 , except for using the compound obtained in Preparation Example 54 instead of the compound obtained in
Preparation Example 9, whereby 63 mg of the title compound was obtained at 74% yield. IH NMR (500 MHz, CD3OD); 7.96 (2H, d), 7.87 (IH, s), 7.75 (IH, d), 7.60 (IH, d),
7.48 (IH, t), 7.37 (2H, d), 4.44 (2H, s), 4.34 (IH, m), 4.18 (IH, m), 3.60 (IH, m), 3.35
(3H, s), 3.11 (2H, dd), 2.70 (IH, m), 1.84 (IH, m), 1.77-1.61 (4H, m), 1.49-1.38 (4H, m), 1.33 (3H, d), 1.14 (3H, d), 0.96 (3H, d), 0.94 (3H, d), 0.91 (3H, t)
ESI MS (m/e) = 661 [M+H]+
[Preparation Example 55]
Preparation of ethyl 3-r(benzylsulfonyl)amino1benzoate A process was conducted in the same manner as in Preparation Example 14, except for using toluenesulfonylchloride instead of propanesulfonylchloride, whereby 2.48 g of the title compound was obtained at 78% yield.
IH NMR (500 MHz, CDC13); 7.84 (IH, m), 7.71 (IH, s), 7.44-7.40 (2H, m), 7.38-7.32
(3H, m), 7.29-7.25 (2H, m), 6.36 (IH, s), 4.39 (2H, q), 4.36 (2H, s), 1.41 (3H, t)
[Preparation Example 56] Preparation of 3-[(benzylsulfonyl (methyl)amino]benzoic acid A process was conducted in the same manner as in Preparation Example 29, except for using the compound obtained in Preparation Example 55 instead of the compound obtained in Preparation Example 14, whereby 2.3 g of the title compound was obtained at 98% yield.
IH NMR (500 MHz, CD3OD); 7.90-7.86 (2H, m), 7.49-7.32 (7H, m), 4.44 (2H, s), 3.24 (3H, s)
[Preparation Example 57] Preparation of S-rrbenzylsulfonvnfmethvnaminol-N-iα^-S-methyl-l-^i?^/? ^- methyl-5-oxotetrahvdro-2-furanyllbutyl}benzamide A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 56 instead of the compound obtained in Preparation Example 4, whereby 0.2 g of the title compound was obtained at 83 % yield.
1H ΝMR (500 MHz, CDC13); 7.56 (IH, s), 7.52 (IH, d), 7.43-7.36 (7H,m), 5.93 (IH, d), 4.63 (IH, m), 4.48 (IH, m), 4.31 (2H, s), 3.18 (3H, s), 2.61 (IH, m), 2.43 (IH, m), 2.00 (IH, m), 1.78-1.64 (2H, m), 1.51 (IH, m), 1.26 (3H, d), 0.98 (3H, d), 0.96 (3H, d)
[Preparation Example 58]
Preparation of (2i?,4S,5S)-5-('{3-[(benzylsulfonyπrmethyl)aminolbenzoyl}amino')-4- { [tert-butylCdimethvDsilylloxy} -2,7-dimethyloctanoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 57 instead of the compound obtained in Preparation Example 5, whereby 0.24 g of the title compound was obtained at 97% yield.
IH NMR (500 MHz, CDC13); 7.68 (IH, s), 7.55 (IH, d), 7.45-7.33 (7H, m), 6.32 (IH, d), 4.34-4.25 (3H, m), 3.82 (IH, dd), 3.15 (3H, s), 2.66 (IH, m), 1.90 (IH, m), 1.65 (IH, m), 1.58-1.40 (3H, m), 1.21 (3H, d), 0.97 (3H, d), 0.96 (3H, d), 0.91 (9H, s), 0.13 (3H, s), 0.10 (3H, s)
[Preparation Example 59]
Preparation of benzyl 4-(f4S,7i?,9SV9-r(lS)-l-('(3- [(benzylsulfonyl')(methyl)aminolbenzoyl}amino)-3-methylbutyl]-4,7, 11 , 11 , 12, 12- hexamethyl-3 ,6-dioxo- 10-oxa-2,5-diaza- 11 -silatridec- 1 -yl I benzoate A process was conducted in the same manner as in Preparation Example 9, except for using the compound obtained in Preparation Example 58 instead of the compound obtained in Preparation Example 6, whereby 83 mg of the title compound was obtained at 73% yield.
IH NMR (500 MHz, CDC13); 8.01 (2H, d), 7.73 (IH, s), 7.54 (IH, d), 7.45-7.28 (14H, m), 6.93 (IH, t), 6.89 (IH, d), 6.25 (IH, d), 5.35 (2H, s), 4.53-4.30 (4H, m), 4.28 (2H, s), 3.73 (IH, dd), 3.17 (3H, s), 2.54 (IH, m), 1.70-1.56 (3H, m), 1.49 (IH, m), 1.38 (IH, m), 1.16 (3H, d), 1.13 (3H, d), 0.97 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.09 (3H, s)
[Example 12]
Preparation of 4-fr(f2SV2-U(2i;.4S.5SV5-((3-
[(benzylsulfonyl (methyl amino1benzoyl}amino)-4-hydroxy-2.7- dimethyloctano yl] amino } propano vDaminol methyl ) benzoic acid A process was conducted in the same manner as in Example 1 , except for using the compound obtained in Preparation Example 59 instead of the compound obtained in Preparation Example 9, whereby 23 mg of the title compound was obtained at 38% yield.
IH NMR (500 MHz, CD3OD); 7.95 (2H, d), 7.76 (IH, s), 7.71 (IH, d), 7.44-7.32 (9H, m), 4.46 (2H, s), 4.43 (2H, s), 4.33 (IH, m), 4.18 (IH, m), 3.61 (IH, m), 3.25 (3H, s), 2.70 (IH, m), 1.85 (IH, m), 1.70-1.62 (2H, m), 1.50-1.38 (2H, m), 1.33 (3H, d), 1.14 (3H, d), 0.96 (3H, d), 0.95 (3H, d) ESI MS (m/e) = 695 [M+H]+
[Preparation Example 60]
Preparation of ethyl 3 -(" { [2-( 1 -naphthvPethyl] sulfonyl I amino)benzoate A process was conducted in the same manner as in Preparation Example 14, except for using 2-(l-naphthyl)ethanesulfonylchloride instead of propanesulfonylchloride, whereby 0.3 g of the title compound was obtained at 99% yield.
IH NMR (500 MHz, CDC13); 7.85 (IH, d), 7.80-7.74 (3H, m), 7.56 (IH, s), 7.48-7.29 (5H, m), 7.24 (IH, d), 6.30 (IH, s), 4.38 (2H, q), 3.65-3.44 (4H, m), 1.39 (3H, s)
[Preparation Example 61]
Preparation of 3 -("methyl ( [2-( 1 -naphthvDethyl] sulfonyl 1 amino)benzoic acid A process was conducted in the same manner as in Preparation Example 29, except for using the compound obtained in Preparation Example 60 instead of the compound obtained in Preparation Example 14, whereby 0.24 g of the title compound was obtained at 83% yield.
IH NMR (500 MHz, CD3OD); 8.09 (IH, s), 7.94 (IH, d), 7.89 (IH, d), 7.86 (IH, d), 7.76 (IH, t), 7.67 (IH, d), 7.52-7.44 (3H, m), 7.39 (2H, d), 3.54-3.42 (4H, m), 3.38 (3H, s)
[Preparation Example 62]
Preparation of N- l S)-3 -methyl- 1 - rC2i?.4i? -4-methyl-5 -oxotetrahvdro-2- furanyl]butyl I -3-fmethyl ( \2-( 1 -naphthvDethyll sulfonyl } amino benzamide A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 61 instead of the compound obtained in Preparation Example 4, whereby 0.28 g of the title compound was obtained at 97% yield. IH NMR (500 MHz, CDC13); 7.91 (IH, d), 7.86 (IH, d), 7.83 (IH, s), 7.76 (IH, d), 7.60 (IH, d), 7.57 (IH, d), 7.55-7.42 (3H, m), 7.39 (IH, t), 7.34 (IH, d), 6.13 (IH, d), 4.62 (IH, m), 4.46 (IH, m), 3.63-3.55 (2H, m), 3.41 (3H, s), 3.38-3.32 (2H, m), 2.58 (IH, m), 2.40 (IH, m), 1.97 (IH, m), 1.78-1.58 (2H, m), 1.48 (IH, m), 1.22 (3H, d), 0.94 (6H, d)
[Preparation Example 63] Preparation of (2i?.4S,5S)-4-irtert-butyl(dimethyl silyl1oxyl-2.7-dimethyl-5-{[3- (methyl { [2-( 1 -naphthvDethyll sulfonyl } amino benzoyl1 amino I octanoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 62 instead of the compound obtained in Preparation Example 5, whereby 0.31 g of the title compound was obtained at 93% yield.
IH NMR (500 MHz, CDC13); 7.91 (IH, d), 7.86 (IH, d), 7.82 (IH, s), 7.75 (IH, d), 7.62 (IH, d), 7.57 (IH, d), 7.55-7.42 (3H, m), 7.39 (IH, t), 7.33 (IH, d), 6.36 (IH, d), 4.26 (IH, m), 3.80 (IH, dd), 3.62-3.54 (2H, m), 3.40 (3H, s), 3.37-3.31 (2H, m), 2.63 (IH, m), 1.87 (IH, m), 1.63 (IH, m), 1.54-1.37 (3H, m), 1.18 (3H, d), 0.95 (3H, d), 0.94 (3H, d), 0.90 (9H, s), 0.12 (3H, s), 0.09 (3H, s)
[Preparation Example 64]
Preparation of benzyl 4-[(4S,7i?.9S)-4.7.11.11.12.12-hexamethyl-9-((lS -3-methyl-l- { [3 -(methyl { [2-( 1 -naphthvDethyll sulfonyl } amino)benzoyl] amino } butyl)-3 ,6-dioxo- 10- oxa-2.5-diaza-l l-silatridec-l-yllbenzoate A process was conducted in the same manner as in Preparation Example 9, except for using the compound obtained in Preparation Example 63 instead of the compound obtained in Preparation Example 6, whereby 108 mg of the title compound was obtained at 84% yield.
IH NMR (500 MHz, CDC13); 8.00 (2H, d), 7.93-7.83 (3H, m), 7.74 (IH, d), 7.62-7.56 (2H, m), 7.53-7.30 (10H, m), 7.28 (2H, d), 6.86 (IH, d), 6.85 (IH, t), 6.30 (IH, d), 5.35 (2H, s), 4.50-4.34 (3H, m), 4.26 (IH, m), 3.73 (IH, dd), 3.60-3.54 (2H, m), 3.38 (3H, s), 3.36-3.30 (2H, m), 2.51 (IH, m), 1.66-1.54 (2H, m), 1.47 (IH, m), 1.37 (IH, m), 1.25 (IH, m), 1.11 (3H, d), 1.08 (3H, d), 0.94 (3H, d), 0.93 (3H, d), 0.90 (9H, s), 0.10 (3H, s), 0.08 (3H, s)
[Example 13]
Preparation of 4-r({(2S)-2-r((2i?,4S.5S)-4-hvdroxy-2,7-dimethyl-5-(r3-(methvUr2-(l- naphthv ethy 1] sulfonyl 1 amino benzoyll amino I octanoyl amino propano yl I amino meth yl] benzoic acid A process was conducted in the same manner as in Example 1 , except for using the compound obtained in Preparation Example 64 instead of the compound obtained in Preparation Example 9, whereby 41 mg of the title compound was obtained at 58% yield.
IH NMR (500 MHz, CD3OD); 7.98-7.84 (5H, m), 7.79-7.73 (2H, m), 7.62 (IH, d),
7.53-7.44 (3H, m), 7.38 (2H, d), 7.35 (2H, d), 4.42 (2H, s), 4.31 (IH, m), 4.17 (IH, m),
3.59 (IH, m), 3.55-3.42 (4H, m), 3.39 (3H, s), 2.68 (IH, m), 1.81 (IH, m), 1.70-1.58 (2H, m), 1.48-1.36 (2H, m), 1.28 (3H, d), 1.10 (3H, d), 0.93 (6H, d)
ESI MS (m/e) = 759 [M+H]+
[Preparation Example 65]
Preparation of 3- [methyl (2-thienylsulfonvDaminolbenzoic acid A process was conducted in the same manner as in Preparation Example 29, except for using the compound obtained in Preparation Example 24 instead of the compound obtained in Preparation Example 14, whereby 0.2 g of the title compound was obtained at 95%) yield.
IH NMR (400 MHz, CDC13); 8.01 (IH, d), 7.75 (IH, s), 7.61 (IH, d), 7.59 (IH, d), 7.46 (IH, t), 7.34 (IH, d), 7.10 (IH, dd), 3.28 (3H, s)
[Example 14]
Preparation of N-((lS,2S.4J?V5-{r(lS)-2-(benzylaminoVl-methyl-2-oxoethyllamino>-2- hvdroxy- 1 -isobutyl-4-methyl-5-oxopentvD-3-[methyl(2- thienylsulfonvDamino]benzamide A process was conducted in the same manner as in Example 2, except for using the compound obtained in Preparation Example 65 instead of l-methyl-2,2,4-trioxo- tetrahydro-2λ6,l-benzothiazene-7-carboxylic acid, whereby 74 mg of the title compound was obtained at 57% yield.
IH NMR (400 MHz, CDC13); 7.79 (IH, d), 7.60 (IH, d), 7.54 (IH, s), 7.43-7.21 (8H, m), 7.09 (IH, dd), 6.56 (IH, d), 6.51 (IH, t), 6.39 (IH, d), 4.46-4.36 (3H, m), 4.11 (IH, m), 3.86 (IH, br), 3.75 (IH, m), 3.25 (3H, s), 2.64 (IH, m), 1.78-1.55 (4H, m), 1.42 (IH, m), 1.32 (3H, d), 1.17 (3H, d), 0.95 (3H, d), 0.93 (3H, d) ESI MS (m/e) = 643 [M+H]+
[Preparation Example 66]
Preparation of 3-rmethyl(phenylsulfonvDaminolbenzoic acid A process was conducted in the same manner as in Preparation Example 29, except for using the compound obtained in Preparation Example 19 instead of the compound obtained in Preparation Example 14, whereby 0.2 g of the title compound was obtained at 92% yield.
IH NMR (400 MHz, CDC13); 8.01 (IH, d), 7.71 (IH, s), 7.61 (IH, t), 7.58-7.42 (6H, m), 3.22 (3H, s)
[Example 15]
Preparation of N-((lS.2S.4i? -5-(r(lS)-2-(benzylamino -l-methyl-2-oxoethyllaminol-2- hvdroxy-l-isobutyl-4-methyl-5-oxopentvD-3-[methyl(phenylsulfonvDamino]benzamide A process was conducted in the same manner as in Example 2, except for using the compound obtained in Preparation Example 66 instead of l-methyl-2,2,4-trioxo- tetrahydro-2λ6,l-benzothiazene-7-carboxylic acid, whereby 71 mg of the title compound was obtained at 56% yield.
IH NMR (500 MHz, CDC13); 7.67 (IH, d), 7.58 (IH, t), 7.54 (2H, d), 7.49 (IH, s), 7.45
(2H, t), 7.35 (IH, t), 7.29 (2H, d), 7.27-7.20 (4H, m), 6.65 (IH, d), 6.62 (IH, t), 6.40
(IH, d), 4.43 (IH, m), 4.39 (2H, d), 4.10 (IH, m), 3.92 (IH, d), 3.73 (IH, m), 3.17 (3H, s), 2.63 (IH, m), 1.76-1.58 (4H, m), 1.40 (IH, m), 1.31 (3H, d), 1.15 (3H, d), 0.93 (3H, d), 0.92 (3H, d)
ESI MS (m/e) = 637 [M+H]+
[Preparation Example 67]
Preparation of ethyl 3-r(l-naphthylsulfonvDamino]benzoate A process was conducted in the same manner as in Preparation Example 19, except for using 1-naphthalenesulfonylchloride instead of benzylsulfonylchloride, whereby 0.53 g of the title compound was obtained at 74% yield.
IH NMR (400 MHz, CDC13); 8.67 (IH, d), 8.22 (IH, d), 8.04 (IH, d), 7.94 (IH, d)7.74- 7.65 (2H, m), 7.61 (IH, t), 7.52 (IH, s), 7.48 (IH, t), 7.24-7.18 (2H, m), 6.89 (IH, s), 4.29 (2H, q), 1.32 (3H, t)
[Preparation Example 68]
Preparation of 3-[methyl(l-naphthylsulfonvDamino]benzoic acid A process was conducted in the same manner as in Preparation Example 29, except for using the compound obtained in Preparation Example 67 instead of the compound obtained in Preparation Example 14, whereby 0.17 g of the title compound was obtained at 100% yield.
IH NMR (400 MHz, CDC13); 8.28 (IH, d), 8.13 (IH, d), 8.07 (IH, d), 7.96 (IH, d),
7.90 (IH, d), 7.70 (IH, s), 7.55-7.35 (5H, m), 3.25 (3H, s)
[Example 16]
Preparation of N-(( 1 S.2S.4i?)-5- ( [( 1 S)-2-(benzylamino)- 1 -methyl-2-oxoethvH amino } -2- hvdroxy-l-isobutyl-4-methyl-5-oxopentvD-3-[methyl(l- naphthylsulfonvDaminolbenzamide A process was conducted in the same manner as in Preparation Example 2, except for using the compound obtained in Preparation Example 68 instead of 1 -methyl -
2,2,4-trioxo-tetrahydro-2λ6,l-benzothiazene-7-carboxylic acid, whereby 72 mg of the title compound was obtained at 53% yield.
IH ΝMR (400 MHz, CDC13); 8.28 (IH, d), 8.11 (IH, d), 8.06 (IH, d), 7.89 (IH, d),
7.64 (IH, d), 7.54-7.36 (4H, m), 7.34-7.20 (7H, m), 6.70-6.62 (2H, m), 6.28 (IH, d), 4.44 (IH, m), 4.39 (2H, d), 4.06 (IH, m), 3.91 (IH, br), 3.48 (IH, m), 3.22 (3H, s), 2.63
(IH, m), 1.75-1.52 (4H, m), 1.38 (IH, m), 1.30 (3H, d), 1.15 (3H, d), 0.92 (6H, d)
ESI MS (m/e) = 687 [M+H]+
[Preparation Example 69] Preparation of ethyl 3-r(2-naphthylsulfonvDamino~|benzoate A process was conducted in the same manner as in Preparation Example 19, except for using 2-naphthalenesulfonylchloride instead of benzenesulfonylchloride, whereby 0.57 g of the title compound was obtained at 81% yield. IH ΝMR (400 MHz, CDC13); 8.39 (IH, s), 7.89 (2H,d), 7.87 (IH, d), 7.75 (2H, t), 7.68 (IH, s), 7.66-7.56 (2H, m), 7.41 (IH, d), 7.31 (IH, t), 6.85 (IH, s), 4.32 (2H, q), 1.33 (3H, t)
[Preparation Example 70] Preparation of 3-[methyl(2-naphthylsulfonyDamino]benzoic acid A process was conducted in the same manner as in Preparation Example 29, except for using the compound obtained in Preparation Example 69 instead of the compound obtained in Preparation Example 14, whereby 0.17 g of the title compound was obtained at 99% yield. IH NMR (400 MHz, CDC13); 8.21 (IH, s), 8.01 (IH, d), 7.90 (3H, t), 7.76 (IH, s), 7.68-
7.56 (2H, m), 7.53-7.41 (3H, m), 3.25 (3H, s)
[Example 17]
Preparation of N-(( 1 S2SAR )-5- i \( 1 S -2-(benzylamino 1 -methyl-2-oxoethyll amino I -2- hvdroxy-l-isobutyl-4-methyl-5-oxopentvD-3-[methyl(2- naphthylsulfonvDaminolbenzamide A process was conducted in the same manner as in Example 2, except for using the compound obtained in Preparation Example 70 instead of 1 -methyl -2,2,4-trioxo- tetrahydro-2λ6,l-benzothiazene-7-carboxylic acid, whereby 78 mg of the title compound was obtained at 57% yield.
IH NMR (400 MHz, CDCI3); 8.20 (IH, s), 7.89 (3H, t), 7.72-7.56 (4H, m), 7.46 (IH, d), 7.38-7.18 (7H, m), 6.66 (IH, d), 6.63 (IH, t), 6.44 (IH, d), 4.42 (IH, m), 4.40 (2H, d), 4.10 (IH, m), 3.87 (IH, br), 3.71 (IH, m), 3.22 (3H, s), 2.63 (IH, m), 1.74-1.56 (4H, m), 1.39 (IH, m), 1.31 (3H, d), 1.15 (3H, d), 0.92 (3H, d), 0.90 (3H, d) ESI MS (m/e) = 687 [M+H]+
[Preparation Example 71]
Preparation of ethyl 3 -( { [5-(dimethylamino)- 1 -naphthyl] sulfonyl } amino)benzoate A process was conducted in the same manner as in Preparation Example 19, except for using dansyl chloride instead of benzenesulfonylchloride, whereby 0.31 g of the title compound was obtained at 79% yield.
IH NMR (400 MHz, CDC13); 8.50 (IH, d), 8.32 (IH, d), 8.21 (IH, d), 7.69 (IH, t), 7.58
(IH, t), 7.54 (IH, s), 7.44 (IH, t), 7.27-7.17 (3H, m), 6.95 (IH, s), 4.30 (2H, q), 2.87 (6H, s), 1.33 (3H, t)
[Preparation Example 72]
Preparation of 3 - [ { [5 -(dimethylamino)- 1 -naphthyl] sulfonyl } (methvDaminol benzoic acid A process was conducted in the same manner as in Preparation Example 29, except for using the compound obtained in Preparation Example 71 instead of the compound obtained in Preparation Example 14, whereby 0.25 g of the title compound was obtained at 87% yield.
IH NMR (400 MHz, CDC13); 8.55 (IH, d), 8.11 (IH, d), 7.99 (IH, d), 7.95 (IH, d), 7.70 (IH, s), 7.54-7.44 (2H, m), 7.39 (IH, t), 7.33 (IH, dd), 7.12 (IH, d), 3.26 (3H, s),
2.87 (6H, s)
[Example 18]
Preparation of N-((lS.2S.4i?V5-(r(lS)-2-(benzylamino -l-methyl-2-oxoethyll amino 1-2- hydroxy- 1 -isobutyl-4-methyl-5-oxopentyD-3-[ { [5 -(dimethylamino)- 1 - naphthyl] sulfonyl } (methyl)aminol benzamide A process was conducted in the same manner as in Example 2, except for using the compound obtained in Preparation Example 72 instead of 1 -methyl -2,2,4-trioxo- tetrahydro-2λ6,l-benzothiazene-7-carboxylic acid, whereby 69 mg of the title compound was obtained at 47% yield.
IH NMR (400 MHz, CDC13); 8.54 (IH, d), 8.09 (IH, d), 8.00 (IH, d), 7.65 (IH, d),
7.58 (IH, s), 7.46 (IH, t), 7.38-7.20 (8H, m), 7.11 (IH, d), 6.76 (IH, s), 6.75 (IH, s),
6.43 (IH, s), 4.43 (IH, m), 4.38 (2H, d), 4.09 (IH, m), 3.97 (IH, br), 3.71 (IH, m), 3.22 (3H, s), 2.87 (6H, s), 2.63 (IH, m), 1.74-1.56 (4H, m), 1.40 (IH, m), 1.29 (3H, d), 1.14
(3H, d), 0.93 (6H, d)
ESI MS (m/e) = 730 [M+H]+
[Preparation Example 73] Preparation of. ethyl 3-({[2-(acetylamino)-4-methyl-l,3-thiazol-5- yll sulfonyl } amino benzoate A process was conducted in the same manner as in Preparation Example 19, except for using 2-acetamido-4-methyl-5-thiazolsulfonylchloride instead of benzenesulfonylchloride, whereby 0.18 g of the title compound was obtained at 46% yield.
IH NMR (400 MHz, CDC13); 9.12 (IH, s), 7.85 (IH, d), 7.74 (IH, s), 7.51 (IH, d), 7.38 (IH, t), 7.32 (IH, s), 4.36 (2H, q), 2.32 (3H, s), 2.26 (3H, s), 1.38 (3H, t)
[Preparation Example 74] Preparation of 3-[{[2-(acetylamino)-4-methyl-l,3-thiazol-5- yl] sulfonyl } (methvPamino]benzoic acid A process was conducted in the same manner as in Preparation Example 29, except for using the compound obtained in Preparation Example 73 instead of the compound obtained in Preparation Example 14, whereby 0.12 g of the title compound was obtained at 75% yield.
IH NMR (400 MHz, DMSO, d6); 13.05 (IH, br), 8.15 (IH, d), 7.72 (IH, t), 7.64 (IH, s), 7.35(2H, d), 3.06 (3H, s), 2.65 (3H, d), 1.73 (3H, s)
[Example 19]
Preparation of. 3-[( [2-(acetylamino -4-methyl- 1 ,3-thiazol-5- yllsulfonv (methyDaminol-N-((lS.2S,4i?)-5-(r(lS -2-(benzylamino -l-methyl-2- oxoethyl]amino}-2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyl)benzamide A process was conducted in the same manner as in Example 2, except for using the compound obtained in Preparation Example 74 instead of l-methyl-2,2,4-trioxo- tetrahydro-2λ6,l-benzothiazene-7-carboxylic acid, whereby 65 mg of the title compound was obtained at 45% yield.
IH ΝMR (400 MHz, CDC13); 7.70 (IH, d), 7.53 (2H, d), 7.42 (IH, t), 7.36-7.22 (5H, m), 6.76 (IH, d), 6.55 (IH, t), 6.34 (IH, d), 6.23 (IH, d), 4.41 (2H, d), 4.16 (IH, m), 3.85- 3.72 (2H, m), 3.29 (3H, s), 2.94 (3H, d), 2.64 (IH, m), 2.02 (3H, s), 1.80-1.54 (4H, m), 1.42 (IH, m), 1.32 (3H, d), 1.18 (3H, d), 0.96 (3H, d), 0.95 (3H, d) ESI MS (m/e) = 715 [M+H]+
[Example 20] Preparation of N-((lS.2S.4J/?V5-(r(lS)-2-(benzylaminoVl-methyl-2-oxoethyllamino>-2- hydroxy- 1 -isobutyl -4-methyl-5-oxopentyl)-3-
[(benzylsulfonyD(methvDaminolbenzamide A process was conducted in the same manner as in Example 2, except for using the compound obtained in Preparation Example 56 instead of l-methyl-2,2,4-trioxo- tetrahydro-2λ6,l-benzothiazene-7-carboxylic acid, whereby 41 mg of the title compound was obtained at 63 % yield.
IH ΝMR (400 MHz, CD3OD); 7.77 (IH, s), 7.72 (IH, d), 7.46-7.21 (12H, m), 4.47 (2H, s), 4.36 (2H, d), 4.33 (IH, m), 4.19 (IH, m), 3.60 (IH, m), 3.26 (3H, s), 2.70 (IH, m), 1.82 (IH, m), 1.72-1.62 (2H, m), 1.52-1.36 (2H, m), 1.32 (3H, d), 1.14 (3H, d), 0.97
(6H, d)
ESI MS (m/e) = 651 [M+H]+
[Preparation Example 75] Preparation of tert-butyl ( 1 S)- 1 - [(benzylamino)carbonyll -2-methylpropylcarbamate 4.35 g (20 mmol) of t-butoxycarbonyl-(s)-valine was dissolved in Ν,Ν- dimethylformamide and cooled to 0°C, then 2.62 ml (24 mmol) of benzylamine, 4.6 g(24 mmol) of EDC and 1.05 g (30 mmol) of HOBT were added thereto. 20.9 ml (120 mmol) of N,N-diisopropylethylamine was added, and heated to room temperature, followed by stirring overnight. After removing solvent by distillation under reduced pressure, the residue is dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the residue was precipitated using ethyl acetate and hexane to obtain 4.57 g of the title compound at 75% yield.
IH NMR (400 MHz, CDC13); 7.38-7.22 (5H, m), 6.25 (IH, br), 5.02 (IH, br), 4.46 (2H, d), 3.90 (IH, dd), 2.19 (IH, m), 1.43 (9H, s), 0.97 (3H, d), 0.93 (3H, d)
[Preparation Example 76]
Preparation of tert-butyl (lS.2S.4i -5-(((lSVl-r(benzylamino)carbonyl]-2- methylpropyll amino)-2- { [tert-butyl(dimethyDsiryl]oxy } - 1 -isobutyl-4-methyl-5- oxopentylcarbamate A process was conducted in the same manner as in Preparation Example 12, except for using the compound obtained in Preparation Example 75 instead of the compound obtained in Preparation Example 11, whereby 1.73 g of the title compound was obtained at 95% yield.
IH NMR (400 MHz, CDC13); 7.38-7.22 (5H, m), 6.43-6.32 (2H, m), 4.56-4.36 (3H, m),
4.11 (IH, t), 3.73 (IH, m), 3.66 (IH, m), 2.53 (IH, m), 2.17 (IH, m), 1.79 (IH, m), 1.50-1.38 (11H, m), 1.30-1.18 (2H, m), 1.09 (3H, d), 0.98-0.86 (21H, m), 0.08 (3H, s),
0.07 (3H, s)
[Preparation Example 77]
Preparation of tert-butyl (lS,2S.4#)-5-(((lS)-l-r(benzylamino)carbonyll-2- methylpropyl}amino)-2-hvdroxy-l-isobutyl-4-methyl-5-oxopentylcarbamate A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 76 instead of the compound obtained in Preparation Example 12, whereby 1.27 g of the title compound was obtained at 91%) yield. IH NMR (400 MHz, CDC13); 7.36-7.18 (5H, m), 6.52 (IH, d), 6.45 (IH, s), 4.63 (IH, d), 4.48-4.34 (2H, m), 4.20 (IH, t), 3.62-3.42 (3H, m), 2.65 (IH, m), 2.15 (IH, m), 1.75- 1.58 (4H, m), 1.43 (9H, s), 1.26 (IH, m), 1.15 (3H, d), 0.96 (3H, d), 0.94 (3H, d), 0.87 (6H, d)
[Example 21]
Preparation of N-r(lS,2S,4J?)-5-(((lS -l-F(benzylamino)carbonyll-2- methylpropyl } amino)-2-hydroxy- 1 -isobutyl -4-methyl-5 -oxopentyl]-3 - [(benzylsulfonvD(methyDamino1benzamide 49 mg (0.1 mmol) of the compound obtained in Preparation Example 77 was dissolved in 1.5 ml of 20% trifluoroacetic acid (dichloromethane solution) and stirred for 30 minutes. After removing solvent by distillation under reduced pressure below room temperature, the residue was dissolved in 3 ml of Ν,Ν-dimethylformamide, and cooled to 0°C, then 46 mg (0.15 mmol) of the compound obtained in Preparation Example 56 and 57 mg (0.15 mmol) of HATU were added thereto. 0.5 ml (excess amount) of N,N-diisopropylethylamine was further added, and heated to room temperature, followed by stirring for 4 hours. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 3:1 mixture of ethyl acetate and hexane to obtain 41 mg of the title compound at 60% yield. IH NMR (400 MHz, CD3OD); 7.78 (IH, s), 7.73 (IH, d), 7.47-7.22 (12H, m), 4.48 (2H, s), 4.37 (2H, d), 4.22 (IH, m), 4.13 (IH, d), 3.63 (IH, m), 3.27 (3H, s), 2.77 (IH, m), 2.01 (IH, m), 1.87 (IH, m), 1.74-1.64 (2H, m), 1.52-1.40 (2H, m), 1.14 (3H, d), 0.98 (6H, d), 0.90 (3H, d), 0.88 (3H, d) ESI MS (m/e) = 679 [M+H]+
[Preparation Example 78]
Preparation of tert-butyl ( IS)- l-\(2RAS)-4-(l -hydroxy- l-methylethyl)-5-oxotetrahydro- 2-furanyl1-3-methylbutylcarbamate 0.95 g(3.5 mmol) of the compound obtained in Preparation Example 1 was dissolved in 20 ml of anhydrous tetrahydrofurane, and cooled to -78°C, then 10.5 ml (10.5 mmol tetrahydrofurane solution) of 1.0 M litiumbis(trimethylsilyl)amide was added thereto. After stirring for 30 minutes, 1.28 ml (17.5 mmol) of acetone was added and stirred for 1 hour. The reaction was terminated using saturated ammonium chloride solution, then the solvent was removed by distillation under reduced pressure, followed by eluting with ethylacetate and washing with sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 1 :2 mixture of ethyl acetate and hexane to obtain 0.72 g of the title compound at 13% yield.
IH NMR (400 MHz, CDC13); 4.49 (IH, m), 4.38 (IH, d), 3.85 (IH, m), 3.29 (IH, s), 2.73 (IH, dd), 2.39 (IH, m), 2.13 (IH, m), 1.64 (IH, m), 1.53-1.42 (11H, m), 1.27 (3H, s), 1.23 (3H, s), 0.93 (3H, d), 0.91 (3H, d)
[Preparation Example 79]
Preparation of tert-butyl (lS)-l-[(2i?,4S)-4-isopropenyl-5-oxotetrahvdro-2-furanyl1-3- methylbutylcarbamate 0.72 g(2.18 mmol) of the compound obtained in Preparation Example 78 was dissolved in 30 ml of dichloromethane and cooled to 0°C, then 0.5 g(2.4 mmol) of phosphorous (V) chloride was added thereto and stirred for 3 hours. After elution using dichloromethane by adding saturated sodium bicarbonate solution, the solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography using a 1 :4 mixture of ethyl acetate and hexane to obtain 0.29 g of the title compound at 43% yield.
IH NMR (400 MHz, CDC13); 4.97 (IH, s), 4.90 (IH, s), 4.51 (IH, dd), 4.39 (IH, d), 3.86 (IH, m), 3.29 (IH, dd), 2.37 (IH, m), 2.22 (IH, m), 1.81 (3H, s), 1.67 (IH, m), 1.55 (IH, m), 1.44 (9H, s), 1.35 (IH, m), 0.93 (3H, d), 0.92 (3H, d)
[Preparation Example 80]
Preparation of tert-butyl (lS)-l-[(2i?,4S)-4-isopropyl-5-oxotetrahvdro-2-furanyl]-3- methylbutylcarbamate 0.28 g (0.9 mmol) of the compound obtained in Preparation Example 79 was dissolved in 30 ml of methanol, and active carbon supported palladium (10%) was added thereto and stirred overnight in a hydrogen atmosphere. After removing solid by filtration under reduced pressure using Cellite, the solvent was removed by distillation under reduced pressure and then purified by column chromatography using a 1:4 mixture of ethyl acetate and hexane, then 0.19 g of the title compound was obtained at 68% yield.
IH NMR (400 MHz, CDC13); 4.43 (IH, dd), 4.36 (IH, d), 3.84 (IH, m), 2.56 (IH, m), 2.26-2.02 (3H, m), 1.68 (IH, m), 1.52 (IH, m), 1.44 (9H, s), 1.34 (IH, m), 1.00 (3H, d), 0.96-0.90 (9H, m) [Preparation Example 81]
Preparation of (2S,4S,5S)-5-[(tert-butoxycarbonyPamino]-4-{[tert- butyl(dimethyl)silyl]oxy}-2-isopropyl-7-methyloctanoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 80 instead of the compound obtained in Preparation Example 5, whereby 0.21 g of the title compound was obtained at 95% yield.
IH NMR (400 MHz, CDC13); 4.52 (IH, d), 3.70-3.62(2H, m), 2.38 (IH, m), 1.94 (IH, m), 1.82 (IH, m), 1.62 (IH, m), 1.52 (IH, m), 1.45 (9H, s), 1.40-1.24 (2H, m), 0.98 (3H, d), 0.97 (3H, d), 0.95-0.90 (15H, m), 0.10 (6H, s)
[Preparation Example 82]
Preparation of tert-butyl (lS,2S,4S -4-((r(lS)-2-(benzylaminoVl-methyl-2- oxoethyl] amino} carbonyl)-2- { [tert-butvKdimethvDsilyl] oxy} - 1 -isobutyl-5 - methylhexylcarbamate A process was conducted in the same manner as in Preparation Example 12, except for using the compound obtained in Preparation Example 81 instead of the compound obtained in Preparation Example 10, whereby 91 mg of the title compound was obtained at 61% yield.
IH NMR (400 MHz, CDC13); 7.38-7.20 (5H, m), 6.97 (IH, s), 6.03 (IH, d), 4.52-4.40
(4H, m), 3.68-3.58 (2H, m), 2.11 (IH, m), 1.80-1.52 (4H, m), 1.43 (9H, s), 1.38 (3H, d),
1.30-1.22 (2H, m), 0.98-0.82 (21H, m), 0.10 (6H, s) [Preparation Example 83]
Preparation of tert-butyl (lS.2S.4S)-4-((r(lS)-2-(benzylamino l-methyl-2- oxoethyl]amino)carbonvD-2-hvdroxy-l-isobutyl-5-methylhexylcarbamate A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 82 instead of the compound obtained in Preparation Example 12, whereby 59 mg of the title compound was obtained at 81% yield.
IH NMR (400 MHz, CDC13); 7.35-7.22 (5H, m), 6.58 (IH, s), 6.26 (IH, d), 4.58 (IH, d), 4.48 (IH, m), 4.41(2H, d), 3.50-3.42 (2H, m), 3.34 (IH, br), 2.12 (IH, m), 1.85 (IH, m), 1.77-1.52 (4H, m), 1.44 (9H, s), 1.41 (3H, d), 1.26 (IH, m), 0.94-0.86 (9H, m), 0.83
(3H, d)
[Example 22]
Preparation of N-r(lS.2S.4S)-4-((r(lS)-2-(benzylamino -l-methyl-2- oxoethyl]amino}carbonvD-2-hvdroxy-l-isobutyl-5-methylhexyl]-3- [(benzylsulfonvD(methvDamino1benzamide 49 mg (0.1 mmol) of the compound obtained in Preparation Example 83 was dissolved in 1.5 ml of 20% trifluoroacetic acid (dichloromethane solution) and stirred for 30 minutes. After distillation under reduced pressure below room temperature for concentration, the residue was dissolved in 3 ml of Ν,Ν-dimethylformamide, and cooled to 0°C, then 46 mg (0.15 mmol) of the compound obtained in Preparation Example 56 and 57 mg (0.15 mmol) of HATU were added thereto. 0.5 ml (excess amount) of N,N- diisopropylethylamine was then added thereto and heated to room temperature, followed by stirring for 4 hours. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate, followed by washing with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 3:1 mixture of ethyl acetate and hexane to obtain 48 mg of the title compound at 71% yield
IH NMR (400 MHz, CDC13); 7.68 (IH, s), 7.61 (IH, d), 7.44-7.21 (12H, m), 6.62 (IH, t), 6.51 (IH, d), 6.48 (IH, d), 4.50-4.31 (3H, m), 4.29 (2H, s), 4.10 (IH, m), 3.71 (IH, d), 3.15 (3H, s), 2.14 (IH, m), 1.94-1.62 (5H, m), 1.44 (IH, m), 1.34 (3H, d), 0.96 (3H, d), 0.95 (3H, d), 0.91 (3H, d), 0.84 (3H, d) ESI MS (m/e) = 679 [M+H]+
[Preparation Example 84]
Preparation of tert-butyl (lS,2S,4S -4-r(((lS)-l-r(benzylamino')carbonyll-2- methylpropyllamino)carbonyl]-2-(rtert-butyl(dimethvDsilyl]oxy)-l-isobutyl-5- methylhexylcarbamate 103 mg (0.336 mmol) of the compound obtained in Preparation Example 75 was dissolved in 5 ml of 4.0 N hydrochloride soluton diluted with ethyl acetate, followed by stirring for 2 hours. After distillation under reduced pressure for concentration, the residue was dissolved in 5 ml of N,N-dimethylformamide and cooled to 0°C, then 100 mg (0.224 mmol) compound obtained in Preparation Example 81 and 128 mg (0.336 mmol) of HATU were added thereto. 0.5 ml (excess amount) of N,N- diisopropylethylamine was then added thereto and heated to room temperature, followed by stirring for 4 hours. After removing solvent by distillation under reduced pressure, the residue is dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 1 :3 mixture of ethyl acetate and hexane to obtain 101 mg of the title compound at 72% yield IH NMR (400 MHz, CDC13); 7.36-7.23 (5H, m), 6.26 (IH, t), 6.07 (IH, d), 4.52-4.39 (3H, m), 4.18 (IH, m), 3.66 (IH, br), 3.58 (IH, br), 2.18-2.04 (2H, m), 1.84-1.50 (6H, m), 1.42 (9H, s), 1.00-0.80 (27H, m), 0.11 (6H, s)
[Preparation Example 85] Preparation of tert-butyl (lS,2S.4S)-4-r({(lS)-l-r(benzylamino')carbonyll-2- methylpropyl}amino)carbonyll-2-hydroxy-l-isobutyl-5-methylhexylcarbamate A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 84 instead of the compound obtained in Preparation Example 12, whereby 63 mg of the title compound was obtained at 79% yield.
IH NMR (400 MHz, CDC13); 7.38-7.20 (5H, m), 6.41 (2H, br), 4.63 (IH, d), 4.48-4.35 (2H, m), 4.21 (IH, t), 3.56-3.42 (3H, br), 2.20-2.12 (2H, m), 1.87 (IH, m), 1.80-1.40 (5H, m), 1.43 (9H, s), 0.97 (3H, d), 0.95 (3H, d), 0.94-0.88 (9H, m), 0.85 (3H, d)
[Example 23]
Preparation of. N- l S.2SAS)-4- \( { ( 1 S)- 1 -r(benzylamino)carbonyll-2- methylpropyl}amino)carbonvn-2-hvdroxy-l-isobutyl-5-methylhexyl}-3- [(benzylsulfonvD(methvDamino]benzamide A process was conducted in the same manner as in Preparation Example 22, except for using the compound obtained in Preparation Example 85 instead of the compound obtained in Preparation Example 83, whereby 57 mg of the title compound was obtained at 80% yield.
IH NMR (400 MHz, CDC13); 7.69 (IH, s), 7.58 (IH, d), 7.42-7.12 (12H, m), 6.96-6.88 (2H, m), 6.63 (IH, d), 4.46-4.20 (6H, m), 4.14 (IH, m), 3.70 (IH, d), 3.12 (3H, s), 2.21 (IH, m), 2.08 (IH, m), 1.94-1.82 (2H, m), 1.75-1.60 (3H, m), 1.45 (IH, m), 1.00-0.85 (15H, m), 0.82 (3H, d) ESI MS (m/e) = 707 [M+H]+
[Preparation Example 86]
Preparation of tert-butyl (lS)-l-r(2i?.4i?)-4-allyl-5-oxotetrahvdro-2-furanyll-3- methylbutylcarbamate A process was conducted in the same manner as in Preparation Example 2, except for using allylbromide instead of iodomethane, whereby 0.86 g of the title compound was obtained at 69% yield.
IH NMR (400 MHz, CDC13); 5.74 (IH, m), 5.13 (IH, d), 5.10 (IH, s), 4.47 (IH, m), 4.35 (IH, d), 3.84 (IH, m), 2.73 (IH, m), 2.54 (IH, m), 2.38-2.22 (2H, m), 2.02 (IH, m), 1.69-1.51 (2H, m), 1.43 (9H, s), 1.34 (IH, m), 0.93 (3H, d), 0.92 (IH, d)
[Preparation Example 87]
Preparation of N- i ( 1 S)- 1 - r(2i?.4^V4-allyl-5-oxotetrahvdro-2-furanyll -3 -methylbutyl 1 - 3-[(benzylsulfonvP(methvPamino1benzamide 0.45 g(1.44 mmol) of the compound obtained in Preparation Example 86 was dissolved in 5 ml of 4.0 N hydrochloride solution diluted with ethyl acetate, and stirred for 1 hour. After distillation under reduced pressure for concentration, the residue was dissolved in 8 ml of N,N-dimethylformamide and cooled to 0°C, then 0.53 g(1.73 mmol) of the compound obtained in Preparation Example 56 and 0.33 g(1.73 mmol) of EDC and 0.29 g(2.16 mmol) of HOBT were added thereto. 1.51 ml (8.64 mmol) of N,N-diisopropylethylamine was then added thereto and heated to room temperature, followed by stirring overnight. After removing solvent by distillation under reduced pressure, the residue is dissolved in ethyl acetate and washed with water, 1.0 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the residue was precipitated using ethyl acetate and hexane to obtain 0.69 g of the title compound at 96% yield.
IH NMR (400 MHz, CDC13); 7.58 7.38 (9H, m), 5.98 (IH, d), 5.74 (IH, m), 5.15-5.10 (2H, m), 4.61 (IH, m), 4.48 (IH, m), 4.33 (2H, s), 3.19 (3H, s), 2.67 (IH, m), 2.48 (IH, m), 2.31 (2H, m), 2.09 (IH, m), 1.79-1.47 (3H, m), 0.99 (3H, d), 0.97 (3H, d)
[Preparation Example 88]
Preparation of (2R)-2-((2S3S)-3 -( { 3 - [(benzylsulfonylXmethyPaminolbenzoyl } amino -
2-(rtert-butyl(dimethvPsilyl1oxy}-5-methylhexyP-4-pentenoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 87 instead of the compound obtained in Preparation Example 5, whereby 0.86 g of the title compound was obtained at 100% yield.
IH NMR (400 MHz, CDC13); 7.69 (IH, s), 7.55 (IH, d), 7.43-7.37 (7H, m), 6.30 (IH, d), 5.77 (IH, m), 5.09 (IH, d), 5.06 (IH, d), 4.30 (2H, s), 4.26 (IH, m), 3.85 (IH, dd), 2.65 (IH, m), 2.44 (IH, m), 2.27 (IH, m), 1.85 (IH, m), 1.65-1.58 (2H, m), 1.50-1.44 (2H, m), 0.99 (3H, d), 0.97 (3H, d), 0.92 (9H, s), 0.14 (3H, s), 0.12 (3H, s)
[Preparation Example 89] Preparation of N-((lS.2S.4fl)-4-((r(lSV2-(benzylamino)-l-methyl-2- oxoethyl] amino 1 carbonvP-2- { rtert-butyKdimethyPsilyl] oxy I - 1 -isobutyl-6-heptenvP-3 - r(benzylsulfonvP(methvPamino]benzamide A process was conducted in the same manner as in Preparation Example 12, except for using the compound obtained in Preparation Example 88 instead of the compound obtained in Preparation Example 10, whereby 66 mg of the title compound was obtained at 66% yield.
IH ΝMR (400 MHz, CDC13); 7.72 (IH, s), 7.55 (IH, d), 7.44-7.20 (12H, m), 6.74 (IH, d), 6.65 (IH, t), 6.24 (IH, d), 5.66 (IH, m), 4.99 (IH, d), 4.82 (IH, d), 4.45-4.30 (4H, m), 4.29 (2H, s), 3.79 (IH, dd), 3.16 (3H, s), 2.55-2.42 (2H, m), 2.16 (IH, m), 1.70-1.52 (4H, m), 1.40 (IH, m), 1.16 (3H, d), 0.98 (3H, d), 0.97 (3H, d), 0.92 (9H, s), 0.11 (3H, s), 0.10 (3H, s)
[Example 24]
Preparation of N-r(lS.2S.4^)-4-((r(lS)-2-(benzylamino -l-methyl-2- oxoethyl]amino}carbonvP-2-hvdroxy-l-isobutyl-6-heptenyl]-3- [(benzylsulfonvP(methvPamino]benzamide A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 89 instead of the compound obtained in Preparation Example 12, whereby 54 mg of the title compound was obtained at 98% yield.
IH NMR (400 MHz, CDC13); 7.68 (IH, s), 7.62 (IH, d), 7.45-7.20 (12H, m), 6.67 (IH, d), 6.64 (IH, t), 6.49 (IH, d), 5.66 (IH, m), 4.98 (IH, d), 4.89 (IH, d), 4.45 (IH, m), 4.37 (2H, dd), 4.29 (2H, s), 4.11 (IH, m), 3.73 (IH, d), 3.16 (3H, s), 2.59 (IH, m), 2.37 (IH, m), 2.19 (IH, m), 1.84-1.62 (4H, m), 1.44 (IH, m), 1.32 (3H, d), 0.96 (3H, d), 0.94 (3H, d) ESI MS (m/e) = 677 [M+H]+
[Preparation Example 90] Preparation of N-((lS,2S,4i? -4-r({(lS)-l-r(benzylamino carbonyll-2- methylpropyl}amino carbonyl]-2-{[tert-butyl(dimethvPsilylloxyl-l-isobutyl-6- heptenyP-3-[(benzylsulfonyP(methvPamino]benzamide 55 mg (0.18 mmol) of the compound obtained in Preparation Example 75 was dissolved in 3 ml of 4.0 Ν hydrochloride solution diluted with ethyl acetate, and stirred for 2 hours. After distillation under reduced pressure for concentration, the residue was dissolved in 5 ml of Ν,Ν-dimethylformamide and cooled to 0°C, then 95 mg (0.15 mmol) of the compound obtained in Preparation Example 88 and (35 mg, 0.18 mmol) of EDC and 30 mg (0.225 mmol) of HOBT were added thereto. 1.0 ml (excess amount) of N,N-diisopropylethylamine was then added thereto and heated to room temperature, followed by stirring overnight. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 80 mg of the title compound at 65% yield. IH NMR (400 MHz, CDC13); 7.77 (IH, s), 7.58 (IH, d), 7.42-7.20 (12H, m), 6.57 (IH, d), 6.38 (IH, t), 6.28 (IH, d), 5.72 (IH, m), 5.02 (IH, d), 4.88 (IH, d), 4.46-4.32 (3H, m), 4.26 (2H, s), 4.13 (IH, dd), 3.79 (IH, dd), 3.16 (3H, s), 2.62 (IH, m), 2.42 (IH, m), 2.20-2.04 (2H, m), 1.74-1.50 (4H, m), 1.43 (IH, m), 0.99 (3H, d), 0.97 (3H, d), 0.93 (9H, s), 0.71 (3H, d), 0.69 (3H, d), 0.12 (3H, s), 0.11 (3H, s)
[Example 25]
Preparation of N- S.2S.4in-4-r((αS)-l-r(benzylamino')carbonvn-2- methylpropyl } amino)carbonyl1 -2-hydroxy- 1 -isobutyl-6-heptenyl } -3 - [(benzylsulfonvP(methyl)amino]benzamide A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 90 instead of the compound obtained in Preparation Example 12, whereby 58 mg of the title compound was obtained at 87% yield.
IH ΝMR (400 MHz, CDC13); 7.69 (IH, s), 7.60 (IH, d), 7.40-7.17 (12H, m), 6.84 (IH, d), 6.78 (IH, t), 6.59 (IH, d), 5.65 (IH, m), 4.98 (IH, d), 4.88 (IH, d), 4.40-4.20 (4H, m), 4.28 (2H, s), 4.12 (IH, m), 3.73 (IH, d), 3.14 (3H, s), 2.66 (IH, m), 3.80 (IH, m), 2.22-2.10 (2H, m), 1.88-1.62 (4H, m), 1.43 (IH, m), 0.95 (3H, d), 0.94 (3H, d), 0.90 (3H, d), 0.88 (3H, d)
ESI MS (m/e) = 705 [M+H]+
[Preparation Example 91]
Preparation of benzyl 4-{(4S.7i?.9S)-7-alryl-9-[(lSVl-((3- r(benzylsulfonyP(methyPaminolbenzoyl I amino)-3 -methylbutyll -4,11,11,12,12- pentamethyl-3 ,6-dioxo- 10-oxa-2,5-diaza- 11 -silatridec- 1 -yl } benzoate A process was conducted in the same manner as in Preparation Example 9, except for using the compound obtained in Preparation Example 88 instead of the compound obtained in Preparation Example 6, whereby 99 mg of the title compound was obtained at 71% yield.
IH NMR (400 MHz, CDC13); 8.01 (2H, d), 7.71 (IH, s), 7.54 (IH, d), 7.45-7.29 (14H, m), 6.85 (IH, t), 6.78 (IH, d), 6.24 (IH, d), 5.65 (IH, m), 5.35 (2H, s), 4.98 (IH, d), 4.83 (IH, d), 4.43-4.29 (6H, m), 3.79 (IH, m), 3.15 (3H, s), 2.53-2.41 (2H, m), 2.15 (IH, m), 1.66-1.58 (4H, m), 1.41 (IH, m), 1.16 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.1 l (3H, s), 0.09 (3H, s)
[Example 26]
Preparation of 4-((r(2S -2-(((27?V2-r(2S.3S)-3-((3- [(benzylsulfonyP(methyPamino1benzoyl}amino)-2-hydroxy-5-methylhexyl]-4- penteno yl ) amino)propanoyl] amino } methypbenzoic acid A process was conducted in the same manner as in Example 5, except for using the compound obtained in Preparation Example 91 instead of the compound obtained in Preparation Example 28, whereby 44 mg of the title compound was obtained at 57% yield.
IH NMR (400 MHz, CD3OD); 7.96 (2H, d), 7.75 (IH, s), 7.69 (IH, d), 7.48-7.32 (9H, m), 5.75 (IH, m), 5.10-4.80 (2H, overlap with the H2O), 4.46 (2H, s), 4.41 (2H, s), 4.36 (IH, m), 4.16 (IH, m), 3.60 (IH, d), 3.25 (3H, s), 2.67 (IH, m), 2.35 (IH, m), 2.18 (IH, m), 1.82 (IH, m), 1.68-1.50 (3H, m), 1.40 (IH, m), 1.34 (3H, d), 0.96 (6H, d) ESI MS (m/e) = 721 [M+H]+
[Preparation Example 92]
Preparation of benzyl 4- [( ( (2S1-2- [(tert-butoxycarbonvPamino] -3 - methylbutanoyl}amino methyl]benzoate A process was conducted in the same manner as in Preparation Example 8, except for using t-butoxycarbonyl-(S)-valine instead of t-butoxycarbonyl-(S)-alanine, whereby 3.71 g of the title compound was obtained at 84% yield.
IH NMR (400 MHz, CDC13); 8.03 (2H, d), 7.46-7.34 (5H, m), 7.33 (2H, d), 6.37 (IH, br), 5.36 (2H, s), 4.98 (IH, br), 4.51 (2H, d), 3.89 (IH, dd), 2.18 (IH, m), 1.43 (9H, s),
0.97 (3H, d), 0.93 (3H, d)
[Preparation Example 93]
Preparation of benzyl 4-((4S,7J?.9S -7-alryl-9-rαSH-((3- [(benzylsulfonvP(methyPamino]benzoyl}amino)-3-methylbutyl]-4-isopropyl- 11.11.12.12-tetramethyl-3,6-dioxo-10-oxa-2,5-diaza-l l-silatridec-l-yl}benzoate A process was conducted in the same manner as in Preparation Example 90, except for using the compound obtained in Preparation Example 92 instead of the compound obtained in Preparation Example 75, whereby 107 mg of the title compound was obtained at 75% yield.
IH NMR (400 MHz, CDC13); 8.02 (2H, d), 7.75 (IH, s), 7.57 (IH, d), 7.48-7.25 (14H, m), 6.58 (IH, d), 6.55 (IH, t), 6.27 (IH, d), 5.71 (IH, m), 5.36 (2H, s), 5.02 (IH, d), 4.89 (IH, d), 4.50-4.30 (3H, m), 4.29 (2H, s), 4.12 (IH, dd), 3.78 (IH, dd), 3.15 (3H, s), 2.62 (IH, m), 2.43 (IH, m), 2.20-2.04 (2H, m), 1.74-1.50 (4H, m), 1.41 (IH, m), 0.98 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.69 (6H, d), 0.12 (3H, s), 0.10 (3H, s)
[Example 27]
Preparation of 4-({r(2S)-2-(((2/?V2-f(2S,3S)-3-((3- [(benzylsulfonvP(methvPamino1benzoyl}amino)-2-hvdroxy-5-methylhexyl]-4- pentenoyl } amino)-3 -methylbutanoyl] amino } methyPbenzoic acid A process was conducted in the same manner as in Preparation Example 5, except for using the compound obtained in Preparation Example 93 instead of the compound obtained in Preparation Example 28, whereby 58 mg of the title compound was obtained at 71 % yield.
IH NMR (400 MHz, CD3OD); 7.95 (2H, d), 7.75 (IH, s), 7.70 (IH, d), 7.44-7.32 (9H, m), 5.72 (IH, m), 5.01 (IH, d), 4.95-4.75 (IH, overlap with the H2O), 4.46 (2H, s), 4.45-4.40 (2H, m), 4.22-4.12 (2H, m), 3.62 (IH, d), 3.25 (3H, s), 2.73 (IH, m), 2.34 (IH, m), 2.17 (IH, m), 2.02 (IH, m), 1.83 (IH, m), 1.68-1.58 (2H, m), 1.54 (IH, m), 1.41 (IH, m), 0.96 (3H, d), 0.95 (3H, d), 0.91 (3H, d), 0.89 (3H, d) ESI MS (m/e) = 749 [M+H]+
[Preparation Example 94]
Preparation of benzyl 4-{(4S,7i?,9S)-9-f(lS)-l-({3- [(benzylsulfonvP(methvPamino1benzoyl}amino -3-methylbutyl]-4-isopropyl-
7,11,1 l,12,12-pentamethyl-3,6-dioxo-10-oxa-2,5-diaza-l 1-silatridec-l-yl} benzoate 83 mg (0.188 mmol) of the compound obtained in Preparation Example 92 was dissolved in 3 ml of 4.0 N hydrochloride solution diluted with ethyl acetate, and stirred for 2 hours. After distillation under reduced pressure for concentration, the residue was dissolved in 5 ml of N,N-dimethylformamide and cooled to 0°C, then 95 mg (0.157 mmol) of the compound obtained in Preparation Example 58 and 36 mg (0.188 mmol) of EDC and 32 mg (0.236 mmol) of HOBT were added thereto. 1.0 ml (excess amount) of N,N-diisopropylethylamine was then added thereto and heated to room temperature, followed by stirring overnight. After removing solvent by distillation under reduced pressure, the residue is dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 108 mg of the title compound at 14% yield
IH NMR (400 MHz, CDC13); 8.01 (2H, d), 7.77 (IH, s), 7.57 (IH, d), 7.46-7.32 (12H, m), 7.30 (2H, d), 6.71 (IH, d), 6.55 (IH, t), 6.27 (IH, d), 5.36 (2H, s), 4.51-4.29 (3H, m), 4.29 (2H, s), 4.09 (IH, dd), 3.74 (IH, dd), 3.16 (3H, s), 2.65 (IH, m), 2.03 (IH, m), 1.76-1.48 (4H, m), 1.41 (IH, m), 1.14 (3H, d), 0.97 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.74 (3H, d), 0.64 (3H, d), 0.12 (3H, s), 0.10 (3H, s)
[Example 28]
Preparation of 4-{r((2S)-2-(r(2i-,4S,5S)-5-((3-
[(benzylsulfonvP(methyPamino]benzoyl } amino)-4-hvdroxy-2.7- dimethyloctano yl] amino } -3 -methylbutanovPamino] methyl } benzoic acid A process was conducted in the same manner as in Example 1 , except for using the compound obtained in Preparation Example 94 instead of the compound obtained in Preparation Example 9, whereby 36 mg of the title compound was obtained at 43% yield. IH NMR (400 MHz, CD3OD); 7.95 (2H, d), 7.77 (IH, s), 7.71 (IH, d), 7.44-7.34 (9H, m), 4.46 (2H, s), 4.42 (2H, s), 4.20 (IH, m), 4.13 (IH, d), 3.62 (IH, m), 3.25 (3H, s), 2.76 (IH, m), 2.01 (IH, m), 1.86 (IH, m), 1.71-1.62 (2H, m), 1.49-1.39 (2H, m), 1.13 (3H, d), 0.96 (6H, d), 0.89 (3H, d), 0.87 (3H, d) ESI MS (m/e) = 723 [M+H]+
[Example 29]
Preparation of 4-(r((2S)-2-{[(2i?,4S,5S)-5-({3-
[(benzylsulfonvP(methvPamino]benzoyl}amino -4-hvdroxy-7-methyl-2- propyloctanoyl]amino}propanovPamino]methyllbenzoic acid A process was conducted in the same manner as in Example 1 , except for using the compound obtained in Preparation Example 91 instead of the compound obtained in Preparation Example 9, whereby 36 mg of the title compound was obtained at 50%) yield. IH NMR (400 MHz, CD3OD); 8.04 (2H, d), 7.75 (IH, s), 7.70 (IH, d), 7.46-7.32 (9H, m), 4.46 (2H, s), 4.42 (2H, s), 4.37 (IH, m), 4.17 (IH, m), 3.58 (IH, m), 3.25 (3H, s), 2.59 (IH, m), 1.83 (IH, m), 1.68-1.55 (3H, m), 1.50 (IH, m), 1.43-1.22 (7H, m), 0.97 (3H, d), 0.95 (3H, d), 0.85 (3H, t) ESI MS (m/e) = 723 [M+H]+
[Example 30]
Preparation of N- { ( 1 S.2S,4i?V 4-K ( ( 1 S)- 1 -Kbenzylaminotearbonyll -2- methylpropyl } amino carbonyl]-2-hvdroxy- 1 -isobutylheptyl I -3 - [(benzylsulfonvP(methvPamino]benzamide 10 mg (0.014 mmol) of the compound obtained in Preparation Example 25 was dissolved in 2 ml of methanol, and active carbn-supported palladium (10%) was added thereto, followed by stirring overnight in a hydrogen atmosphere. After removing solid by filteraion under reduced pressure using Cellite, the solvent was removed by distillation under reduced pressure to obtain 10 mg of the title compound at 100% yield. IH NMR (400 MHz, CDC13); 7.69 (IH, s), 7.60 (IH, d), 7.39-7.21 (12H, m), 6.68 (IH, d), 6.54-6.48 (2H, m), 4.45-4.30 (2H, m), 4.29 (2H, s), 4.21 (IH, dd), 4.11 (IH, m), 3.74 (IH, m), 3.67 (IH, br), 3.16 (3H, s), 2.54 (IH, m), 2.09 (IH, m), 1.82-1.20 (9H, m), 0.97-0.84 (15H, m) ESI MS (m/e) = 707 [M+H]+
[Example 31]
Preparation of 4-{r((2S)-2-(r(2i?.4S.5S)-5-((3-
[(benzylsulfonyP(methyl)amino1benzoyl}amino)-4-hydroxy-7-methyl-2- propyloctanoyl] amino } -3 -methy lbutanoy Damino]methyl } benzoic acid A process was conducted in the same manner as in Example 30, except for using the compound obtained in Example 27 instead of the compound obtained in
Example 25, whereby 10 mg of the title compound was obtained at 100% yield.
IH NMR (400 MHz, CD3OD); 8.49 (IH, s), 7.92 (2H, d), 7.75 (IH, s), 7.42-7.31 (9H, m), 4.46 (2H, s), 4.42-4.34 (2H, m), 4.20-4.12 (2H, m), 3.60 (IH, m), 3.26 (3H, s), 2.63
(IH, m), 1.99 (IH, m), 1.82 (IH, m),1.66-1.23 (8H, m), 0.96-0.83 (15H, m)
ESI MS (m/e) = 751 [M+H]+
[Example 32] Preparation of N-l(lS.2S.4^V5-(((lS)-l-r(benzylamino)carbonyl1-2- methylpropyl}amino)-2-hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[methyl(2- thienylsulfonyPaminolbenzamide A process was conducted in the same manner as in Example 21, except for using the compound obtained in Preparation Example 65 instead of the compound obtained in Preparation Example 56, whereby 38 mg of the title compound was obtained at 57% yield.
IH ΝMR (400 MHz, CDC13); 7.68 (IH, d), 7.60 (IH, d), 7.52 (IH, s), 7.40 (IH, t),
7.38-7.24 (7H, m), 7.09 (IH, t), 6.42 (IH, d), 6.35 (IH, d), 6.15 (IH, t), 4.50-4.36 (2H, m), 4.18-4.09 (2H, m), 3.88 (IH, d), 3.77 (IH, m), 3.25 (3H, s), 2.68 (IH, m), 2.09 (IH, m), 1.72-1.41 (5H, m), 1.21 (3H, d), 1.03 (3H, d), 1.01 (3H, d), 0.90 (3H, d), 0.86 (3H,
d)
ESI MS (m/e) = 671 [M+H]+
[Example 33]
Preparation of N-(( 1 S.2SAR )-5- i \( 1 S)-2-(benzylamino)- 1 -methyl-2-oxoethyllamino } -2- hvdroxy-l-isobutyl-4-methyl-5-oxopentvP-3-[methyl(propylsulfonyPamino]benzamide A process was conducted in the same manner as in Example 2, except for using the compound obtained in Preparation Example 29 instead of 1 -methyl -2,2,4-trioxo- tetrahydro-2λ6,l-benzothiazene-7-carboxylic acid, whereby 36 mg of the title compound was obtained at 60% yield.
IH ΝMR (400 MHz, CDC13); 7.86 (IH, s), 7.65 (IH, d), 7.56 (IH, d), 7.42 (IH, t), 7.33-7.22 (5H, m), 6.72 (IH, d), 6.66 (IH, t), 6.57 (IH, d), 4.45-4.39 (3H, m), 4.14 (IH, m), 4.01 (IH, br), 3.74 (IH, m), 3.35 (3H, s), 2.97 (2H, t), 2.64 (IH, m), 1.87-1.66 (6H, m), 1.42 (IH, m), 1.32 (3H, d), 1.15 (3H, d), 1.02 (3H, t), 0.95 (3H, d), 0.94 (3H, d) ESI MS (m/e) = 603 [M+H]+
[Example 34] Preparation of N-r(lS,2S.4igV5-( S)-l-r(berιzylaminofcarbonyll-2- methylpropyl)amino -2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyl1-3- rmethyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 21, except for using the compound obtained in Preparation Example 29 instead of the compound obtained in Preparation Example 56, whereby 45 mg of the title compound was obtained at 71% yield.
IH ΝMR (400 MHz, CDCl3+CD3OD); 7.84 (IH, s), 7.72 (IH, d), 7.55 (IH, d), 7.45 (IH, t), 7.34-7.23 (5H, m), 4.49-4.32 (2H, m), 4.16-4.06 (2H, m), 3.65 (IH, m), 3.36 (3H, s), 3.00 (2H, dd), 2.65 (IH, m), 2.02 (IH, m), 1.89-1.80 (2H, m), 1.75 (IH, m), 1.67-4.56 (3H, m), 1.42 (IH, m), 1.15 (3H, d), 1.04 (3H, t), 0.96-0.91 (6H, m), 0.89 (3H, d), 0.86 (3H, d) ESI MS (m/e) = 631 [M+H]+
[Example 35] Preparation of. N-r(lS.2S.4J?V5-({(lS>-l-r(benzylamino')carbonyll-2- methylpropyl}amino)-2-hydroxy-l-isobutyl-4-methyl-5-oxopentyl1-5- [(benzylsulfonvP(methyPamino]-2-chlorobenzamide A process was conducted in the same manner as in Example 21, except for using 5-[(benzylsulfonyl)(methyl)amino]-2-chlorobenzoic acid instead of the compound obtained in Preparation Example 56, whereby 18 mg of the title compound was obtained at 60% yield.
1H-NMR (300 MHz, CDC13); 7.48 (IH, d, J= 2.67), 7.39 ~ 7.11 (12H, m), 6.60(lH,bs), 6.45 (IH, bs), 6.42 ~ 6.32 (IH, m), 4.49 ~ 4.31 (2H, m), 4.29 (2H, s), 4.12 ~ 3.93 (3H, m), 3.82 ~ 3.73 (IH, m), 3.12 (3H, s), 2.74 ~ 2.60 (IH, m), 2.14 ~ 1.98 (IH, m), 1.82 ~ 1.49 (4H, m), 1.48 ~ 1.31 (IH, m), 1.20 (3H, d, J= 6.99), 0.99 ~ 0.78 (m, 12H) FAB MS (m/e) = 713 [M+H]+
[Example 36] Preparation of. N-\(l S.2SAR)-5-(i (1S)-1- Kbenzylaminolcarbonyll -2- methylpropyl}amino -2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonyP(methvPamino1-5-(trifluoromethvPbenzamide A process was conducted in the same manner as in Example 21, except for using 3-[(benzylsulfonyl)(methyl)amino]-5-(trifluoromethyl)benzoic acid instead of the compound obtained in Preparation Example 56, whereby 17 mg of the title compound was obtained at 55% yield.
1H-NMR (300 MHz, CDC13); 7.86 ~ 7.83 (2H, m)7.39 ~ 7.20 (m, 11H), 6.70 (IH, d, J= 8.58), 6.58 (IH, d, J= 9.34), 6.52 ~ 6.41 (IH, m), .4.52 ~ 4.27 (4H, m), 4.26 ~ 4.09 (3H, m), 3.83 ~ 3.69 (IH, m), 3.22 (3H, s), 2.69 ~ 2.60 (IH, m), 2.19 ~ 1.98 (IH, m), 1.82 ~ 1.51 (4H, m), 1.48 ~ 1.31 (IH, m), 1.20 (3H, d, J= 6.60), 1.07 ~ 0.70 (m, 12H) FAB MS (m/e) = 747 [M+H]+
[Example 37]
Preparation of N-r(lS,2S.4i?V5-({(lS)-l-r(benzylamino)carbonyl1-2- methylpropyl ) amino -2-hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl1 -3 -
[(benzylsulfonvP(methvPaminol-5-bromobenzamide A process was conducted in the same manner as in Example 21, except for using 3-[(benzylsulfonyl)(methyl)amino]-5-bromobenzoic acid instead of the compound obtained in Preparation Example 56, whereby 20 mg of the title compound was obtained at 63% yield.
IH-NMR (300 MHz, CDC13); 7.71 (IH, s), 7.59 (IH, s), 7.44 ~ 7.13 (11H, m), 6.80 (IH, d, J = 8.68), 6.63 ~ 6.52 (IH, m), 6.50 (IH, d, J= 9.54), 4.46 ~ 4.02 (7H, m), 3.80 ~
3.67 (IH, m), 3.13 (3H, s), 2.72 ~ 2.58 (IH, m), 2.18 ~ 1.93 (IH, m), 1.81 ~ 1.49 (4H, m), 1.48 ~ 1.33 (IH, m), 1.16 (3H, d, J= 6.90), 1.01 ~ 0.69 (m, 12H)
FAB MS (m/e) = 757 [M+H]+
[Example 38]
Preparation of N-r(lS.2S.4i?)-5-(((lS)-l-r(benzylamino carbonyll-2- methylpropyl}amino)-2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonvP(methyPamino]-5-nitrobenzamide A process was conducted in the same manner as in Example 21, except for using 3-[(benzylsulfonyl)(methyl)amino]-5-nitrobenzoic acid instead of the compound obtained in Preparation Example 56, whereby 19 mg of the title compound was obtained at 52% yield.
1H-ΝMR (300 MHz, CDC13); 8.31 (IH, s), 7.97 (IH, s), 7.87 (IH, s), 7.43 - 7.10 (10H, m), 7.05 (IH, d, J= 8.78), 6.98 ~ 6.83 (2H, m), 4.48 ~ 4.08 (7H, m), 3.82 ~ 3.69 (IH, m), 3.20 (3H, s), 2.78 ~ 2.59 (IH, m), 2.17 ~ 1.93 (IH, m), 1.90 ~ 1.52 (4H, m), 1.51 ~ 1.38 (IH, m), 1.15 (3H, d, J= 6.80), 1.06 ~ 0.75 (m, 12H) FAB MS (m/e) = 724 [M+H]+
[Example 39]
Preparation of 3 -amino-N- f( 1 S2SAR )-5 -( { ( 1 S)- 1 - Kbenzylamino arbonyll -2- methylpropyl}amino -2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyl]-5- [(benzylsulfonvP(methyl)amino]benzamide 10 mg (0.014 mmol) of the compound obtained in Example 38 and 5 mg of 10% Pd-C were dissolved in 1 ml of ethanol and stirred for 16 hours in a hydrogen atmosphere. After filtration using Celite, the solvent was removed by distillation under reduced pressure to obtain 9 mg of the title compound at 90% yield.
1H-ΝMR (300 MHz, CDC13); 7.45 ~ 7.09 (11H, m), 6.97 ~ 6.79 (2H, m), 6.69 ~ 6.38 (3H, m), 4.48 ~ 3.99 (7H, m), 3.79 ~ 3.62 (IH, m), 3.12 (3H, s), 2.78 ~ 2.59 (IH, m), 2.21 ~ 1.93 (IH, m), 1.90 ~ 1.49 (4H, m), 1.48 ~ 1.12 (3H, m), 1.15 (3H, J= 5.35, d), 1.03 ~ 0.68 (m, 12H) FAB MS (m/e) = 694 [M+H]+
[Example 40]
Preparation of N-[(lS.2S.4i?)-5-(((lSn-r(benzylamino)carbonyl]-2- methylpropyl)amino)-2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonvP(methvPamino]-5-cyanobenzamide A process was conducted in the same manner as in Example 21, except for using 3-[(benzylsulfonyl)(methyl)amino]-5-cyanobenzoic acid instead of the compound obtained in Preparation Example 56, whereby 12 mg of the title compound was obtained at 40% yield.
-I l l- IH-NMR (300 MHz, CDC13); 7.89 ~ 7.75(2H, m), 7.48 ~ 7.06(1 IH, m), 6.80(1H, bs), 6.72 ~ 6.55(2H, m), 4.49 ~ 4.02(7H, m), 3.79 ~ 3.66(1H, m), 3.21(3H, s), 2.74 ~ 2.59(1H, m), 2.19 ~ 1.91(1H, m), 1.86 ~ 1.51(4H, m), 1.50 ~ 1.33(1H, m), 1.17(3H, d, J = 6.93), 1.06 ~ 0.72(m, 12H) FAB MS (m/e) = 704 [M+H]+
[Example 41]
Preparation of N-r(lS.2S.4i?V5-({(lS -l-r(benzylamino')carbonyll-2- methylpropyllamino -2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonvP(methvPamino]-5-methylbenzamide A process was conducted in the same manner as in Example 21, except for using 3-[(benzylsulfonyl)(methyl)amino]-5-methylbenzoic acid instead of the compound obtained in Preparation Example 56, whereby 21 mg of the title compound was obtained at 73% yield. 1H-ΝMR (300 MHz, CDC13); 7.54 ~ 7.15 (12H, m), 7.11 (IH, s), 6.72 (IH, bs), 6.52 ~ 6.33 (2H, m), 4.48 ~ 4.99 (7H, m), 3.76 ~ 3.63 (IH, m), 3.14 (3H, s), 2.75 ~ 2.56 (IH, m), 2.33 (3H, s), 2.18 - 1.97 (IH, m), 1.82 ~ 1.49 (4H, m), 1.16 (3H, d, J= 6.92), 1.01 ~ 0.63 (12H, m) FAB MS (m/e) = 693 [M+H]+
[Example 42]
Preparation of N-\(lS.2SAR)-5-(i(lS)-l-\(benz\lammo)caτbo Y\-2- methylpropyl } amino -2 -hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl] -3 - [(benzylsulfonvP(methvPamino]-5-chlorobenzamide A process was conducted in the same manner as in Example 21, except for using 3-[(benzylsulfonyl)(methyl)amino]-5-chlorobenzoic acid instead of the compound obtained in Preparation Example 56, whereby 19 mg of the title compound was obtained at 64% yield.
IH-NMR (300 MHz, CDC13); 7.56 ~ 7.53 (2H, m), 7.30 ~ 7.09 (m, 1 IH), 6.64 (IH, bs), 6.44 ~ 6.34 (2H, m), 4.48 ~ 4.18 (6H, m), 4.16 ~ 4.05 (IH, m), 3.80 ~ 3.68 (IH, bs), 3.09 (3H, s), 2.75 ~ 2.60 (IH, m), 1.82 ~ 1.51 (5H, m), 1.17 (3H, d, J = 6.78), 0.99 ~ 0.68 (12H, m) FAB MS (m/e) = 713 [M+H]+
[Example 43]
Preparation of N-r(lS.2S.4 ?V5-(((lS)-l-r(benzylamino)carbonyll-2- methylpropyl } amino -2-hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl1-5- r(benzylsulfonyl)(methvPamino]isophthalamide A process was conducted in the same manner as in Example 21, except for using 3-(aminocarbonyl)-5-[(benzylsulfonyl)(methyl)amino]benzoic acid instead of the compound obtained in Preparation Example 56, whereby 17 mg of the title compound was obtained at 57% yield.
1H-ΝMR (300 MHz, CDC13); 8.41 (IH, s), 7.92 (IH, s), 7.65 (IH, s), 7.50 ~ 7.26 (11H, m), 6.40 (2H, m), 4.63 ~ 4.48 (6H, m), 4.37 ~ 4.32 (4H, m), 3.23 ~ 3.19 (3H, bs), 2.79 ~
2.59 (IH, m), 2.59 ~ 2.45 (IH, m), 2.01 ~ 1.51 (5H, m), 1.39 ~ 1.36 (3H, d, J= 9.09),
0.99 - 0.68 (12H, m)
FAB MS (m/e) = 722 [M+H]+ [Example 44]
Preparation of methyl S-drdS^S g S-dd^-l-Kbenzylaminolcarbonyll^- methylpropyl|amino)-2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyl]amino|carbonvP-5-
[(benzylsulfonvP(methyl)aminolbenzoate A process was conducted in the same manner as in Example 21, except for using 3-[(benzylsulfonyl)(methyl)amino]-5-(methoxycarbonyl)benzoic acid instead of the compound obtained in Preparation Example 56, whereby 19 mg of the title compound was obtained at 63% yield.
IH-NMR (300 MHz, CDC13); 8.25 (IH, s), 7.93 (2H, d, J= 8.81), 7.28 ~ 7.19 (11H, m), 6.69 ~ 6.49 (IH, m), 6.49 ~ 6.30 (IH, m), 4.58 ~ 4.18 (6H, m), 3.90 (3H, s), 3.80 ~ 3.71
(IH, m), 3.18 (3H, s), 2.75 ~ 2.60 (IH, m), 2.18 - 1.51 (5H, m), 1.18 (3H, d, J= 6.89),
0.99 - 0.68 (12H, m)
FAB MS (m/e) = 737 [M+H]+
[Example 45]
Preparation of benzyl 3-((r(lS.2S.4i? -5-((dS)-l-r(benzylamino)carbonyll-2- methylpropyl>amino)-2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyllamino}carbonvP-5- (benzylsulfonvP(methvPamino]benzoate A process was conducted in the same manner as in Example 21, except for using 3-[(benzyloxy)carbonyl]-5-[(benzylsulfonyl)(methyl)amino]benzoic acid instead of the compound obtained in Preparation Example 56, whereby 19 mg of the title compound was obtained at 56% yield.
IH-NMR (300 MHz, CDC13); 8.03 - 7.90 (IH, m), 7.80 - 7.60 (2H, m)7.49 - 7.10 (15H, m), 6.65 - 6.20 (3H, m), 4.65 - 4.46 (3H, m), 4.45 - 4.18 (6H, m), 4.16 - 4.05 (IH, m), 3.76 - 3.66 (IH, bs), 3.17 (3H, s), 2.75 - 2.60 (IH, m), 1.82 - 1.51 (5H, m), 1.02 (3H, d, J= 6.82), 0.99 - 0.68 (12H, m) FAB MS (m/e) = 813 [M+H]+
[Example 46]
Preparation of N-rdS.2S.4i?)-5-({(lS)-l-l(benzylamino arbonyl]-2- methylpropyl}amino)-2-hydroxy-l-isobutyl-4-methyl-5-oxopentyl1-3- f(benzylsulfonvP(methyPamino]-4-methoxybenzamide A process was conducted in the same manner as in Example 21, except for using 3-[(benzylsulfonyl)(methyl)amino]-4-methoxybenzoic acid instead of the compound obtained in Preparation Example 56, whereby 19 mg of the title compound was obtained at 66% yield.
1H-ΝMR (300 MHz, CDC13); 7.83 (IH, d, J= 8.70), 7.56 (IH, s), 7.49 - 7.22 (10H, m),
6.97 (IH, d, J= 8.73), 6.67 (IH, bs), 6.59 - 6.48 (IH, m), 6.35 (IH, bs), 4.48 - 4.22 (4H, m), 4.21 - 4.03 (2H, m), 3.96 (3H, s), 3.92 - 3.77 (IH, m), 3.75 - 3.62 (IH, m), 3.09
(3H, s), 2.74 - 2.58 (IH, m), 2.19 - 1.98 (IH, m), 1.82 - 1.48 (4H, m), 1.15 (3H, d, J =
6.92), 1.01 - 0.69 (12H, m)
FAB MS (m/e) = 709 [M+H]+
[Example 47]
Preparation of. N-r(lS,2S.4J?V5-(((lS)-l-r(benzylamino)carbonyll-2- methylpropyl}amino)-2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyl1-3- [(benzylsulfonvP(methyPamino]-4-fluorobenzamide A process was conducted in the same manner as in Example 21, except for using 3-[(benzylsulfonyl)(methyl)amino]-4-fluorobenzoic acid instead of the compound obtained in Preparation Example 56, whereby 20 mg of the title compound was obtained at 69% yield.
IH-NMR (300 MHz, CDC13); 7.83 - 7.61 (2H, m), 7.53 - 7.09 (1 IH, m), 6.84 (IH, bs), 6.79 - 6.65 (IH, m), 6.49 (IH, bs), 4.50 - 4.01 (7H, m), 3.74 - 3.62 (IH, m), 3.09 (3H, s), 2.77 - 2.58 (IH, m), 2.12 - 1.92 (IH, m), 1.85 - 1.51 (4H, m), 1.50 - 1.32 (IH, m), 1.14 (3H, d, J= 6.93), 1.01 - 0.68 (12H, m) FAB MS (m/e) = 697 [M+H]+
[Example 48]
Preparation of N-r(lS,2S,4i?)-5-(((lS)-l-r(benzylamino)carbonyll-2- methylpropyl}amino -2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyl]-3- r(benzylsulfonvP(methyPamino]-4-chlorobenzamide A process was conducted in the same manner as in Example 21, except for using 3-[(benzylsulfonyl)(methyl)amino]-4-chlorobenzoic acid instead of the compound obtained in Preparation Example 56, whereby 18 mg of the title compound was obtained at 60% yield.
1H-ΝMR (300 MHz, CDC13); 7.71 - 7.56 (2H, m), 7.49 - 7.10 (1 IH, m), 6.80 (IH, bs),
6.73 - 6.62 (IH, m), 6.49 (IH, bs), 4.43 - 4.02 (7H, m), 3.76 - 3.61 (IH, m), 3.11 (3H, s), 2.72 - 2.58 (IH, m), 2.11 - 1.92 (IH, m), 1.81 - 1.48 (4H, m), 1.46 - 1.32 (IH, m),
1.14 (3H, d, J= 6.90), 0.99 - 0.67 (12H, m)
FAB MS (m/e) = 713 [M+H]+
[Example 49] Preparation of. N-r(lS,2S.4i?V5-((dS)-l-r(benzylamino carbonyl1-2- methylpropyl}amino)-2-hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-5-
[(benzylsulfonyP(methvDamino1-2-methoxybenzamide A process was conducted in the same manner as in Example 21, except for using 5-[(benzylsulfonyl)(methyl)amino]-2-methoxybenzoic acid instead of the compound obtained in Preparation Example 56, whereby 18 mg of the title compound was obtained at 61% yield.
1H-ΝMR (300 MHz, CDC13); 8.39 (IH, d, J= 8.40), 8.04 (IH, s), 7.49 - 7.15 (13H, m),
6.9 7(1H, d, J= 8.97), 6.50 - 6.30 (IH, m), .4.48 - 4.18 (5H, m), 4.24 (2H, s), 3.98 (3H, s), 3.12 (3H, s), 2.75 - 2.60 (IH, m), 1.82 - 1.51 (5H, m), 1.16 (3H, d, J= 7.08), 0.99 -
0.68 (12H, m)
FAB MS (m/e) = 709 [M+H]+
[Example 50] Preparation of N-r(lS.2S.4i?)-5-((dS)-l-[(benzylamino)carbonyll-2- methylpropyl}amino)-2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyll-3-(methyl[(2- nitrobenzvPsulfonyllaminolbenzamide A process was conducted in the same manner as in Example 21, except for using 3- {methyl [(2-nitrobenzyl)sulfonyl] amino} benzoic acid instead of the compound obtained in Preparation Example 56, whereby 19 mg of the title compound was obtained at 63% yield.
1H-ΝMR (300 MHz, CDC13); 8.09 - 7.91 (IH, m), 7.77 (IH, s), 7.70 - 7.12 (10H, m), 7.00 (IH, bs), 6.93 - 6.81 (IH, m), 6.64 (IH, bs), 4.85 (2H, s), 4.42 - 4.03 (5H, m), 3.78 - 3.64 (IH, m), 3.30 (3H, s), 2.78 - 2.69 (IH, m), 2.15 - 1.97 (IH, m), 1.87 - 1.64 (4H, m), 1.47 - 1.32 (IH, m), 1.12 (3H, d, J= 6.81), 1.01 - 0.70 (12H, m) FAB MS (m/e) = 724 [M+H]+
[Example 51] Preparation of 3-rr(2-aminobenzyPsulfonyll(methvPaminol-N-r(lS.2S.4i?)-5-({(lS)-l - [(benzylamino)carbonyll -2-methylpropyl I amino -2-hydroxy- 1 -isobutyl-4-methyl-5- oxopentyllbenzamide A process was conducted in the same manner as in Example 39, except for using the compound obtained in Example 50 instead of the compound obtained in Example 38, whereby 8 mg of the title compound was obtained at 80% yield.
1H-ΝMR (300 MHz, CDC13); 7.79 - 7.52 (2H, m), 7.43 - 6.88 (10H, m), 6.85 - 6.39 (4H, m), 4.53 - 4.01 (7H, m), 3.80 - 3.60 (IH, m), 3.24 (3H, s), 2.76 - 2.58 (IH, m), 2.21 - 1.94(1H, m), 1.88 - 1.51 (4H, m), 1.48 - 1.19 (3H, m), 1.13 (3H, d, J = 6.28), 1.02 - 0.62 (12H, m) FAB MS (m/e) = 694 [M+H]+
[Example 52]
Preparation of N-r(lS.2S.4i?V5-(((lS -l-r(benzylamino)carbonyll-2- methylpropyl}amino)-2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-{methyl[(2- methylbenzvPsulfonyllaminolbenzamide A process was conducted in the same manner as in Example 21, except for using 3-{methyl[(2-methylbenzyl)sulfonyl]amino}benzoic acid instead of the compound obtained in Preparation Example 56, whereby 19 mg of the title compound was obtained at 65% yield. IH-NMR (300 MHz, CDC13); 8.04 (IH, d, J= 8.40), 7.68 (IH, d, J= 8.34), 7.56 (2H, t, J= 6.96), 7.49 - 7.09 (1 IH, m), 7.01 (IH, bs), 6.80 - 6.70 (IH, m), 4.70 - 4.60 (IH, m), 4.48 - 4.18 (7H, m), 3.89 (3H, s), 3.76 - 3.66 (IH, m), 3.05 (3H, s), 2.75 - 2.40 (IH, m), 2.01 - 1.51 (5H, m), 1.15 (3H, d, J= 6.93), 0.99 - 0.68 (12H, m) FAB MS (m/e) = 693 [M+H]+
[Example 53]
Preparation of N-r(lS,2S,4i-V5-({(lS)-l-r(benzylamino carbonyll-2- methylpropyl ) amino)-2-hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl1-3- (methyl[(3- methylbenzyPsulfonyl] amino I benzamide A process was conducted in the same manner as in Example 21, except for using 3 -{methyl [(3 -methylbenzyPsulfonyl] amino} benzoic acid instead of the compound obtained in Preparation Example 56, whereby 14 mg of the title compound was obtained at 50% yield. 1H-ΝMR (300 MHz, CDCI3); 7.76 (IH, s), 7.69 - 7.55 (IH, m), 7.48 - 6.99 (13H, m), 6.78 - 6.59 (IH, m), 4.49 - 4.02 (7H, m), 3.79 - 3.63 (IH, m), 3.16 (3H, s), 2.79 - 2.56 (IH, m), 2.32 (3H, s), 2.18 - 1.93 (IH, m), 1.82 - 1.49 (4H, m), 1.47 - 1.32 (IH, m), 1.11 (3H, d, J= 6.15), 1.01 - 0.62 (12H, m) FAB MS (m/e) = 693 [M+H]+
[Example 54]
Preparation of N-r(lS.2S,4i?V5-(((lS)-l-r(benzylamino)carbonyl1-2- methylpropyl ) amino -2-hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl] -3 - {methyl [(4- methylbenzyPsulfonyllaminolbenzamide A process was conducted in the same manner as in Example 21, except for using 3-{methyl[(4-methylbenzyl)sulfonyl]amino}benzoic acid instead of the compound obtained in Preparation Example 56, whereby 19 mg of the title compound was obtained at 65% yield.
IH-NMR (300 MHz, CDC13); 8.04 (IH, d, J= 8.40), 7.68 (IH, d, J= 8.34), 7.56 (2H, t, J= 6.96), 7.51 - 7.10 (1 IH, m), 7.01 (IH, bs), 6.93 - 6.71 (IH, m), 4.70 - 4.18 (7H, m), 3.88 (3H, s), 3.76 - 3.66 (IH, m), 3.04 (3H, s), 2.75 - 2.40 (IH, m), 2.01 - 1.51 (5H, m), 1.15 (3H, d, J= 6.93), 0.97 - 0.66 (12H, m) FAB MS (m/e) = 693 [M+H]+
[Preparation Example 95]
Preparation of tert-butyl (lS)-3-methyl-l-[(2J?,4i?)-5-oxo-4-(2-propynyPtetrahvdro-2- furanyl]butylcarbamate A process was conducted in the same manner as in Preparation Example 2, except for using propargyl bromide instead of iodomethane, whereby 0.32 g of the title compound was obtained at 52% yield.
IH NMR (400 MHz, CDC13); 4.57 (IH, t), 4.33 (IH, d), 3.88 (IH, m), 2.84 (IH, m), 2.65-2.50 (2H, m), 2.44 (IH, m), 2.30 (IH, m), 2.02 (IH, t), 1.66 (IH, m), 1.52 (IH, m), 1.44 (9H, s), 1.35 (IH, m), 0.94 (3H, d), 0.92 (3H, d)
[Preparation Example 96]
Preparation of 3-r(benzylsulfonvP(methvPamino]-N-((lS -3-methyl-l-r(2i?.4i?)-5-oxo- 4-(2-propynvDtetrahvdro-2-furanvHbutyl } benzamide A process was conducted in the same manner as in Preparation Example 87, except for using the compound obtained in Preparation Example 95 instead of the compound obtained in Preparation Example 86, whereby 0.42 g of the title compound was obtained at 81% yield.
IH NMR (400 MHz, CDC13); 7.57 (IH, s), 7.52 (IH, d), 7.43-7.32 (7H, m), 5.95 (IH, d), 4.71 (IH, m), 4.50 (IH, m), 4.32 (2H, s), 3.18 (3H, s), 2.76 (IH, m), 2.65-2.33 (4H, m), 2.03 (IH, m), 1.70-1.63 (2H, m), 1.51 (IH, m), 0.98 (3H, d), 0.97 (3H, d)
[Preparation Example 97]
Preparation of (2i?)-2-((2S,3S)-3-({3-[(benzylsulfonvD(methvDaminolbenzoyllamino)- 2- { [tert-butyl(dimethvDsilyl]oxy} -5-methylhexyD-4-pentynoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 96 instead of the compound obtained in Preparation Example 5, whereby 0.45 g of the title compound was obtained at 85% yield. IH NMR (400 MHz, CDCI3); 7.68 (IH, s), 7.56 (IH, d), 7.44-7.33 (7H, m), 6.31 (IH, d), 4.34 (IH, m), 4.30 (2H, s), 3.16 (3H, s), 2.83 (IH, m), 2.64-2.43 (2H, m), 2.04 (IH, t), 1.91 (IH, m), 1.76 (IH, m), 1.66 (IH, m), 1.56 (IH, m), 1.45 (IH, m), 0.98 (6H, d),
0.93 (9H, s), 0.15 (3H, s), 0.14 (3H, s)
[Preparation Example 98]
Preparation of N-((lS.2S.4i?)-4-r((dS)-l-[(benzylamino)carbonyll-2- methylpropyl}amino carbonyl1-2-{[tgrt-butyl(dimethvPsilyl]oxy}-l-isobutyl-6- heptvnvP-3-[(benzylsulfonyP(methvPamino]benzamide A process was conducted in the same manner as in Preparation Example 90, except for using the compound obtained in Preparation Example 97 instead of the compound obtained in Preparation Example 88, whereby 0.1 g of the title compound was obtained at 84% yield.
IH NMR (400 MHz, CDC13); 7.75 (IH, s), 7.37 (IH, d), 7.42-7.21 (12H, m), 6.72 (IH, d), 6.45 (IH, t), 6.21 (IH, d), 4.42 (IH, m), 4.40 (2H, d), 4.30 (3H, s), 4.16 (IH, dd), 3.92 (IH, dd), 3.16 (3H, s), 2.85 (IH, m), 2.54 (IH, m), 2.33 (IH, m), 2.14 (IH, m), 1.82-1.52 (5H, m), 1.38 (IH, m), 0.98 (3H, d), 0.96 (3H, d), 0.93 (9H, s), 0.71 (3H, d), 0.69 (3H, d), 0.12 (3H, s), 0.11 (3H, s)
[Example 55]
Preparation of. N- ( (1 S.2S,4i? -4-K { ( 1 SI- 1 - r(benzylamino)carbonyll-2- methylpropyl } amino carbonyl] -2-hydroxy- 1 -isobutyl-6-heptynyl } -3 -
[(benzylsulfonvP(methyPamino]benzamide A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 98 instead of the compound obtained in Preparation Example 12, whereby 81 mg of the title compound was obtained at 91%) yield.
IH ΝMR (400 MHz, CD3OD); 7.75 (IH. s), 7.69 (IH, d), 7.48-7.15 (12H, m), 4.46 (2H, s), 4.35 (2H, s), 4.24-4.13 (2H, m), 3.66 (IH, m), 3.25 (3H, s), 2.88 (IH, m), 2.44 (IH, m), 2.32 (IH, m), 2.14 (IH, t), 2.06 (IH, m), 1.85 (IH, m), 1.73-1.57 (2H, m), 1.42 (IH, m), 0.96 (3H, d), 0.95 (3H, d), 0.90 (3H, d), 0.88 (3H, d)
ESI MS (m/e) = 703 [M+H]+
[Preparation Example 99] Preparation of tert-butyl (lS)-l-[(2i?V4-(l-hvdroxyethyP-5-oxotetrahvdro-2-furanyll-3- methylbutylcarbamate A process was conducted in the same manner as in Preparation Example 78, except for using acetaldehyde instead of acetone, whereby 1.33 g of the title compound was obtained at 85% yield.
IH NMR (400 MHz, CDC13); 4.60-4.54 (2H, m), 4.35 (IH, d), 3.85 (IH, m), 2.87 (IH, m), 2.51-2.32 (2H, m), 1.66-1.50 (6H, m), 1.42 (9H, s), 0.93-0.91 (6H, m)
[Preparation Example 100] Preparation of tert-butyl dS)-l-((2i?)-4-r(E)ethylidenel-5-oxotetrahvdro-2-furanyll-3- methylbutylcarbamate A process was conducted in the same manner as in Preparation Example 79, except for using the compound obtained in Preparation Example 99 instead of the compound obtained in Preparation Example 78, whereby 0.33 g of the title compound was obtained at 25% yield.
IH NMR (400 MHz, CDC13); 6.75 (IH, m), 4.55 (IH, m), 4.35 (IH, d), 3.88 (IH, m), 2.85-2.80 (2H, m), 1.82 (3H, d), 1.62-1.56 (3H, m), 1.39 (9H, s), 0.93 (3H, d), 0.92 (3H,
d)
[Preparation Example 101]
Preparation of 3-r(benzylsulfonvP(methyl)aminol-N-((lS)-l-{(2^)-4-r(E)ethylidenel-5- oxotetrahvdro-2-furanyl I -3 -methylbutvDbenzamide A process was conducted in the same manner as in Preparation Example 87, except for using the compound obtained in Preparation Example 100 instead of the compound obtained in Preparation Example 86, whereby 0.29 g of the title compound was obtained at 54%) yield.
IH NMR (400 MHz, CDC13); 7.50 (IH, t), 7.46 (IH, m), 7.41-7.33 (7H, m), 6.71 (IH, m), 5.98 (IH, d), 4.68 (IH, m), 4.54 (IH, m), 4.30 (2H, s), 3.16 (3H, s), 2.80 (IH, m), 2.77 (IH, m), 1.76 (3H, d), 1.74-1.65 (2H, m), 1.53 (IH, m), 0.97 (6H, d)
[Preparation Example 102]
Preparation of (Z)-2-((2S,3S)-3-( { 3 - [(benzylsulfonvP(methvPamino]benzoyl } amino)-2-
{ [tert-butyl(dimethvPsilyl]oxy} -5-methylhexyP-2-butenoic acid A process was conducted in the same manner as in Preparation Example 6, except for using the compound obtained in Preparation Example 101 instead of the compound obtained in Preparation Example 5, whereby 0.30 g of the title compound was obtained at 81% yield.
IH NMR (400 MHz, CDC13); 7.73 (IH, t), 7.56 (IH, m), 7.45-7.34 (7H, m), 7.14 (IH, q), 6.63 (IH, d), 4.29 (2H, s), 4.10 (IH, m), 4.02 (IH, m), 3.17 (3H, s), 2.58-2.43 (2H, m), 1.81 (3H, d), 1.60 (IH, m), 1.47-1.43 (2H, m), 0.96-0.88 (15H, m), 0.15 (6H, s)
[Preparation Example 103]
Preparation of N-((lS,2S,4Z)-4-r(((lS)-l-r(benzylamino carbonyll-2- methylpropyl} amino)carbonyl1-2- { [tert-butyl(dimethvPsilyl]oxy } - 1 -isobutyl-4- hexenvP-3-[(benzylsulfonvP(methyPamino]benzamide A process was conducted in the same manner as in Preparation Example 90, except for using the compound obtained in Preparation Example 102 instead of the compound obtained in Preparation Example 88, whereby 0.20 g of the title compound was obtained at 51% yield.
IH NMR (400 MHz, CDC13); 7.83 (IH, t), 7.61 (IH, m), 7.37-7.26 (12H, m),6.85 (IH, d), 6.48 (IH, d), 6.43 (IH, t), 6.34 (IH, q), 4.48 (IH, dd), 4.37 (IH, dd), 4.29 (2H, s), 4.27 (IH, m), 4.10 (IH, m), 4.00 (IH, m), 3.16 (3H, s), 2.61-2.52 (2H, m), 2.11 (IH, m), 1.76 (3H, d), 1.62 (IH, m), 1.47-1.42 (2H, m), 0.94-0.87 (21H, m), 0.14 (3H, s), 0.13 (3H, s)
[Example 56]
Preparation of N-{dS.2S.4Z)-4-r({(lS)-l-r(benzylamino carbonyll-2- methylpropyl ) amino)carbonyl] -2-hydroxy- 1 -isobutyl-4-hexenyl } -3 - r(benzylsulfonyP(methvPamino1benzamide A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 103 instead of the compound obtained in Preparation Example 12 whereby 54 mg of the title compound was obtained at 59% yield.
IH ΝMR (400 MHz, CDC13); 7.68 (IH, t), 7.61 (IH, m), 7.43-7.23 (12H, m), 6.67 (IH, d), 6.61 (IH, d), 6.33 (IH, q), 6.26 (IH, t), 4.48 (IH, dd), 4.36 (IH, dd), 4.29 (2H, s), 4.26 (IH, m), 4.19 (IH, m), 3.72 (IH, m), 3.16 (3H, s), 2.62 (IH, m), 2.32 (IH, m), 2.08 (IH, m), 1.81 (3H, d), 1.77-1.66 (2H, m), 1.46 (IH, m), 1.00-0.87 (12H, m) ESI MS (m/e) = 691 [M+H]+
[Preparation Example 104]
Preparation of N-((1S.2SAK or 4S -r({dS)-l-[(benzylamino)carbonyl]-2- methylpropyl } amino)carbonyl]-2- { [tert-butyl(dimethvDsilyl] oxy} - 1 -isobutylhexyP-3 - l(benzylsulfonvD(methvPamino]benzamide 0.20 g (0.25 mmol) of the compound obtained in Preparation Example 103 was dissolved in 20 ml of methanol, and active carbon-supported palladium (10%>) was added, followed by stirring overnight in a hydrogen atmosphere. After removing solid by filtration under reduced pressure using Cellite and removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a
2:3 mixture of ethyl acetate and hexane to obtain 54 mg of the title compound at 27% yield.
IH NMR (400 MHz, CDC13); 7.79 (IH, t), 7.60 (IH, m), 7.41-7.23 (12H, m), 6.58 (IH, d), 6.43 (IH, t), 6.31 (IH, d), 4.47-4.34 (3H, m), 4.30 (2H, s), 4.13 (IH, m), 3.75 (IH, m), 3.17 (3H, s), 2.40 (IH, m), 2.03 (IH, m), 1.76-1.61 (4H, m), 1.62-1.42 (3H, m),
1.01-0.83 (24H, m), 0.13 (3H, s), 0.11 (3H, s)
[Example 57] Preparation of N-((lS.2S.4i? or 4S -[(((lS)-l-r(benzylaminotearbonvH-2- methylpropyl I amino)carbonyl] -2-hydroxy- 1 -isobutylhexyl I -3 -
[(benzylsulfonyP(methvPamino]benzamide A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 104 instead of the compound obtained in Preparation Example 12, whereby 25 mg of the title compound was obtained at 54% yield..
IH ΝMR (400 MHz, CDC13); 7.69 (IH, t), 7.60 (IH, m), 7.39-7.21 (12H, m), 6.65 (IH, d), 6.49-6.45 (2H, m), 4.45-4.31 (3H, m), 4.29 (2H, s), 4.22 (IH, m), 4.13 (IH, m), 3.75
(IH, m), 3.16 (3H, s), 2.45 (IH, m), 2.08 (IH, m), 1.85-1.41 (7H, m), 0.98-0.84 (15H, m)
ESI MS (m/e) = 693 [M+H]+
[Preparation Example 105] Preparation of N-((1S.2SAR or 4S)-4-r({(lSyi-r(benzylamino arbonyr)-2- methylpropyl I amino)carbonyl1 -2- { [tert-butvKdimethyPsilyl] oxy 1-1 -isobutylhexyP-3 - [(benzylsulfonyl)(methvPaminolbenzamide 37 mg of the title compound which is an isomer corresponding to the compound in Preparation Example 104 was obtained at 19% yield. IH NMR (400 MHz, CDC13); 7.70 (IH, t), 7.54 (IH, m), 7.44-7.28 (12H, m), 6.35 (IH, d), 6.29 (IH, t), 6.23 (IH, d), 4.55 (IH, dd), 4.35 (IH, dd), 4.30 (2H, s), 4.27 (IH, m)4.23 (IH, m), 3.73 (IH, m), 3.18 (3H, s), 2.29 (IH, m), 2.16 (IH, m), 1.82-1.37 (7H, m), 1.01-0.85 (24H, m), 0.14 (3H, s), 0.10 (3H, s)
[Example 58]
Preparation of N-U1S.2SAR or 4S)-4-r({(lS)-l-r(benzylamino)carbonyll-2- methylpropyl } amino)carbonyl]-2 -hydroxy- 1 -isobutylhexyl } -3 - [(benzylsulfonvP(methvPamino]benzamide A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 105 instead of the compound obtained in Preparation Example 12, whereby 16 mg of the title compound was obtained at 50% yield.
IH ΝMR (400 MHz, CDC13); 7.68 (IH, t), 7.60 (IH, m), 7.41-7.24 (12H, m), 6.65 (IH, t), 6.30 (IH, d), 6.13 (IH. d), 4.40 (2H, d), 4.32-4.28 (3H, m), 4.14 (IH, m), 3.68 (IH, m), 3.35 (IH, d), 3.17 (3H, s), 2.30-2.21 (2H, m), 1.94-1.31 (7H, m), 0.98-0.87 (15H, m)
ESI MS (m/e)= 693 [M+H]+
[Preparation Example 106]
Preparation of methyl (2S)-2-f((2i?.4S.5S)-5-((3-
[(benzylsulfonvP(methvPamino]benzoyl}amino)-4-{[tert-butyl(dimethyDsilyl]oxy}- 2,7-dimethyloctanovPamino]-3-methylbutanoate 70 mg (0.116 mmol) of the compound obtained in Preparation Example 58 was dissolved in 5 ml of N,N-dimethylformamide and heated to 0°C, then 25 mg (0.151 mmol) of (S)-valinemethylesterhydrochloride and 57 mg (0.151 mmol) of HATU were added thereto. 0.5 ml (excess amount) of N,N-diisopropylethylamine was then added thereto and heated to room temperature, followed by stirring for 3 hours. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 72 mg of the title compound at 87% yield. IH NMR (400 MHz, CDC13); 7.74 (IH, s), 7.56 (IH, m), 7.43-7.33 (7H, m), 6.57 (IH, d), 6.22 (IH, d), 4.44-4.34 (2H, m), 4.29 (2H, s), 3.78 (IH, d), 3.70 (3H, s), 3.16 (3H, s), 2.66 (IH, m), 1.96 (IH, m), 1.80-1.49 (4H, m), 1.41 (IH, m), 1.16 (3H, d), 0.99 (3H, d), 0.97 (3H, d), 0.93 (9H, s), 0.72 (3H, d), 0.69 (3H, d), 0.12 (3H, s), 0.11 (3H, s) [Example 59]
Preparation of methyl (2S)-2-(r(2i?.4S,5S)-5-((3- r(benzylsulfonyP(methyPamino1benzoyUamino)-4-hvdroxy-2,7- dimethyloctano yl] amino 1-3 -methylbutanoate A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 106 instead of the compound obtained in Preparation Example 12, whereby 54 mg of the title compound was obtained at 92% yield.
IH NMR (400 MHz, CDC13); 7.66 (IH, s), 7.61 (IH, d), 7.44-7.34 (7H, m), 6.37 (IH, d), 6.23 (IH, d), 4.50 (IH, dd), 4.30 (2H, s), 4.14 (IH, m), 4.01 (IH, d), 3.82 (IH, m),
3.74 (3H, s), 3.17 (3H, s), 2.72 (IH, m), 2.11 (IH, m), 1.82-1.62 (4H, m), 1.46 (IH, m),
1.25 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.87 (3H, d), 0.84 (3H, d)
ESI MS (m/e) = 604 [M+H]+
[Example 60]
Preparation of (2S)-2-ir(2i?.4S,5S)-5-((3-
[(benzylsulfonyl)(methvPamino]benzov amino)-4-hydroxy-2,7- dimethyloctanoyl] amino } -3 -methylbutanoic acid 49 mg (0.081 mmol) of the compound obtained in Example 59 was dissolved in 3 ml of tetrahydrofurane and 5 ml of methanol, and 2 ml of 1.0 N lithium hydroxide solution was added thereto, followed by stirring for 2 hours. After removing solvent by distillation under reduced pressure, the residue was diluted with water, and the solid produced by acidification with 1.0 N hydrochloride solution was filtered to obtain 34 mg of the title compound at 71% yield. IH NMR (400 MHz, CD3OD); 7.94 (IH, d), 7.76 (IH, s), 7.47-7.31 (7H, m), 4.67 (2H, s), 4.29 (IH, m), 4.20 (IH, m), 3.62 (IH, m), 3.26 (3H, s), 2.76 (IH, m), 2.11 (IH, m), 1.86 (IH, m), 1.73-1.58 (2H, m), 1.50-1.34 (2H, m), 1.15 (3H, d), 0.96 (6H, d), 0.90 (6H, d) ESI MS (m/e) = 590 [M+H]+
[Preparation Example 107]
Preparation of N-((lS,2S,4ig -5-{[(lS)-l-(aminocarbonvP-2-methylpropyl]amino|-2-
{[tert-butyl(dimethvPsilyl]oxy}-l-isobutyl-4-methyl-5-oxopentvP-3- [(benzylsulfonvP(methypamino1benzamide A process was conducted in the same manner as in Preparation Example 106, except for using (S)-valineamide instead of (S)-valinemethylesterhydrochloride, whereby 62 mg of the title compound was obtained at 74% yield.
IH ΝMR (400 MHz, CDC13); 7.77 (IH, s), 7.58 (IH, d), 7.47-7.32 (7H, m), 6.70 (IH, d), 6.29 (IH, d), 6.10 (IH, s), 5.34 (IH, s), 4.38 (IH, m), 4.31 (2H, s), 4.15 (IH, dd),
3.76 (IH, dd), 3.18 (3H, s), 2.66 (IH, m), 2.00 (IH, m), 1.82-1.48 (4H, m), 1.41 (IH, m),
1.17 (3H, d), 0.98 (3H, d), 0.97 (3H, d), 0.93 (9H, s), 0.76 (3H, d), 0.66 (3H, d), 0.12
(3H, s), 0.11 (3H, s)
[Example 61]
Preparation of N-(( 1 S,2S,4i?)-5- { \( 1 S)- 1 -(aminocarbonyP-2-methylpropyl]amino 1-2- hvdroxy- 1 -isobutyl -4-methyl-5-oxopentyP-3 [(benzylsulfonyP(methyPamino1benzamide A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 107 instead of the compound obtained in Preparation Example 12, whereby 41 mg of the title compound was obtained at 82% yield.
IH NMR (400 MHz, CD3OD); 7.76 (IH, s), 7.71 (IH, d), 7.45-7.33 (7H, m), 4.47 (2H, s), 4.20 (IH, m), 4.16 (IH, d), 3.62 (IH, m), 3.26 (3H, s), 2.76 (IH, m), 2.00 (IH, m), 1.86 (IH, m), 1.73-1.60 (2H, m), 1.50-1.36 (2H, m), 1.14 (3H, d), 0.96 (6H, d), 0.91 (3H, d), 0.89 (3H, d) ESI MS (m/e) = 589 [M+H]+
[Preparation Example 108]
Preparation of methyl (2SV2-r((2i?,4S.5S)-5-( f 3-
[(benzylsulfonyP(methvPamino1benzoyl}amino)-4-{[tert-butyl(dimethvPsilyl]oxy}-
2,7-dimethyloctanoyPamino]butanoate A process was conducted in the same manner as in Preparation Example 106, except for using methyl (2S)-2-aminobutanate hydrochloride instead of (S)- valinemethylesterhydrochloride, whereby 91 mg of the title compound was obtained at
86% yield.
IH NMR (400 MHz, CDC13); 7.75 (IH, s), 7.56 (IH, t), 7.43-7.33 (7H, m), 6.67 (IH, d),
6.23 (IH, d), 4.40 (IH, m), 4.29 (2H, s), 3.78 (IH, dd), 3.70 (3H. s), 3.17 (3H, s), 2.61 (IH, m), 1.78-1.46 (6H, m), 1.40 (IH, m), 1.17 (3H, d), 0.99 (3H, d), 0.97 (3H, d), 0.92
(9H, s), 0.67 (3H, t), 0.12 (3H, s), 0.11 (3H, s)
[Preparation Example 109]
Preparation of methyl (2S)-2-{r(2i?.4S.5S)-5-((3- [(benzylsulfonyP(methvPamino]benzoyliamino -4-hydroxy-2.7- dimethyloctanoyl] amino } butanoate A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 108 instead of the compound obtained in Preparation Example 12, whereby 66 mg of the title compound was obtained at 90%) yield.
IH NMR (400 MHz, CDC13); 7.67 (IH, s), 7.61 (IH, d), 7.44-7.35 (7H, m), 6.38 (IH. d), 6.28 (IH, d), 4.51 (IH, m), 4.30 (2H, s), 4.14 (IH, m), 4.00 (IH, s), 3.81 (IH, m),
3.74 (3H, s), 3.17 (3H, s), 2.69 (IH, m), 1.84 (IH, m), 1.78-1.62 (5H, m), 1.47 (IH, m), 1.25 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.84 (3H, t)
[Example 62]
Preparation of (2SV2-{r(2fl,4S.5S)-5-((3-
[(benzylsulfonyP(methvPamino]benzovUamino)-4-hvdroxy-2,7- dimethyloctanoyl] amino Ibutanoic acid A process was conducted in the same manner as in Example 60, except for using the compound obtained in Preparation Example 109 instead of the compound obtained in Example 59, whereby 44 mg of the title compound was obtained at 68% yield. IH NMR (400 MHz, CD3OD); 7.76 (IH, s), 7.71 (IH, m), 7.46-7.32 (7H, m), 4.46 (2H, s), 4.26 (IH, dd), 4.19 (IH, m), 3.61 (IH, m), 3.26 (3H, s), 2.73 (IH, m), 1.92-1.77 (2H, m), 1.73-1.59 (3H, m), 1.50-1.36 (2H, m), 1.16 (3H, d), 0.96 (6H, d), 0.89 (3H, t)
ESI MS (m/e) = 576 [M+H]+ [Example 63]
Preparation of N-[(lS,2S,4i?)-5-(((lS -l -[(benzylamino)carbonyl]propyl}arnino)-2- hvdroxy- 1 -isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonyP(methyPamino]benzamide 18 mg (0.031 mmol) of the compound obtained in Example 62 was dissolved in
3 ml of Ν,Ν-dimethylformamide and heated to 0°C, then 5 mg (0.047 mmol) of benzylamine and 18 mg (0.047 mmol) of HATU were added thereto. 0.5 ml (excess amount) of N,N-diisopropylethylamine was added, and heated to room temperature, followed by stirring for 3 hours. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 5:1 mixture of ethyl acetate and hexane to obtain 18 mg of the title compound at 86% yield IH NMR (400 MHz, CD3OD); 7.77 (IH. s), 7.71 (IH, m), 7.44-7.18 (12H, m), 4.45 (2H. s), 4.36 (2H, dd), 4.26-4.12 (2H, m), 3.60 (IH, m), 3.25 (3H, s), 2.72 (IH, m), 1.90-1.56 (5H, m), 1.51-1.35 (2H, m), 1.13 (3H, d), 0.97 (3H, d), 0.95 (3H, d), 0.87 (3H, t) ESI MS (m/e) = 665 [M+H]+
[Preparation Example 110]
Preparation of methyl (2S.3R)-2-\((2RAS.5S)-5-(V3-
[(benzylsulfonvP(methyPamino]benzoyl} amino)-4- { [tert-butyl(dimethvPsilyl]oxy) - 2.7-dimethyloctanoyPamino] -3 -methylpentanoate A process was conducted in the same manner as in Preparation Example 106, except for using methyl (2S,3Λ)-2-amino-3-methylpentanoate hydrochloride instead of (S)-valinemethylesterhydrochloride, whereby 91 mg of the title compound was obtained at 83%) yield.
IH NMR (400 MHz, CDC13); 7.73 (IH, s), 7.57 (IH, m), 7.44-7.33 (7H, m), 6.58 (IH, d), 6.21 (IH, d), 4.50-4.35 (2H, m), 4.29 (2H, s), 3.78 (IH, m), 3.69 (3H, s), 3.17 (3H, s), 2.65 (IH, m), 1.79-1.47 (6H, m), 1.40 (IH, m), 1.23 (IH, m), 1.16 (3H, d), 0.99 (3H, d), 0.97 (3H, d), 0.93 (9H, s), 0.69 (3H, d), 0.65 (3H, t), 0.12 (3H, s), 0.11 (3H, s)
[Preparation Example 111] Preparation of methyl (2S.3i?)-2-(r(2i?.4S,5S)-5-((3-
[(benzylsulfonvP(methvPamino]benzov amino)-4-hydroxy-2,7- dimethyloctanoyl]amino}-3-methylpentanoate A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 108 instead of the compound obtained in Preparation Example 12, whereby 65 mg of the title compound was obtained at 85% yield.
IH NMR (400 MHz, CDC13); 7.66 (IH, s), 7.61 (IH, d), 7.45-7.35 (7H, m), 6.37 (IH, d), 6.25 (IH, d), 4.55 (IH, dd), 4.30 (2H, s), 4.13 (IH, m), 4.00 (IH, d), 3.81 (IH, m),
3.73 (3H, s), 3.17 (3H, s), 2.71 (IH, m), 1.85 (IH, m), 1.78-1.62 (4H, m), 1.47 (IH, m), 1.36 (IH, m), 1.24 (3H, d), 1.12 (IH, m), 0.98 (3H, d), 0.96 (3H, d), 0.85 (3H, t), 0.84
(3H, d)
[Example 64]
Preparation of (2S3R)-2-iϊ(2RAS,5S)-5-(V3- [(benzylsulfonyP(methvPamino]benzoyllamino)-4-hydroxy-2,7- dimethyloctanoyl]amino}-3-methylpentanoic acid A process was conducted in the same manner as in Example 60, except for using the compound obtained in Preparation Example 111 instead of the compound obtained in example 59, whereby 62 mg of the title compound was obtained at 98% yield.
IH NMR (400 MHz, CD3OD); 7.76 (IH, s), 7.70 (IH, m), 7.48-7.27 (7H, m), 4.46 (2H, s), 4.33 (IH, m), 4.20 (IH, m), 3.60 (IH, m), 3.26 (3H, s), 2.77 (IH, m), 1.93-1.76 (2H, m), 1.73-1.58 (2H, m), 1.52-1.35 (3H, m), 1.29 (IH, m), 1.14 (3H, d), 0.96 (6H, d), 0.88 (3H, d), 0.83 (3H, t)
ESI MS (m/e) = 604 [M+H]+
[Example 65]
Preparation of N-r(lS.2S.4J?V5-(((lS.2J?)-l-r(benzylamino carbonyll-2- methylbutyl } amino -2-hydroxy- 1 -isobutyl -4-methyl-5-oxopentyl] -3 -
[(benzylsulfonvP(methyl)amino]benzamide A process was conducted in the same manner as in Example 63, except for using the compound obtained in Example 64 instead of the compound obtained in
Example 62, whereby 20 mg of the title compound was obtained at 63% yield. IH ΝMR (400 MHz, CD3OD); 7.77 (IH, s), 7.71 (IH, m), 7.45-7.18 (12H, m), 4.45 (2H, s), 4.35 (2H, dd), 4.23-4.12 (2H, m), 3.61 (IH, m), 3.25 (3H, s), 2.75 (IH, m), 1.90-1.58
(4H, m), 1.52-1.37 (3H, m), 1.12 (3H, d), 1.11 (IH, m), 0.96 (6H, d), 0.84 (3H, d), 0.78
(3H, t)
ESI MS (m/e) = 693 [M+H]+ [Preparation Example 112]
Preparation of methyl (2S -2-K(2i?.4S.5S)-5-((3-
[(benzylsulfonvP(methvPamino]benzoyl)amino -4-{[tert-butyl(dimethvPsilyl]oxy}- 2,7-dimethyloctanovPamino1-3,3-dimethylbutanoate A process was conducted in the same manner as in Preparation Example 106, except for using methyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride instead of (S)-valinemethylesterhydrochloride, whereby 93 mg of the title compound was obtained at 85% yield. IH NMR (400 MHz, CDC13); 7.72 (IH, s), 7.56 (IH, d), 7.43-7.33 (7H, m), 6.52 (IH, d), 6.19 (IH, d), 4.38 (IH, m), 4.32 (IH, d), 4.29 (2H, s), 3.79 (IH, dd), 3.68 (3H, s), 3.16 (3H, s), 2.70 (IH, m), 1.80-1.50 (4H, m), 1.40 (IH, m), 1.14 (3H, d), 0.99 (3H, d), 0.97 (3H, d), 0.93 (9H, s), 0.77 (9H, s), 0.12 (3H, s), 0.11 (3H, s)
[Example 66]
Preparation of methyl (2S -2-(r(2i?.4S.5S)-5-((3-
[(benzylsulfonyP(methvPamino]benzoyl}amino)-4-hvdroxy-2,7- dimethyloctanoy 11 amino } -3 ,3 -dimethylbutanoate A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 112 instead of the compound obtained in Preparation Example 12, whereby 74 mg of the title compound was obtained at 95% yield.
IH NMR (400 MHz, CDCI3); 7.65 (IH, s), 7.59 (IH, d), 7.44-7.34 (7H, m), 6.33 (IH, d), 6.24 (IH, d), 4.41 (IH, d), 4.30 (2H, s), 4.13 (IH, m), 3.97 (IH, d), 3.83 (IH, m), 3.72 (3H, s), 3.17 (3H, s), 2.72 (IH, m), 1.82-1.62 (4H, m), 1.46 (IH, m), 1.24 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.91 (9H, s)
ESI MS (m/e) = 618 [M+H]+
[Example 67]
Preparation of (2S)-2-{r(2i?.4S,5S)-5-({3- r(benzylsulfonvP(methvPamino]benzoyl}amino -4-hvdroxy-2,7- dimethyloctanoyl] amino 1-3 ,3 -dimethylbutanoic acid A process was conducted in the same manner as in Example 60, except for using the compound obtained in Example 66 instead of the compound obtained in
Example 59, whereby 60 mg of the title compound was obtained at 91% yield.
IH NMR (400 MHz, CDC13); 7.68 (IH, s), 7.63 (IH, m), 7.42-7.33 (7H, m), 6.64 (IH, d), 6.60 (IH, d), 4.38 (IH, d), 4.31 (2H, s), 4.12 (IH, m), 3.84 (IH, m), 3.16 (3H, s),
2.73 (IH, m), 1.82-1.58 (4H, m), 1.46 (IH, m), 1.19 (3H, d), 0.95 (9H, s), 0.89 (3H, d), 0.87 (3H, d)
ESI MS (m/e) = 604 [M+H]+
[Example 68]
Preparation of. N-r(lS,2S.4i? -5-(((lS)-l-r(benzylamino)carbonyll-2.2- dimethy Ipropyl } amino)-2-hydroxy- 1 -isobutyl-4-methyl-5 -oxopentyl] -3 - [(benzylsulfonvP(methvPaminolbenzamide A process was conducted in the same manner as in Example 63, except for using the compound obtained in Example 67 instead of the compound obtained in example 62 whereby 39 mg of the title compound was obtained at 49% yield. IH NMR (400 MHz, CDC13); 7.69 (IH, s), 7.60 (IH, d), 7.44-7.18 (12H, m), 6.59 (IH, d), 6.44 (IH, d), 6.22 (IH, t), 4.48-4.27 (2H, m), 4.29 (2H, s), 4.22 (IH, d), 4.13 (IH, m), 4.09 (IH, d), 3.79 (IH, m), 3.16 (3H, s), 2.71 (IH, m), 1.78 (IH, m), 1.74-1.60 (3H, m), 1.45 (IH, m), 1.19 (3H, d), 0.97 (3H, d), 0.94 (3H, d), 0.93 (9H, s) ESI MS (m/e) = 693 [M+H]+
[Example 69]
Preparation of N-r(lS,2S.4i-)-5-({(lS)-l-r(benzylamino)carbonyll-2,2- dimethylpropyUamino)-2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyl1-3- [(benzylsulfonvP(methvPamino]benzamide 7 mg of the title compound as a byproduct in Example 68, was obtained at 9% yield.
IH ΝMR (400 MHz, CDC13); 7.71 (IH, s), 7.59 (IH, d), 7.44-7.18 (12H, m), 6.46 (IH, d), 6.33 (IH, d), 6.19 (IH, t), 4.50-4.30 (2H, m), 4.29 (2H, s), 4.20 (IH, d), 4.08 (IH, m), 4.07 (IH, d), 3.60 (IH, m), 3.18 (3H, s), 2.68 (IH, m), 1.78-1.53 (4H, m), 1.33 (IH, m), 1.21 (3H, d), 1.00 (9H, s), 0.94 (3H, d), 0.92 (3H, d)
ESI MS (m/e) = 693 [M+H]+
[Preparation Example 113] Preparation of tert-butyl 1 -f (benzylamino carbonyllcyclopentylcarbamate A process was conducted in the same manner as in Preparation Example 75, except for using l-[(t-butoxycarbonyl)amino]cyclopentancarboxylic acid instead of t- butoxycarbonyl (S)-valine, whereby 133 mg of the title compound was obtained at 48% yield. IH NMR (400 MHz, CDC13); 7.35-7.20 (5H, m), 7.02 (IH, br), 4.73 (IH, br), 4.46 (2H, d), 2.40-2.25 (2H, m), 1.98-1.66 (6H, m), 1.39 (9H, s)
[Preparation Example 114] Preparation of N-((lS,2SAR)-5-({ l-[(benzylamino)carbonyl]cyclopentyl)amino)-2- { [tert-butyKdimethvPsilylloxy} - 1 -isobutyl-4-methyl-5-oxopentvP-3- [(benzylsulfonyP(methvPamino]benzamide 72 mg (0.225 mmol) of the compound obtained in Preparation Example 113 was dissolved in 3 ml of 4.0 Ν hydrochloride solution diluted with ethyl acetate, and stirred for 2 hours. After distillation under reduced pressure for concentration, the residue was dissolved in 5 ml of Ν,Ν-dimethylformamide and cooled to 0°C, then 91 mg (0.15 mmol) of the compound obtained in Preparation Example 58 and 43 mg (0.225 mmol) of EDC and 41 mg (0.3 mmol) of HOBT were added thereto. 0.5 ml (excess amount) of N,N-diisopropylethylamine was then added thereto and heated to room temperature, followed by stirring overnight. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 51 mg of the title compound at 42% yield.
IH NMR (400 MHz, CDC13); 7.69 (IH, s), 7.52-7.29 (9H, m), 7.20-7.14 (5H, m), 6.84 (IH, s), 6.17 (IH, d), 4.43-4.14 (5H, m), 3.73 (IH, dd), 3.19 (3H, s), 2.55 (IH, m), 2.33 (IH, m), 2.20 (IH, m), 2.10-1.92 (2H, m), 1.72-1.31 (9H, m), 1.12 (3H, d), 0.97 (6H, d), 0.91 (9H, s), 0.10 (3H, s), 0.06 (3H, s) [Example 70]
Preparation of N-[(lS,2SAK)-5-( j 1 -r(benzylamino)carbonyl]cyclopentyllamino)-2- hydroxy- 1 -isobutyl-4-methyl-5 -oxopentyl] -3 - l(benzylsulfonvP(methvDamino1benzamide A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 114 instead of the compound obtained in Preparation Example 12, whereby 40 mg of the title compound was obtained at 93% yield. IH ΝMR (400 MHz, CDC13); 7.66 (IH, s), 7.55 (IH, t), 7.43-7.33 (7H, m), 7.30-7.13
(6H, m), 6.34 (IH, s), 6.19 (IH, d), 4.44-4.22 (4H, m), 4.09 (IH, m), 3.64 (IH, m), 3.26
(IH, d), 3.18 (3H, s), 2.59 (IH, m), 2.35-2.17 (2H, m), 2.08 (IH, m), 1.89 (IH, m),
1.78-1.50 (8H, m), 1.34 (IH, m), 1.13 (3H, d), 0.94 (3H, d), 0.93 (3H, d)
ESI MS (m/e) = 691 [M+H]+
[Example 71]
Preparation of (2i?,4S,5S)-5-({3-r(benzylsulfonvP(methvPamino benzoyl)amino)-4- hvdroxy-2.7-dimethyloctanoic acid A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 58 instead of the compound obtained in Preparation Example 12, whereby 10 mg of the title compound was obtained at 33% yield.
IH ΝMR (400 MHz, CD3OD); 7.74 (IH, s), 7.71 (IH, m), 7.46-7.32 (7H, m), 4.47 (2H, s), 4.17 (IH, m), 3.63 (IH, m), 3.26 (3H, s), 2.68 (IH, m), 1.83 (IH, m), 1.72-1.59 (2H, m), 1.50-1.34 (2H, m), 1.15 (3H, d), 0.97 (6H, d) ESI MS (m/e) = 491 [M+H]+
[Preparation Example 115]
Preparation of 3-amino-2-piperidinone hydrochloride According to the known method (Tetrahedron 2002, 58, 3137-3143), the title compound could be obtained.
IH NMR (400 MHz, DMSO, d6); 8.28 (3H, s), 8.04 (IH, s), 3.71 (IH, m), 3.20-3.03 (2H, m), 2.13 (IH, m), 1.90-1.62 (3H, m)
[Preparation Example 116]
Preparation of 3 - KbenzylsulfonvPfaethvPaminol -N-(( 1 S,2S,4i?)-2- { Ttert- butyl(dimethvPsilylloxyl-l-isobutyl-4-methyl-5-oxo-5-(r(3i? or 3S)-2- oxopiperidinyl] amino } pentvPbenzamide 91 mg (0.15 mmol) of the compound obtained in Preparation Example 58 was dissolved in 5 ml of N,N-dimethylformamide and cooled to 0°C, then 34 mg (0.225 mmol) obtained in Preparation Example 115 and 86 mg (0.225 mmol) of HATU were added thereto. 0.5 ml (excess amount) of N,N-diisopropylethylamine was then added thereto and heated to room temperature, followed by stirring for 3 hours. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 21 mg of the title compound at 20%) yield.
IH NMR (400 MHz, CDC13); 7.82 (IH, s), 7.59(1H, d), 7.45-7.33 (7H, m), 6.79 (IH, d), 6.27 (IH, d), 5.48 (IH, s), 4.50-4.20 (4H, m), 3.80 (IH, m), 3.23 (3H, s), 3.22-3.12 (2H, m), 2.54 (IH, m), 2.28 (IH, m), 1.97 (IH, m), 1.92-1.48 (6H, m), 1.39 (IH, m), 1.17 (3H, d), 0.98 (3H, d), 0.97 (3H, d), 0.91 (9H, s), 0.12 (3H, s), 0.11 (3H, s)
[Example 72]
Preparation of 3-[(benzylsulfonvP(methvPamino]-N-((lS.2S.4J?)-2-hvdroxy- 1 -isobutyl-
4-methyl-5-oxo-5-{ \(3R or 3S)-2-oxopiperidinyl]amino}pentvPbenzamide A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained form Preparation Example 116 instead of the compound obtained in Preparation Example 12, whereby 13 mg of the title compound was obtained at 76%o yield.
IH ΝMR (400 MHz, CDC13); 7.73 (IH, s), 7.65 (IH, m), 7.45-7.32 (7H, m), 6.58 (IH, d), 6.41 (IH, d), 6.03 (IH, s), 4.67 (IH, br), 4.46 (IH, m), 4.32 (2H, s), 4.16 (IH, m),
3.75 (IH, br), 3.28 (2H, br), 3.16 (3H, s), 2.60 (IH, m), 2.31 (IH, m), 1.98-1.50 (7H, m),
1.39 (IH, m), 1.18 (3H, d), 0.96 (3H, d), 0.93 (3H, d)
ESI MS (m/e) = 587 [M+H]+
[Preparation Example 117]
Preparation of 3 - r(benzylsulfonvP(methvPamino]-N-(( 1 S.2SAR )-2- ( Ttert- butyl(dimethvPsilylloxy)-l-isobutyl-4-methyl-5-oxo-5-(r(3i? or 3SV2- oxopiperidinyl]amino}pentvPbenzamide In purification procedure of Preparation Example 116, 36 mg of the title compound as an isomer corresponding to the compound in Preparation Example 116 was obtained at 34% yield.
IH NMR (400 MHz, CDC13); 7.81 (IH, s), 7.53 (IH, d), 7.43-7.33 (6H, m), 7.30 (IH, m), 6.81 (IH, d), 6.27 (IH, d), 5.69 (IH, s), 4.37 (IH, m), 4.34 (2H, s), 4.17 (IH, m), 3.77 (IH, m), 3.28-3.18 (2H, m), 3.19 (3H, s), 2.55 (IH, m), 2.26 (IH, m), 1.82-1.34 (8H, m), 1.17 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.13 (3H, s), 0.11 (3H, s)
[Example 73]
Preparation of 3 - [(benzylsulfonvP(methvPamino] -N-(( 1 S,2S,4i?)-2-hvdroxy- 1 -isobutyl- 4-methyl-5-oxo-5-{[(3i? or 3S)-2-oxopiperidinyllamino}penτyPbenzamide A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 117 instead of the compound obtained in Preparation Example 12, whereby 28 mg of the title compound was obtained at 99% yield. IH ΝMR (400 MHz, CDC13); 7.71 (IH, s), 7.65 (IH, m), 7.43-7.33 (7H, m), 6.76 (IH, d), 6.62 (IH, d), 5.99 (IH, s), 4.59 (IH, br), 4.31 (2H, s), 4.18-4.03 (2H, m), 3.80 (IH, m), 3.39-3.24 (2H, m), 3.17 (3H, s), 2.65 (IH, m), 2.36 (IH, m), 1.96-1.57 (7H, m),
1.44 (IH, m), 1.21 (3H, d), 0.97 (3H, d), 0.95 (3H, d)
ESI MS (m/e) = 587 [M+H]+
[Preparation Example 118]
Preparation of methyl 4-{[(tert-butoxycarbonvPamino1methyl}cyclohexanecarboxylate 1.23 g (4.78 mmol) of trans-4-{[(tert- butoxycarbonyl)amino]methyl}cyclohexanecarboxylic aicd and 1.98 g(14.34 mmol) of potassium carbonate were dissolved in 20 ml of N,N-dimethylformamide, then 0.89 ml (14.34 mmol) of iodomethane was added thereto, followed by stirring for 3 hours. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water and sodium chloride solution. The solvent was removed by distillation under reduced pressure to obtain 1.2 g of the title compound at 92% yield.
IH NMR (400 MHz, CDC13); 4.56 (IH, br), 3.66 (3H, s), 2.98 (2H, t), 2.24 (IH, m), 2.00 (2H, d), 1.82 (2H, d), 1.44 (9H, s), 1.50-1.34 (3H, m), 1.03-0.88 (2H, m)
[Preparation Example 119]
Preparation of methyl 4-(l((2J?.4S.5S)-5-((3-
[(benzylsulfonvP(methvPamino]benzoyl}amino)-4-([tert-butyl(dimethyPsilyl]oxy}- 2.7-dimethyloctano vPamino] methyl } cyclohexanecarboxylate A process was conducted in the same manner as in Preparation Example 114, except for using the compound obtained in Preparation Example 118 instead of the compound obtained in Preparation Example 113, whereby 89 mg of the title compound was obtained at 78%) yield.
[Example 74] Preparation of methyl 4-({r(2i?.4S.5S)-5-({3-
[(benzylsulfonvP(methvPamino1benzoyl}amino -4-hvdroxy-2,7- dimethyloctano yl] amino ) methvPcyclohexanecarboxylate A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 119 instead of the compound obtained in Preparation Example 12, whereby 52 mg of the title compound was obtained at 68% yield.
IH NMR (400 MHz, CDC13); 7.65 (IH, s), 7.60 (IH, m), 7.43-7.33 (7H, m), 6.36 (IH, d), 5.86 (IH, t), 4.31 (2H, s), 4.18 (IH, d), 4.14 (IH, m), 3.81 (IH, m), 3.65 (3H, s), 3.17 (3H, s), 3.16-2.98 (2H, m), 2.60 (IH, m), 2.19 (IH, m), 2.00-1.88 (2H, m), 1.81- 1.61 (6H, m), 1.52-1.26 (6H, m), 1.23 (3H, d), 0.98 (3H, d), 0.96 (3H, d) ESI MS (m/e) = 587 [M+H]+
[Example 75] Preparation of 4-({[(2J?.4S,5S -5-({3-[(benzylsulfonvP(methyPamino1benzoyl}amino)- 4-hvdroxy-2,7-dimethyloctanoyl]amino}methvPcvclohexanecarboxylic acid A process was conducted in the same manner as in Example 60, except for using the compound obtained in Example 74 instead of the compound obtained in Example 59, whereby 36 mg of the title compound was obtained at 80%> yield. IH NMR (400 MHz, CD3OD); 7.75 (IH, s), 7.71 (IH, d), 7.50-7.30 (7H, m), 4.47 (2H, s), 4.18 (IH, m), 3.58 (IH, m), 3.26 (3H, s), 3.12-2.90(2H, m), 2.65 (IH, m), 2.15 (IH, m), 2.00-1.58 (8H, m), 1.50-1.21 (6H, m), 1.13 (3H, d), 0.97 (6H, d) ESI MS (m/e) = 630 [M+H]+
[Preparation Example 120]
Preparation of methyl 4-r(tert-butoxycarbonyPamino]cvclohexanecarboxylate A process was conducted in the same manner as in Preparation Example 118, except for using 4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid instead of t «5-4-{[(tert-butoxycarbonyl)amino]methyl}cyclohexanecarboxylic acid, whereby 0.89 g of the title compound was obtained at 98% yield.
IH NMR (400 MHz, CDC13); 4.56 (IH, br), 3.68 (3H, s), 3.63 (IH, m), 2.47 (IH, m),
2.12-1.48 (5H, m), 1.44 (9H, s)
[Preparation Example 121]
Preparation of methyl 4-r((2i?,4S,5S)-5-((3- r(benzylsulfonvP(methvPaminolbenzoyl|amino)-4-{[tert-butyl(dimethvPsilyl]oxy}-
2 ,7-dimethyloctano vPamino] cyclohexanecarboxylate A process was conducted in the same manner as in Preparation Example 114, except for using the compound obtained in Preparation Example 120 instead of the compound obtained in Preparation Example 113, whereby 84 mg of the title compound was obtained at 75%) yield.
IH NMR (400 MHz, CDC13); 7.64 (IH, s), 7.58 (IH, m), 7.46-7.32 (7H, m), 6.24 (IH, d), 6.20 (IH, d), 4.38 (IH, m), 4.31 (2H, s), 3.80-3.68 (2H, m), 3.65 (3H, s), 3.21 (3H, s), 2.51-2.36 (2H, m), 1.98-1.83 (2H, m), 1.73-1.30 (11H, m), 1.14 (3H, d), 0.98 (3H, d),
0.97 (3H, d)
[Example 76]
Preparation of methyl 4-(r(2i?.4S.5SV5-((3- [(benzylsulfonyP(methvPamino1benzoyl)amino)-4-hydroxy-2,7- dimethyloctanoyllaminolcyclohexanecarboxylate A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 121 instead of the compound obtained in Preparation Example 12, whereby 65 mg of the title compound was obtained at 92%) yield.
IH NMR (400 MHz, CDC13); 7.65 (IH, s), 7.60 (IH, d), 7.45-7.34 (7H, m), 6.38 (IH, d), 5.77 (IH, d), 4.38 (IH, s), 4.31 (2H, s), 4.13 (IH, m), 3.91-3.26 (2H, m), 3.67 (3H, s), 3.18 (3H, s), 1.96-1.81 (2H, m), 1.77-1.48 (10H, m), 1.27 (IH, m), 1.22 (3H, d), 0.98 (3H, d), 0.96 (3H, d)
ESI MS (m/e) = 630 [M+H]+
[Example 77]
Preparation of 4-{ [(2/?,4S,5S)-5-({3-r(benzylsulfonvP(methvPamino]benzoyl}amino)- 4-hydroxy-2.7-dimethyloctanoyl] amino } cyclohexanecarboxylic acid A process was conducted in the same manner as in Example 60, except for using the compound obtained in Example 76 instead of the compound obtained in
Example 59, whereby 61 mg of the title compound was obtained at 87%) yield.
IH NMR (400 MHz, CD3OD); 7.75 (IH, s), 7.70 (IH, m), 7.48-7.30 (7H, m), 4.47 (2H, s), 4.16 (IH, m), 3.73 (IH, m), 3.57 (IH, m), 3.26 (3H, s), 2.63 (IH, m), 2.46 (IH, m),
2.03-1.78 (3H, m), 1.72-1.33 (10H, m), 1.12 (3H, d), 0.96 (6H, d)
ESI MS (m/e) = 616 [M+H]+
[Preparation Example 122] Preparation of methyl 3-[(tert-butoxycarbonvPamino]cvclohexanecarboxylate A process was conducted in the same manner as in Preparation Example 118, except for using 3-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid instead of trans-4-{ [(tert-butoxycarbonyl)amino]methyl} cyclohexanecarboxylic acid, whereby 0.44 g of the title compound was obtained at 90%) yield. IH NMR (400 MHz, CDC13); 4.40 (IH, br), 3.66 (3H, s), 3.46 (IH, m), 2.40 (IH, m), 2.24 (IH, d), 2.02-1.80 (3H, m), 1.45 (9H, s), 1.41-1.17 (3H, m), 1.04 (IH, m)
[Preparation Example 123] Preparation of methyl 3-r((2i?.4S.5S)-5-((3-
[(benzylsulfonyP(methvPamino]benzoyl}amino)-4-{[tert-butyl(dimethvPsilyl]oxyl- 2,7-dimethyloctanoyPamino]cyclohexanecarboxylate A process was conducted in the same manner as in Preparation Example 114, except for using the compound obtained in Preparation Example 122 instead of the compound obtained in Preparation Example 113, whereby 91 mg of the title compound was obtained at 81% yield.
IH NMR (400 MHz, CDC13); 7.71-7.52 (2H, m), 7.46-7.32 (7H, m), 6.34-6.18 (2H, m), 4.40 (IH, m), 4.31 (2H, s), 3.75 (IH, m), 3.64 (IH, m), 3.64, 3.56 (3H, two set of s), 3.18, 3.17 (3H, two set of s), 2.47-2.17 (2H, m), 1.98-1.76 (2H, m), 1.73-1.46 (7H, m), 1.42-1.00 (4H, m), 1.14 (3H, d), 0.99 (3H, d), 0.97 (3H, d), 0.92 (9H, s), 0.12 (3H, s), 0.10 (3H, s)
[Example 78]
Preparation of methyl 3-i\(2RAS,5S)-5-(\3- [(benzylsulfonyP(methvPamino]benzoyl}amino)-4-hydroxy-2,7- dimethyloctano yl] amino } cyclohexanecarboxylate A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 123 instead of the compound obtained in Preparation Example 12, whereby 74 mg of the title compound was obtained at 96%> yield.
IH NMR (400 MHz, CDC13); 7.65 (IH, s), 7.62 (IH, m), 7.46-7.33 (7H, m), 5.84, 5.79 (IH, two set of d), 4.31 (2H, s), 4.24, 4.10 (IH, two set of d), 4.14 (IH, m), 3.86-3.68 (2H, m), 3.66, 3.63 (3H, two set of s), 3.17 (3H, s), 2.55 (IH, m), 2.41 (IH, m), 2.19, 2.06 (IH, two set of d), 1.97-1.60 (7H, m), 1.47 (IH, m), 1.40-1.02 (7H, m), 0.98 (3H, d), 0.96 (3H, d) ESI MS (m/e) = 630 [M+H]+
[Example 79] Preparation of 3-{[(2i-,4S,5S)-5-({3-[(benzylsulfonvP(methypamino]benzoyl}amino)- 4-hydroxy-2 ,7-dimethyloctano yll amino ) cyclohexanecarboxylic acid A process was conducted in the same manner as in Example 60, except for using the compound obtained in Example 78 instead of the compound obtained in Example 59, whereby 60 mg of the title compound was obtained at 86% yield. IH NMR (400 MHz, CD3OD); 7.75 (IH, s), 7.71 (IH, m), 7.48-7.27 (7H, m), 4.47 (2H, s), 4.17 (IH, m), 3.70-3.52 (2H, m), 3.26 (3H, s), 2.60 (IH, m), 2.32 (IH, m), 2.08 (IH, d), 1.97-1.74 (4H, m), 1.72-1.58 (2H, m), 1.49-1.17 (6H, m), 1.13 (3H, d), 0.97 (6H, d) ESI MS (m/e) = 616 [M+H]+
[Preparation Example 124]
Preparation of methyl 5-[(tert-butoxycarbonvPamino pentanoate A process was conducted in the same manner as in Preparation Example 118, except for using 5-[(tert-butoxycarbonyl)amino]pentanic acid instead of trcms-4-{[(tert- butoxycarbonyl)amino]methyl} cyclohexanecarboxylic acid, whereby 0.5 g of the title compound was obtained at 95% yield.
IH NMR (400 MHz, CDC13); 4.54 (IH, br), 3.67 (3H, s), 3.13 (2H, dd), 2.34 (2H, t),
1.71-1.60 (2H, m), 1.56-1.47 (2H, m), 1.44 (9H, s)
[Preparation Example 125]
Preparation of methyl 5-r((2i?.4S.5S)-5-((3- r(benzylsulfonvP(methvPamino1benzoyllamino -4-{rtert-butyl(dimethvPsilyl]oxy}-
2,7-dimethyloctanovPaminolpentanoate A process was conducted in the same manner as in Preparation Example 114, except for using the compound obtained in Preparation Example 124 instead of the compound obtained in Preparation Example 113, whereby 75 mg of the title compound was obtained at 84%> yield.
IH NMR (400 MHz, CDC13); 7.67 (IH, s), 7.56 (IH, d), 7.45-7.33 (7H, m), 6.35 (IH, t),
6.24 (IH, d), 4.40 (IH, m), 4.31 (2H, s), 3.76 (IH, dd), 3.62 (3H, s), 3.17 (3H, s), 3.24- 3.03 (2H, m), 2.44 (IH, m), 2.20 (2H, t), 1.74-1.33 (9H, m), 1.16 (3H, d), 0.99 (3H, d),
0.97 (3H, d)
[Example 80]
Preparation of methyl 5-ir(2i?.4S.5S>-5-((3- [(benzylsulfonvP(methvPamino]benzoyl}amino -4-hvdroxy-2,7- dimethyloctanoyl] amino } pentanoate A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 125 instead of the compound obtained in Preparation Example 12, whereby 57 mg of the title compound was obtained at 92% yield.
IH NMR (400 MHz, CDC13); 7.67 (IH, s), 7.61 (IH, m), 7.44-7.34 (7H, m), 6.46 (IH, d), 5.91 (IH, t), 4.30 (2H, s), 4.26 (IH, d), 4.13 (IH, m), 3.79 (IH, m), 3.65 (3H, s), 3.29 (IH, m), 3.17 (3H, s), 3.16 (IH, m), 2.60 (IH, m), 2.31 (2H, t), 1.79-1.36 (9H, m), 1.22 (3H, d), 0.98 (3H, d), 0.96 (3H, d) ESI MS (m/e) = 604 [M+H]+
[Example 81]
Preparation of 5-{ [(2i?,4S,5S)-5-((3-r(benzylsulfonvP(methvPamino]benzoyl}amino)- 4-hvdroxy-2,7-dimethyloctanoyl]amino}pentanoic acid A process was conducted in the same manner as in Example 60, except for using the compound obtained in Example 80 instead of the compound obtained in
Example 59, whereby 49 mg of the title compound was obtained at 96%> yield.
IH NMR (400 MHz, CD3OD); 7.75 (IH, s), 7.71 (IH, d), 7.50-7.28 (7H, m), 4.46 (2H, s), 4.17 (IH, m), 3.57 (IH, m), 3.26 (3H, s), 3.22-3.07 (2H, m), 2.62 (IH, m), 2.26 (2H, t), 1.84 (IH, m), 1.73-1.35 (8H, m), 1.13 (2H, d), 0.96 (6H, d)
ESI MS (m/e) = 590 [M+H]+
[Preparation Example 126] Preparation of ethyl 3-{(lS)-l-[(tert-butoxycarbonvPamino1-2-methylpropyl}-4.5- dihydro-5-isoxazolecarboxylate According to the known method (J. Chem. Soc, Perkin Trans. I, 1998, 359- 365), the title compound from t-butoxycarbonyl-(S)-valine could be synthesized. IH NMR (500 MHz, CDCI3); 5.01 (IH, t), 4.39 (IH, br), 4.25 (2H, q), 3.26 (IH, t), 2.08 (IH, m), 1.47 (9H, s), 1.32 (3H, t), 1.01 (3H, t), 0.95 (3H, dd)
[Preparation Example 127]
Preparation of ethyj 3-UlS)-l-\((2RAS.5S)-5-(V3- r(benzylsulfonvP(methvPamino]benzoyllamino)-4-([tert-butyl(dimethvPsilyl]oxyl- 2,7-dimethyloctanoyPamino1-2-methylpropyl}-4,5-dihydro-5-isoxazolecarboxylate A process was conducted in the same manner as in Preparation Example 114, except for using the compound obtained in Preparation Example 126 instead of the compound obtained in Preparation Example 113, whereby 133 mg of the title compound was obtained at 83%) yield.
IH NMR (400 MHz, CDC13); 7.74 (IH, d), 7.52 (IH, m), 7.43-7.32 (7H, m), 6.65 (IH, t), 6.22 (IH, d), 4.95 (IH, m), 4.58 (IH, m), 4.30 (2H, s), 4.21 (2H, q), 3.76 (IH, dd), 3.26 (2H, d), 3.18 (3H, s), 2.60 (IH, m), 1.98-1.48 (5H, m), 1.40 (IH, m), 1.28 (3H, t), 1.15 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.92 (9H, s), 0.75 (3H, t), 0.65 (3H, t), 0.11 (3H, s), 0.10 (3H, s)
[Example 82]
Preparation of ethyj 3-((lSH-(r(2fl,4S,5S)-5-({3-
[(benzylsulfonvP(methvPamino]benzoyl } amino)-4-hydroxy-2,7- dimethyloctanoyl]amino}-2-methylpropyP-4,5-dihvdro-5-isoxazolecarboxylate A process was conducted in the same manner as in Preparation Example 13, except for using the compound obtained in Preparation Example 127 instead of the compound obtained in Preparation Example 12, whereby 5 mg of the title compound was obtained at 4%> yield. IH NMR (400 MHz, CDC13); 7.68 (IH, s), 7.61 (IH, d), 7.48-7.30 (7H, m), 6.38 (IH, d), 6.33 (IH, d), 5.00 (IH, m), 4.68 (IH, m), 4.31 (2H, s), 4.30-4.10 (3H, m), 3.99-3.68 (2H, m), 3.25 (2H, t), 3.18 (3H, s), 2.70 (IH, m), 2.05 (IH, m), 1.84-1.62 (4H, m), 1.46 (IH, m), 1.30 (3H, t), 1.22 (3H, d), 0.98 (3H, d), 0.96 (3H, d), 0.91 (3H, t), 0.83 (3H, d) ESI MS (m/e) = 687 [M+H]+
[Example 83]
Preparation of 3-r(benzylsulfonvP(methvPaminol-N-((lS.2S.4 ?)-5-(r(lS)-l-cvano-2- methylpropyl]aminol-2-hvdroxy-l-isobutyl-4-methyl-5-oxopentyPbenzamide 4 mg of the title compound as a byproduct in the procedure of Example 82 could be obtained at 4% yield.
IH ΝMR (400 MHz, CDC13); 7.64 (IH, s), 7.61 (IH, d), 7.46-7.30 (7H, m), 6.75 (IH, d), 6.30 (IH, d), 4.68 (IH, dd), 4.32 (2H, s), 4.20 (IH, m), 3.74 (IH, m), 3.17 (3H, s), 2.98 (IH, d), 2.70 (IH, m), 1.94 (IH, m), 1.80-1.54 (4H, m), 1.45 (IH, m), 1.21 (3H, d), 1.03-0.93 (9H, m), 0.92 (3H, d) ESI MS (m/e)= 571 [M+H]+
[Preparation Example 128]
Preparation of ethyl (3S.4S)-4-[(tert-butoxycarbonyPamino1-3-hvdroxy-6- methylheptanoate According to the known method (Tetrahedron 57, 2001, 8521-8530), the title compound from t-butoxycarbonyl-(S)-leucineallo could be synthesized. IH ΝMR (400 MHz, CDC13); 4.69 (IH, d), 4.17 (2H, q), 4.01 (IH, m), 3.61 (IH, m), 3.25 (IH, d), 2.55-2.45 (2H, m), 1.67-1.48 (3H, m), 1.44 (9H, s), 1.27 (3H, t), 0.93 (6H, d)
[Preparation Example 129]
Preparation of ethyl (3S.4S)-4-({3-[(benzylsulfonvP(methvPamino]benzoyl}amino)-3- hydroxy-6-methylheptanoate A process was conducted in the same manner as in Example 21, except for using the compound obtained in Preparation Example 128 instead of the compound obtained in Preparation Example 77, whereby 3.09 g of the title compound was obtained at 73% yield. IH NMR (400 MHz, CDC13); 7.64-7.59 (2H, m), 7.43-7.36 (7H, m), 6.38 (IH, d), 4.31
(2H, s), 4.24 (IH, m), 4.20-4.09 (3H, m), 3.17 (3H, s), 2.56-2.52 (2H, m), 1.76-1.66 (2H, m), 1.49 (IH, m), 1.25 (3H, t), 0.98 (3H, d), 0.96 (3H, d)
[Preparation Example 130] Preparation of (3SAS)-4-( { 3 - [(benzylsulfonyP(methyPamino]benzoyl } amino)-3 - hydroxy-6-methylheptanoic acid A process was conducted in the same manner as in Example 60, except for using the compound obtained in Preparation Example 129 instead of the compound obtained in Example 59, whereby 1.27 g of the title compound was obtained at 95%) yield.
IH NMR (500 MHz, DMSO-d6); 7.94 (IH, d), 7.75-7.74 (2H, m), 7.43-7.35 (7H, m), 4.99 (IH, brs), 4.57 (2H, s), 4.11 (IH, m), 3.95 (IH, m), 3.28 (3H, s), 2.41 (IH, dd), 2.18 (IH, dd), 1.60-1.55 (2H, m), 1.35 (IH, m), 0.90 (3H, d), 0.86 (3H, d) [Example 84]
Preparation of methyl (2SV2-(r(3S.4SV4-({3-
[(benzylsulfonvP(methvPaminolbenzoyl}amino)-3-hydroxy-6- methylheptanoyl]amino}-3-methylbutanoate A process was conducted in the same manner as in Preparation Example 106, except for using the compound obtained in Preparation Example 130 instead of the compound obtained in Preparation Example 58, whereby 207 mg of the title compound was obtained at 73% yield.
IH NMR (400 MHz, CDC13); 7.66 (IH, t), 7.62 (IH, m), 7.42-7.36 (7H, m), 6.42 (IH, d), 6.38 (IH, d), 4.50 (IH, m), 4.33 (IH, d), 4.31 (2H, s), 4.22 (IH, m), 4.12 (IH, m),
3.75(3H, s), 3.17 (3H, s), 2.46 (2H, d), 2.14 (IH, m), 1.76-1.67 (2H, m), 1.49 (IH, m),
0.99-0.86 (12H, m)
ESI MS (m/e) = 576 [M+H]+
[Example 85]
Preparation of (2S)-2-{ [(3S.4S)-4-({3-[(benzylsulfonvP(methvPamino1benzoyl}amino - 3 -hydroxy-6-methylheptanoyl] amino } -3 -methylbutanoic acid A process was conducted in the same manner as in Example 60, except for using the compound obtained in Example 84 instead of the compound obtained in Example 59, whereby 0.15 g of the title compound was obtained at 77% yield.
IH NMR (400 MHz, DMSO-d6) 12.5 (IH, s), 8.00 (IH, d), 7.96 (IH, d), 7.77-7.74 (2H, m), 7.43-7.33 (7H, m), 4.91 (IH, brs), 4.55 (2H, s), 4.15-4.1 1 (2H, m), 3.90 (IH, m).
3.23 (3H, s), 2.31-2.25 (2H, m), 2.00 (IH, m), 1.61-1.58 (2H, m), 1.32 (IH, m), 0.89- 0.81 (12H, m) ESI MS (m/e) = 561 [M+H]+
[Example 86]
Preparation of N-[(lS,2S -4-({(lS)-l -[(benzylamino carbony 11 -2-methy Ipropyl larnino)- 2-hydroxy-l-isobutyl-4-oxobutyll-3-r(benzylsulfonvP(methvPamino]benzamide A process was conducted in the same manner as in Preparation Example 11 , except for using compound obtained in Example 85 instead of t-butoxycarbonyl-(S)- alanine, whereby 87 mg of the title compound was obtained at 65% yield.
IH ΝMR (500 MHz, CDC13); 7.65 (IH, t), 7.62 (IH, m), 7.42-7.36 (7H, m), 7.34-7.25 (5H, m), 6.52-6.47 (3H, m), 4.45-4.38 (3H,m), 4.31 (2H, s), 4.23-4.10 (3H, m), 3.16
(3H, s), 2.47-2.45 (2H, m), 2.11 (IH, m), 1.76-1.64 (2H, m), 1.49 (IH, m), 0.97-0.88
(12H, m)
ESI MS (m/e) = 651 [M+H]+
[Preparation Example 131]
Preparation of benzyl 4-(r((2SV2-(r(3S.4S)-4-((3-
[(benzylsulfonyP(methvPamino]benzoyl} amino)-3 -hydroxy-6- methylheptano y 1] amino } -3 -methylbutanovPamino] methyl } benzoate 99 mg (0.225 mmol) of the compound obtained in Preparation Example 92 was dissolved in 3 ml of 4.0 Ν hydrochloride solution diluted with ethyl acetate, and stirred for 2 hours. After distillation under reduced pressure for concentration, the residue was dissolved in 5 ml of Ν,Ν-dimethylformamide and cooled to 0°C, then 69 mg (0.15 mmol) of the compound obtained in Preparation Example 130 and 86 mg (0.225 mmol) of HATU were added thereto. 0.5 ml (excess amount) of N,N-diisopropylethylamine was further added thereto and heated to room temperature, followed by stirring overnight. After removing solvent by distillation under reduced pressure, the residue is dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 85 mg of the title compound at 72% yield.
IH NMR (400 MHz, CDC13); 8.01 (2H, d), 7.64-7.56 (2H, m), 7.47-7.56 (14H, m), 6.75 (IH, t), 6.44 (IH, d), 6.40 (IH, d), 5.35 (2H, s), 4.48 (2H, d), 4.30 (2H, s), 4.22 (IH, dd), 4.12 (IH, m), 4.08 (IH, d), 3.15 (3H, s), 2.54-2.38 (2H, s), 2.14 (IH, m), 1.80-1.58 (2H, m), 1.47 (IH, m), 0.98-0.80 (12H, m)
[Example 87]
Preparation of 4-(f((2S -2-(r(3S.4S)-4-((3- [(benzylsulfonvD(methvPamino1benzoyllaminoV3-hvdroxy-6- methylheptano yl] amino } -3 -methylbutanovPamino] methyl } benzoic acid 85 mg (0.108 mmol) of the compound obtained in Preparation Example 131 was dissolved in 3 ml of tetrahydrofurane and 0.5 ml of methanol, then 2 ml of lithium hydroxide was added thereto, followed by stirring for 2 hours. After removing solvent by distillation under reduced pressure, the residue was diluted with water, and the solid produced by acidification with 1.0 N hydrochloride solution was filtered, then the product was purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 72 mg of the title compound at 96%) yield. IH NMR (400 MHz, CD3OD); 7.96 (2H, d), 7.76 (IH, s), 7.70 (IH, m), 7.47-7.29 (9H, m), 4.58-4.38 (2H, m), 4.44 (2H, s), 4.30-4.09 (3H, m), 3.23 (3H, s), 2.60-2.40 (2H, m), 2.20 (IH, m), 1.78-1.54 (2H, m), 1.42 (IH, m), 1.01-0.81 (12H, m) ESI MS (m/e) = 695 [M+H]+
[Preparation Example 132]
Preparation of tert-butyl ( 1 S)- 1 - [(2S)oxiranyl] -2-phenylethyl carbamate According to the known method (Tetrahedron Letters 36(31), 1999, 5453- 5456), the title compound from t-butoxycarbonyl-(S)-phenylalanine could be synthesized. IH NMR (400 MHz, CDC13); 7.36-7.18 (5H, m), 4.43 (IH, br), 3.69 (IH, br), 3.02-2.82 (3H, m), 2.80 (IH, t), 2.76 (IH, m), 1.38 (9H, s)
[Preparation Example 133]
Preparation of benzyl (2/?,3S)-3-[(tert-butoxycarbonyDamino]-2-hydroxy-4- phenylbutyl(3-methoxybenzvPcarbamate 0.74 g (2.81 mmol) of the compound obtained in Preparation Example 132 and 1.93 g (14.05 mmol) of 3-methoxybenzylamine were dissolved in 60 ml of isopropanol, followed by reflux overnight. After cooling to room temperature and removing the solvent by distillation under reduced pressure, the residue was dissolved in 15 ml of dichloromethane and 14 ml of 1.0 N NaOH solution. 4.79 g(28.1 mmol) of benzylchloromate was added thereto and stirred for 1 hour, then the mixture was diluted with dichloromethane, followed by washing with water and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 1 :3 mixture of ethyl acetate and hexane to obtain 1.34 g of the title compound at 89% yield..
IH NMR (400 MHz, CDC13); 7.42-7.02 (12H, m), 6.88-6.58 (3H, m), 5.20 (2H, s), 4.52 (2H, s), 4.30 (IH, s), 3.82 (2H, br), 3.70 (3H, s), 3.52-3.13 (2H, m), 3.00-2.60 (2H, m), 1.33 (9H, s)
[Preparation Example 134]
Preparation of. benzyl (2i?,3S)-2-hydroxy-3-({3-
[methyl(propylsulfonyPamino]benzoyl } amino)-4-phenylbutyl(3 - rnethoxybenzvDcarbamate 500 mg (0.935 mmol) of the compound obtained in Preparation Example 133 was dissolved in 10 ml of dichloromethane and 5 ml of trifluoroacetic acid, and stirred for 1 hour. After distillation under reduced pressure for concentration, the residue was dissolved in 10 ml of N,N-dimethylformamide and cooled to 0°C, then 289 mg (1.122 mmol) of the compound obtained in Preparation Example 29 and 730 mg (1.403 mmol) of PyBob were added thereto. 0.98 ml (5.61 mmol) of N,N-diisopropylethylamine was further added thereto and heated to room temperature, followed by stirring for 1.5 hours. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 1 :1 mixture of ethyl acetate and hexane to obtain 508 mg of the title compound at 81%> yield. IH NMR (400 MHz, DMSO,d6); 8.33 (IH, dd), 7.73 (IH, s), 7.63-7.38 ( 3H, m), 7.36- 7.12 (10H, m), 7.10 (IH, t), 6.84-6.65 (3H, m), 5.31 (IH, dd), 5.20-4.97 (2H, m), 4.69 (IH, dd), 4.46 (IH, d), 4.06 (IH, m), 3.86 (IH, m), 3.66 (3H, s), 3.24 (3H, d), 3.20-2.97 (5H, m), 2.76 (IH, m), 1.72-7.55 (2H, m), 1.00-0.93 (3H, m)
[Example 88]
Preparation of N-{(lS,2i?)-l -benzyl-2-hvdroxy-3-[(3-methoxybenzvDamino]propyl}-3- [methvKpropylsulfonvDaminoJbenzamide 505 mg (0.749 mmol) of the compound obtained in Preparation Example 134 was dissolved in 10 ml of methanol, then active carbon-supported palladium (10%>) was added thereto and stirred for 1 hour in a hydrogen atmosphere. After removing solid by filtration under reduced pressure using Cellite and then solvent by distillation under reduced pressure, the product was purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 355 mg of the title compound at
88% yield.
IH ΝMR (400 MHz, CDC13); 7.69 (IH, s), 7.55 (IH, d), 7.43 (IH, d), 7.35 (IH, d),
7.33-7.18 (6H, m), 7.13 (IH, d), 6.93-6.87 (2H, m), 6.81 (IH, dd), 4.42 (IH, m), 3.88- 3.73 (5H, m), 3.71 (IH, m), 3.33 (3H, s), 3.10-2.78 (6H, m), 1.90-1.77 (2H, m), 1.02
(3H, t)
ESI MS (m/e)= 540 [M+H]+
[Example 89] Preparation of N-((lS)-l-r(5i?)-3-(3-methoxybenzyl)-l,3-oxazolidin-5-yll-2- phenylethyl } -3 - [methvKpropylsulfonvDaminolbenzamide 164 mg (0.304 mmol) of the compound obtained in Example 88 was dissolved in 5 ml of tetrahydrofurane, then 104 mg (1.216 mmol) of 35% formaline was added thereto, followed by stirring overnight. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 2:1 mixture of ethyl acetate and hexane to obtain 150 mg of the title compound at 89% yield.
IH NMR (400 MHz, CDC13); 7.75 (IH, s), 7.56 (IH, d), 7.46 (IH, d), 7.41 (IH, d), 7.34-7.18 (6H, m), 6.92 (IH, d), 6.91 (IH, s),6.83 (IH, d), 6.78 (IH, d), 4.56 (IH, d), 4.43 (IH, m), 4.20 (IH, d), 4.14 (IH, m), 3.88-3.58 (5H, m), 3.35 (3H, s), 3.20 (IH, dd), 3.07 (IH, dd), 2.98-2.82 (4H, m), 1.90-1.78 (2H, m), 1.02 (3H, t) ESI MS (m/e) = 552 [M+H]+
[Preparation Example 135]
Preparation of benzyl (2i?.3S)-3-r(tert-butoxycarbonyDamino]-2-hydroxy-4- phenylbutyl(3-methylbenzvDcarbamate A process was conducted in the same manner as in Preparation Example 133, except for using 3-methylbenzylamine instead of 3-methoxybenzylamine, whereby 86 mg of the title compound was obtained at 83% yield.
IH NMR (400 MHz, CDC13); 7.43-6.87 (15H, m), 5.21 (2H, s), 4.65-4.43 (3H, m), 4.30 (IH, m), 3.88-3.62 (2H, m), 3.55-3.37 (2H, m), 3.02-2.70 (2H, m), 2.28 (3H, s), 1.33 (9H, s)
[Preparation Example 136]
Preparation of benzyl (2i?,3Sl-2-hvdroxy-3-((3-
[methyl(propylsulfonyl)amino]benzoyl}amino)-4-phenylbutyl(3- methylbenzvDcarbamate A process was conducted in the same manner as in Preparation Example 134, except for using the compound obtained in Preparation Example 135 instead of the compound obtained in Preparation Example 133, whereby 98 mg of the title compound was obtained at 90% yield.
IH NMR (400 MHz, CDC13); 7.64 (IH, s), 7.55 (IH, d), 7.48-6.88 (16H, m), 6.60 (IH, d), 5.20 (2H, dd), 4.53 (2H, dd), 4.38 (IH, br), 4.25 (IH, br), 3.94 (IH, br), 3.35 (2H, d), 3.33 (3H, s), 3.03-2.86 (4H, m), 2.25 (3H, s), 1.90-1.77 (2H, m), 1.01 (3H, t)
[Example 90]
Preparation of N-{(lS.2i?)-l-benzyl-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-3- [methyl(propylsulfonyl amino]benzamide A process was conducted in the same manner as in Example 88, except for using the compound obtained in Preparation Example 136 instead of the compound obtained in Preparation Example 134, whereby 63 mg of the title compound was obtained at 82%> yield. IH ΝMR (400 MHz, CDCI3); 7.69 (IH, t), 7.53 (IH, m), 7.42 (IH, d), 7.37-7.18 (7H, m), 7.16-7.06 (4H, m), 4.42 (IH, m), 3.80 (2H, dd), 3.72 (IH, m), 3.33 (3H, s), 3.10-
2.78 (6H, m), 2.33 (3H, s), 1.90-1.77 (2H, m), 1.02 (3H, t)
ESI MS (m/e) = 524 [M+H]+
[Example 91]
Preparation of N- { ( 1 S)- 1 -\(5R)-3-(3 -methylbenzvP- 1.3 -oxazolidin-5-vIl -2- phenylethyl } -3 - [methvKpropylsulfonvPamino] benzamide A process was conducted in the same manner as in Example 89, except for using the compound obtained in Example 90 instead of the compound obtained in Example 88, whereby 19 mg of the title compound was obtained at 19% yield. IH NMR (400 MHz, CDC13); 7.75 (IH, s), 7.57 (IH, d), 7.48-7.18 (7H, m), 7.17-7.06 (4H, m), 6.78 (IH, d), 4.54 (IH, d), 4.42 (IH, m), 4.20 (IH, d), 4.14 (IH, m), 3.70 (2H, dd), 3.35 (3H, s), 3.20 (IH, dd), 3.06 (IH, dd), 2.98-2.81 (4H, m), 2.33 (3H, s), 1.90- 1.77 (2H, m), 1.02 (3H, t) ESI MS (m/e) = 536 [M+H]+
[Preparation Example 137]
Preparation of benzyl (2i?,3S)-3-[(tert-butoxycarbonvPamino]-2-hydroxy-4- phenylbutyl(2-pyridinylmethvPcarbamate A process was conducted in the same manner as in Preparation Example 133, except for using 2-(aminomethyl)-pyridine instead of 3-methoxybenzylamine, whereby
40 mg of the title compound was obtained at 40% yield.
IH NMR (400 MHz, CDC13); 8.51 (IH, m), 7.72, 7.57 (IH, two set of t), 7.40-6.93 (13H, m), 5.06 (IH, m), 4.96 (IH, s), 4.77-4.32 (3H, m), 3.96-3.78 (2H, m), 3.33 (IH, m), 3.05 (IH, m), 2.90 (IH, m), 1.32 (9H, s)
[Preparation Example 138]
Preparation of. benzyl (2i?.3S)-2-hvdroxy-3-((3- [methyl(propylsulfonyPamino]benzoyl}amino)-4-phenylbutyl(2- pyridinylmethvDcarbamate A process was conducted in the same manner as in Preparation Example 134, except for using the compound obtained in Preparation Example 137 instead of the compound obtained in Preparation Example 133, whereby 26 mg of the title compound was obtained at 51% yield.
IH NMR (400 MHz, CDC13); 8.50 (IH, dd), 7.77-6.92 (17H, m), 6.60, 6.26 (IH, two set of d), 5.01 (IH, d), 4.94 (IH, s), 4.71-4.32 (3H, m), 4.04 (IH, m), 3.86 (IH, m), 3.41 (IH, m), 3.32 (3H, d), 3.23-3.07 (2H, m), 2.97-2.88 (2H, m), 1.89-1.77 (2H, m), 1.01 (3H, t)
[Example 92]
Preparation of N- { ( 1 S.2R)- 1 -benzyl-2-hydroxy-3 - [(2-pyridinylmethvPamino] propyl } -3 -
[methvKpropylsulfonvPaminolbenzamide A process was conducted in the same manner as in Example 88, except for using the compound obtained in Preparation Example 138 instead of the compound obtained in Preparation Example 134, whereby 11 mg of the title compound was obtained at 55% yield.
IH ΝMR (400 MHz, CDC13); 8.54 (IH, d), 7.70 (IH, t), 7.66 (IH, dd), 7.53 (IH, m), 7.47 (IH, d), 7.36-7.13 (9H, m), 4.47 (IH, m), 4.02 (2H, s), 3.80 (IH, m), 3.32 (3H, s),
3.15-2.88 (6H, m), 1.89-1.76 (2H, m), 1.02 (3H, t)
ESI MS (m/e) = 511 [M+H]+
[Preparation Example 139] Preparation of benzyl (2i?,3S)-3-[(tgrt-butoχycarbonvDamino]-2-hydroxy-4- phenylbutyl(3-ethylbenzyPcarbamate A process was conducted in the same manner as in Preparation Example 133, except for using 3-ethylbenzylamine instead of 3-methoxybenzylamine, whereby 154 mg of the title compound was obtained at 74% yield. IH NMR (400 MHz, CDC13); 7.38-7.18 (1 IH, m), 7.09-7.07 (2H, m), 6.96 (IH, s), 5.21 (2H, s), 4.52-4.31 (3H, m), 3.85-3.70 (2H, m), 3.45-3.34 (2H, m), 2.94-2.79 (2H, m), 2.57 (2H, q), 1.33 (9H, s), 1.18 (3H, t)
[Preparation Example 140]
Preparation of benzyl 3-ethylbenzyl[(2i?,3S)-2-hydroxy-3-({3-
[methyl(propylsulfonvPaminolbenzovUamino)-4-phenylbutyl]carbamate A process was conducted in the same manner as in Preparation Example 134, except for using the compound obtained in Preparation Example 139 instead of the compound obtained in Preparation Example 133, whereby 71 mg of the title compound was obtained at 35% yield.
IH NMR (400 MHz, CDC13); 7.96-6.87 (18H, m), 6.62 (IH, d), 5.10 (2H, dd), 4.45 (2H, dd), 4.31 (IH, m), 3.88 (IH, m), 3.40-3.33 (2H, m), 3.27 (3H, s), 2.90-2.78 (4H, m),
2.45 (2H, q), 1.79-1.68 (2H, m), 1.06 (3H, t), 0.91 (3H, t)
[Example 93]
Preparation of N- { ( 1 S.2R)- 1 -benzyl-3 - [(3 -ethylbenzyPamino]-2-hydroxypropyl } -3 - methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 88, except for using the compound obtained in Preparation Example 140 instead of the compound obtained in Preparation Example 134, whereby 56 mg of the title compound was obtained at 94% yield.
IH ΝMR (400 MHz, CDC13); 7.70 (IH, t), 7.53-6.97 (13H, m), 4.41 (IH, m), 3.83-3.68
(2H, m), 3.32 (3H, s), 3.05-3.00 (2H, m), 2.97-2.81 (5H, m), 2.62 (2H, q), 1.81 (2H, m), 1.21 (3H, t), 1.01 (3H, t) ESI MS (m/e) = 538 [M+H]+
[Example 94] Preparation of N-((lS)-l-l(5i?V3-(3-ethylbenzyP-l,3-oxazolidin-5-yll-2-phenylethyl>-
3 - [methyKpropylsulfonvPamino] benzamide A process was conducted in the same manner as in Example 89, except for using the compound obtained in Example 93 instead of the compound obtained in
Example 88, whereby 30 mg of the title compound was obtained at 60% yield. IH ΝMR (400 MHz, CDC13); 7.76 (IH, t), 7.58-7.55 (IH, m), 7.49-7.47 (IH, m), 7.43-
7.08 (10H, m), 6.83 (IH, d), 4.55 (IH, d), 4.44 (IH, m), 4.21 (IH, d), 4.15 (IH, m), 3.73
(2H, dd), 3.35 (3H, s), 3.19 (IH, m), 3.07 (IH, m), 2.97-2.86 (4H, m), 2.63 (2H, q),
1.87-1.81 (2H, m), 1.22 (3H, t), 1.03 (3H, t)
ESI MS (m/e) = 550 [M+H]+
[Preparation Example 141]
Preparation of benzyl benzyl{(2i?,3S -3-[(tert-butoxycarbonyPamino]-2-hydroxy-4- phenylbutyl } carbamate A process was conducted in the same manner as in Preparation Example 133, except for using benzylamine instead of 3-methoxybenzylamine, whereby 74 mg of the title compound was obtained at 73% yield.
1H ΝMR (400 MHz, CDC13); 7.43-7.00 (15H, m), 5.21 (2H, s), 4.72-4.40 (3H, m), 4.30
(IH, m), 3.87-3.62 (2H, m), 3.53-3.28 (2H, m), 3.01-2.70 (2H, m), 1.33 (9H, s) [Preparation Example 142]
Preparation of. benzyl benzyl [(2 J?,3S)-2-hydroxy-3-( { 3 - rmethyl(propylsulfonvPamino]benzoyllamino)-4-phenylbutyl]carbamate A process was conducted in the same manner as in Preparation Example 134, except for using the compound obtained in Preparation Example 141 instead of the compound obtained in Preparation Example 133, whereby 86 mg of the title compound was obtained at 91% yield.
IH NMR (400 MHz, CDC13); 7.64 (IH, s), 7.56 (IH, d), 7.51-7.04 (17H, m), 6.53 (IH, s), 5.20 (2H, dd), 4.57 (2H, dd), 4.38 (IH, m), 3.93 (IH, m), 3.46 (2H, d), 3.33 (3H, s), 3.07-2.83 (4H, m), 1.92-1.75 (2H, m), 1.01 (3H, t)
[Example 95]
Preparation of. N-[( 1 S2R)- 1 -benzyl-3 -(benzylamino)-2-hydroxypropyl] -3 -
Fmethyl(propylsulfonvDamino]benzamide A process was conducted in the same manner as in Example 88, except for using the compound obtained in Preparation Example 142 instead of the compound obtained in Preparation Example 134, whereby 41 mg of the title compound was obtained at 60% yield.
IH ΝMR (400 MHz, CDC13); 7.68 (IH, t), 7.53 (IH, m), 7.42 (dt), 7.37-7.18 (11H, m), 7.01 (IH, d), 4.42 (IH, m), 3.87 (2H, dd), 3.74 (IH, m), 3.33 (3H, s), 3.13-2.80 (6H, m),
1.91-1.78 (2H, m), 1.02 (3H, t)
ESI MS (m/e) = 510 [M+H]+
[Example 96] Preparation of N-((lS)-l-r(5i?)-3-benzyl-l .3-oxazolidin-5-yll-2-phenylethyl)-3- rmethyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 89, except for using the compound obtained in Example 95 instead of the compound obtained in Example 88, whereby 26 mg of the title compound was obtained at 70% yield.
IH ΝMR (400 MHz, CDC13); 7.75 (IH, t), 7.56 (IH, m), 7.46 (IH, dt), 7.39 (IH, t),
7.37-7.18 (10H, m), 6.78(1H, d), 4.55 (IH, d), 4.43 (IH, m), 4.19 (IH, d), 4.15 (IH, m),
3.73 (2H, dd), 3.35 (3H, s), 3.19 (IH, dd), 3.07 (IH, dd), 3.00-2.82 (4H, m), 1.91-1.78
(2H, m), 1.02 (3H, t) ESI MS (m/e) = 522 [M+H]+
[Preparation Example 143]
Preparation of benzyl (2i?,3S)-3-[(tgrt-butoxycarbonvPamino]-2-hydroxy-4- phenylbutyl r(l R)- 1 -phenylpropyl] carbamate A process was conducted in the same manner as in Preparation Example 133, except for using (i?)-l-phenylpropylamine instead of 3-methoxybenzylamine, whereby
87 mg of the title compound was obtained at 81% yield.
IH ΝMR (400 MHz, CDC13); 7.46-6.98 (15H, m), 5.25 (2H, s), 5.16 (IH, m), 4.95 (IH, br), 4.71 (IH, d), 3.70-3.28 (2H, m), 3.04 (IH, d), 2.83-2.53 (2H, m), 2.00-1.80 (3H, m), 1.62 (IH, t), 1.40 (9H, s), 0.90 (3H, t)
[Preparation Example 144]
Preparation of. benzyl (2.K.3S)-2-hvdroxy-3-((3-
[methyKpropylsulfonyPamino] benzoyl } amino)-4-phenylbutyl [( 1 R )- 1 - phenylpropyl] carbamate A process was conducted in the same manner as in Preparation Example 134, except for using the compound obtained in Preparation Example 143 instead of the compound obtained in Preparation Example 133, whereby 65 mg of the title compound was obtained at 61%) yield.
IH NMR (400 MHz, CDC13); 7.61 (IH, s), 7.57 (IH, d), 7.45-6.90 (17H, m), 5.66 (IH, d), 5.25 (2H, s), 5.13 (IH, m), 4.10 (IH, m), 3.40 (IH, m), 3.35 (3H, s), 3.08-2.80 (6H, m), 1.95-1.75 (4H, m), 1.03 (3H, t), 0.88 (3H, t)
[Example 97]
Preparation of N-(dS,2J?)-l-benzyl-2-hvdroxy-3-(r(li?Vl- pheny Ipropyl] amino } propyD-3 - [methvKpropylsulfonyPamino] benzamide A process was conducted in the same manner as in Example 88, except for using the compound obtained in Preparation Example 144 instead of the compound obtained in Preparation Example 134, whereby 48 mg of the title compound was obtained at 92% yield.
IH ΝMR (400 MHz, CDC13); 7.70 (IH, t), 7.55 (IH, m), 7.48 (IH, d), 7.39 (IH, t), 7.35-7.13 (10H, m), 7.09 (IH, d), 4.39 (IH, m), 3.63 (IH, dd), 3.47 (IH, t), 3.35(3H, s), 3.01-2.89 (3H, m), 2.82 (IH, dd), 2.72-2.55 (2H, m), 1.92-1.77 (3H, m), 1.72 (IH, m), 1.03 (3H, t), 0.85 (3H, t)
ESI MS (m/e) = 538 [M+H]+
[Example 98]
Preparation of 3 - rmethvKpropylsulfonvPaminol -N-(( 1 Sl-2-phenyl- 1 - { (5R)-3 - \( 1 R)- 1 - phenylpropyl]-!, 3-oxazolidin-5-vUethvPbenzamide A process was conducted in the same manner as in Example 89, except for using the compound obtained in Example 97 instead of the compound obtained in Example 88, whereby 34 mg of the title compound was obtained at 76% yield. IH NMR (400 MHz, CDC13); 7.80 (IH, t), 7.62-7.14 (13H, m), 7.06 (IH, d), 4.68 (IH, d), 4.38 (IH, m), 4.11 (IH, m), 4.09 (IH, d), 3.36 (3H, s), 3.22-3.11 (2H, m), 3.01-2.68 (5H, m), 1.92-1.68 (4H, m), 1.03 (3H, t), 0.69 (3H, t) ESI MS (m/e) = 550 [M+H]+
[Preparation Example 145]
Preparation of benzyl (2i?,3S)-3-[(tert-butoxycarbonyPamino1-2-hydroxy-4- phenylbutyl [( 1 S)- 1 -phenylpropyl] carbamate A process was conducted in the same manner as in Preparation Example 133, except for using (S)-l-phenylpropylamine instead of 3-methoxybenzylamine, whereby 73 mg of the title compound was obtained at 68% yield.
IH NMR (400 MHz, CDC13); 7.49-7.01 (15H, m), 5.23 (2H, s), 5.14 (IH, m), 4.71 (IH, s), 4.64 (IH, m), 3.78-3.47 (2H, m), 3.33-2.70 (3H, m), 2.04-1.73 (3H, m), 1.63 (IH, m), 1.32 (9H, s), 0.94 (3H, t)
[Preparation Example 146]
Preparation of benzyl (2i?.3SV2-hydroxy-3-((3-
[methyl(propylsulfonvPamino]benzoyl I amino)-4-phenylbutyl [( 1 S)- 1 - phenylpropyl] carbamate A process was conducted in the same manner as in Preparation Example 134, except for using the compound obtained in Preparation Example 145 instead of the compound obtained in Preparation Example 133, whereby 58 mg of the title compound was obtained at 63% yield.
IH NMR (400 MHz, CDC13); 7.64 (IH, s), 7.55 (IH, d), 7.50-7.10 (17H, m), 6.64 (IH, m), 5.24 (IH, s), 5.19 (IH, m), 4.27 (IH, m), 3.70 (IH, m), 3.33 (3H, s), 3.28-3.10 (2H, m), 2.98-2.81 (4H, m), 1.96 (IH, m), 1.91-1.76 (3H, m), 1.02 (3H, t), 0.93 (3H, t)
[Example 99]
Preparation of N-((l S.2R)- 1 -benzyl -2-hydroxy-3 - { [( 1 S)- 1 -phenylpropyll amino } propyP- 3-[methyl(propylsulfonyl)amino]benzamide A process was conducted in the same manner as in Example 88, except for using the compound obtained in Preparation Example 146 instead of the compound obtained in Preparation Example 134, whereby 44 mg of the title compound was obtained at 96% yield. IH ΝMR (400 MHz, CDC13); 7.66 (IH, t), 7.54 (IH, m), 7.44 (IH, dt), 7.39 (IH, t),
7.35-7.17 (10H, m), 6.70(1H, d), 4.39 (IH, m), 3.54 (IH, m), 3.49 (IH, t), 3.34 (3H, s),
3.10-2.90 (4H, m), 2.72-2.59 (2H, m), 1.92-1.78 (3H, m), 1.74 (IH, m), 1.03 (3H, t),
0.84 (3H, t)
ESI MS (m/e) = 538 [M+H]+
[Example 100]
Preparation of 3 - fmethvKpropy lsulfony Paminol -N-(( 1 S)-2-phenyl- 1 - { (5R V 3 - f( 1 SI- 1 - phenylpropyl]-!, 3-oxazolidin-5-yl}ethyl)benzamide A process was conducted in the same manner as in Example 89, except for using the compound obtained in Example 99 instead of the compound obtained in Example 88, whereby 15 mg of the title compound was obtained at 37%> yield. IH NMR (400 MHz, CDC13); 7.80 (IH, t), 7.61 (IH, m), 7.55 (IH, dt), 7.44 (IH, t), 7.36-7.17 (10H, m), 7.10 (IH, d), 4.40 (IH, m), 4.24 (IH, d), 4.20 (IH, m), 3.93 (IH, d), 3.36 (3H, s), 3.27 (IH, dd), 3.19 (IH, dd), 3.13 (IH, dd), 2.99-2.91 (2H, m), 2.87 (IH, m), 2.73 (IH, m), 2.00-1.70 (4H, m), 1.02 (3H, t), 0.71 (3H, t) ESI MS (m/e) = 550 [M+H]+
[Preparation Example 147] Preparation of benzyl (2i?.3S)-3-[(tgrt-butoxycarbonypamino]-2-hydroxy-4- phenylbutyl \(lR)-l-(3 -methoxyphenvPethyl] carbamate A process was conducted in the same manner as in Preparation Example 133, except for using (i-)-l-(3-methoxyphenyl)ethylamine instead of 3-methoxybenzylamine, whereby 81 mg of the title compound was obtained at 14% yield. IH NMR (400 MHz, CD3OD); 7.41-7.08 (11H, m), 6.90-6.73 (3H, m), 5.32 (IH, m),
5.15 (2H, s), 3.70 (3H, s), 3.78-3.56 (2H, m), 3.38 (IH, m), 3.12-2.83 (2H, br), 2.53 (IH, t), 1.60 (3H, d), 1.27 (9H, s)
[Preparation Example 148] Preparation of. benzyl (2i-,3S)-2-hvdroxy-3-((3- rmethvKpropylsulfonyDaminolbenzoyl } amino)-4-phenylbutyl f( 1 R)- 1 -(3 - methoxyphenvDethyllcarbamate A process was conducted in the same manner as in Preparation Example 134, except for using the compound obtained in Preparation Example 147 instead of the compound obtained in Preparation Example 133, whereby 83 mg of the title compound was obtained at 83% yield.
IH NMR (400 MHz, CDC13); 7.68 (IH, s), 7.57 (IH, d), 7.45-7.10 (12H, m), 6.97 (IH, br), 6.78-6.59 (3H, m), 6.02 (IH, br), 5.35 (IH, m), 5.23 (IH, d), 4.73 (IH, br), 4.13 (IH, m), 3.64 (3H, s), 3.35 (3H, s), 3.42-3.24 (2H, m), 3.15 (IH, d), 3.02-2.83 (4H, m), 1.92-1.78 (2H, m), 1.45 (3H, d), 1.03 (3H, t)
[Example 101]
Preparation of N-((lS.2i?Vl-benzyl-2-hvdroxy-3-(rdi?Vl-(3- methoxyphenvDethyl] amino } propyD-3 - methvKpropylsulfonyDaminolbenzamide A process was conducted in the same manner as in Example 88, except for using the compound obtained in Preparation Example 148 instead of the compound obtained in Preparation Example 134, whereby 60 mg of the title compound was obtained at 90% yield. IH ΝMR (400 MHz, CDC13); 7.70 (IH, t), 7.55 (IH, m), 7.49 (IH, dt), 7.39 (IH, t),
7.31-7.13 (7H, m), 6.90 (IH, d), 6.88 (IH, t), 6.79 (IH, m), 4.42 (IH, m), 3.77(3H, s),
3.73 (IH, m), 3.65 (IH, dd), 3.35 (3H, s), 3.02-2.89 (3H, m), 2.85 (IH, dd), 2.72 (IH, dd), 2.64 (IH, dd), 1.92-1.78 (2H, m), 1.44 (3H, d), 1.03 (3H, t)
ESI MS (m/e) = 554 [M+H]+
[Example 102]
Preparation of N-(( 1 S - 1 - { (5R)-3 -\(1R)-1 -(3-methoxyphenvPethyll - 1 ,3-oxazolidin-5- yll-2-phenylethvD-3-[methyl(propylsulfonyDamino]benzamide A process was conducted in the same manner as in Example 89, except for using the compound obtained in Example 101 instead of the compound obtained in Example 88, whereby 28 mg of the title compound was obtained at 74%> yield. IH NMR (400 MHz, CDC13); 7.80 (IH, t), 7.62-7.56 (2H, m), 7.45 (IH, t), 7.30-7.16 (6H, m), 7.12 (IH, d), 6.91 (IH, d), 6.89 (IH, s), 6.82 (IH, dd), 4.68 (IH, d), 4.38 (IH, m), 4.14 (IH, m), 4.12 (IH, d), 3.75 (3H, s), 3.42-3.31 (4H, m), 3.20 (IH, dd), 3.01-2.92 (2H, m), 2.86 (IH, dd), 2.74 (IH, dd), 2.65 (IH, dd), 1.92-1.78 (2H, m), 1.40 (3H, d), 1.03 (3H, t) ESI MS (m/e) = 566 [M+H]+
[Preparation Example 149]
Preparation of benzyl (27?,3S)-3-[(tert-butoxycarbonyl)amino -2-hvdroxy-4- pheny lbutyl [dS)-l-(3 -methoxyphenvDethyll carbamate A process was conducted in the same manner as in Preparation Example 133, except for using (S)-l-(3-methoxyphenyl)ethylamine instead of 3-methoxybenzylamine, whereby 75 mg of the title compound was obtained at 68% yield..
IH NMR (400 MHz, CDC13); 7.44-7.10 (11H, m), 6.90-6.64 (3H, m), 5.35 (IH, br), 5.20 (2H, dd), 4.74 (IH, br), 4.58 (IH, br), 3.82-3.60 (4H, m), 3.37 (IH, br), 3.11 (IH, br), 3.02-2.71 (2H, m), 1.50 (3H, d), 1.31 (9H, s)
[Preparation Example 150]
Preparation of benzyl (2i?,3S)-2-hydroxy-3-({3-
[methyl(propylsulfonvPamino]benzoyl I amino -4-phenylbutyl [( 1 S)- 1 -(3 - methoxyphenyDethyl] carbamate A process was conducted in the same manner as in Preparation Example 134, except for using the compound obtained in Preparation Example 149 instead of the compound obtained in Preparation Example 133, whereby 80 mg of the title compound was obtained at 85%> yield.
IH NMR (400 MHz, CD3OD); 7.62-7.53 (2H, m), 7.50-7.38 (2H, m), 7.33-7.08 (12H, m), 6.87-6.72 (3H, m), 5.24-5.07 (3H, m), 4.20 (IH, m), 3.78 (IH, m), 3.66 (3H, s), 3.50 (IH, m), 3.40-3.17 (5H, m), 3.04 (2H, dd), 2.76 (IH, dd), 1.85-1.70 (2H, m), 1.64 (3H, d), 1.00 (3H, t)
[Example 103] Preparation of N-((lS,2 -benzyl-2-hvdroxy-3-{rdSVl-(3- methoxyphenvPethyllamino}propyP-3-[methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 88, except for using the compound obtained in Preparation Example 150 instead of the compound obtained in Preparation Example 134, whereby 60 mg of the title compound was obtained at 94% yield.
IH ΝMR (400 MHz, CDC13); 7.68 (IH, t), 7.54 (IH, m), 7.45 (IH, dt), 7.38 (lH,t), 7.33-7.18 (6H, m), 6.92-6.83 (3H, m), 3.78 (IH, m), 4.39 (IH, m), 3.80 (3H, s), 3.75 (IH, m), 3.59 (IH, dd), 3.34 (3H, s), 3.11-2.90 (4H, m), 2.77-2.62 (2H, m), 1.90-1.78 (2H, m), 1.43 (3H, d), 1.03 (3H, t) ESI MS (m/e) = 554 [M+H]+
[Example 104]
Preparation of N-(dS)-l-{(5Jg)-3-rdS)-l-(3-methoxyphenvPethyll-1.3-oxazolidin-5- yl I -2-phenylethyl)-3 - [methyl (prop ylsulfonyPamino] benzamide A process was conducted in the same manner as in Example 89, except for using the compound obtained in Example 103 instead of the compound obtained in Example 88, whereby 33 mg of the title compound was obtained at 87%) yield. IH NMR (400 MHz, CDC13); 7.80 (IH, t), 7.60 (IH, m), 7.55 (IH, dt), 7.45 (IH, t), 7.34-7.17 (6H, m), 7.09 (IH, d), 6.91-6.84 (2H, m), 6.78 (IH, m), 4.41 (IH, m), 4.29 (IH, d), 4.21 (IH, m), 3.99 (IH, d), 3.76 (3H, s), 3.36 (3H, s), 3.34 (IH, m), 3.26 (IH, dd), 3.14 (IH, dd), 3.00-2.92 (2h, m), 2.88 (IH, dd), 2.75 (IH, dd), 1.91-1.78 (2H, m), 1.44 (3H, d), 1.02 (3H, t) ESI MS (m/e) = 566 [M+H]+
[Preparation Example 151]
Preparation of benzyl (2i?.3S)-3-({3-[(benzylsulfonyP(methvPamino]benzoyl}amino)-
2-hvdroxy-4-phenylbutyl(3-methoxybenzvDcarbamate A process was conducted in the same manner as in Preparation Example 134, except for using the compound obtained in Preparation Example 56 instead of the compound obtained in Preparation Example 29, whereby 75 mg of the title compound was obtained at 93% yield.
IH NMR (400 MHz, CDC13); 7.52-7.10 (20H, m), 6.77 (IH, dd), 6.72 (IH, d), 6.68 (IH, s), 6.49 (IH, d), 5.19 (2H, dd), 4.55 (2H, dd), 4.38 (IH, m), 4.26 (2H, s), 3.95 (IH, dd), 3.68 (3H, s), 3.47 (2H, d), 3.13 (3H, s), 3.00 (2H, d)
[Example 105]
Preparation of N-{(lS,2i?)-l -benzyl-2-hydroxy-3- (3-methoxybenzvPamino1propyl}-3- [(benzylsulfonvP(methvPamino]benzamide 52 mg (0.072 mmol) of the compound obtained in Preparation Example 151 was dissolved in 5 ml of dichloromethane, then 72 mg (0.36 mmol) of iodotrimethylsilane was added thereto, followed by stirring for 30 minutes. The mixture was diluted using dichloromethane and washed with saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography using a 5:95 mixture of methanol and dichloromethane to obtain 13 mg of the title compound at 31% yield IH NMR (400 MHz, CDC13); 7.60 (IH, s), 7.46 (IH, m), 7.38-7.16 (13H, m), 7.09 (IH, s), 7.06 (IH, d), 7.01 (IH, d), 6.87 (IH, dd), 4.38 (IH, m), 4.29 (2H, s), 4.14 (IH, d), 4.12 (IH, m), 3.99 (IH, d), 3.78 (3H, s), 3.24 (IH, dd), 3.13 (3H, s), 3.10 (IH, s), 3.08 (IH, d), 2.94 (IH, dd) ESI MS (m/e) = 588 [M+H]+
[Example 106]
Preparation of 3-[(benzylsulfonvP(methvPaminol-N-{(lS -l-r(5i?)-3-(3- methoxybenzvD- 1.3 -oxazolidin-5 -yl] -2-phenylethyl } benzamide A process was conducted in the same manner as in Example 89, except for using the compound obtained in Example 105 instead of the compound obtained in Example 88, whereby 6 mg of the title compound was obtained at 60% yield.
IH ΝMR (400 MHz, CDC13); 7.59 (IH, t), 7.47-7.18 (14H, m), 6.93 (IH, d), 6.91 (IH, s), 6.82 (IH, dd), 6.67 (IH, d), 4.56 (IH, d), 4.43 (IH, m), 4.27 (2H, s), 4.23 (IH, d), 4.14 (IH, m), 3.78 (3H, s), 3.72 (2H, dd), 3.19 (IH, dd), 3.15 (3H, s), 3.05 (IH, dd), 2.98-2.83 (2H, m) ESI MS (m/e) = 600 [M+H]+
[Preparation Example 152]
Preparation of tert-butyl (lS.2i?)-l-benzyl-3-[r(9H-fluoren-9-ylmethoxy)carbonyl](3- methoxybenzyDamino]-2-hvdroxypropylcarbamate 500 mg (1.90 mmol) of Preparation Example 132 was dissolved in isopropanol, then 0.27 ml (2.09 mmol) of 3-methoxybenzylamine was added thereto at room temperature. After reflux for 16 hours, the solvent was removed by distillation under reduced pressure. The residue was dissolved in 9 ml of tetrahydrofurane and cooled to 0°C. 0.29 ml (2.09 mmol) of triethylamine and 541 mg (2.09 mmol) of 9- fluorenylmethylchloroformate was added thereto, and stirred for 1 hour. The reaction solution was diluted with ethyl acetate and then washed with 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography to obtain 1.90 g of the title compound at 60%) yield.
1Η-NMR (300 MHz, CDC13); 7.78 - 7.49(3H, m), 7.47 - 6.99(12H, m), 6.82 - 6.54(3H, m), 4.75(1H, bs), 4.58 - 4.31(4H, m), 4.29 - 4.10(2H, m), 3.90 - 3.70(1H, m), 3.75(3H, s), 3.50 - 3.30(2H, m), 3.03 - 2.78(2H, m), 1.32(9H, s)
[Example 107]
Preparation of 3-[(butylsulfonyl)(methvDamino]-N-{(lS)- 1 -[(5i?)-3-(3-methoxybenzvP- l,3-oxazolidin-5-yl]-2-phenylethyl)benzamide 90 mg (0.144 mmol) of the compound obtained in Preparation Example 95 was dissolved in 3 ml of 4.0 Ν hydrochloride solution diluted with ethyl acetate, and stirred for 2 hours. After distillation under reduced pressure for concentration, the residue was dissolved in 3 ml of N,N-dimethylformamide and cooled to 0°C, then 37 mg (0.12 mmol) of the compound obtained in Preparation Example 51 and 55 mg (0.144 mmol) of HATU were added thereto. 0.5 ml (excess amount) of N,N-diisopropylethylamine was further added thereto and heated to room temperature, followed by stirring for 4 hours. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and then washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the residue was dissolved in 1 ml of methylenechloride and 0.1 ml of pyperidin was added thereto, followed by stirring for 1 hour. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography to obtain 36 mg of the title compound at 50%) yield. IH-NMR (300 MHz, CDC13); 7.75 (IH, s), 7.56 - 7.72 (IH, m), 7.45 - 7.40 (2H, m), 7.30 - 7.21 (5H, m), 6.92 - 6.90 (2H, m), 6.85 - 6.75 (2H, m), 4.56 - 4.54 (IH, d, J = 3.87), 4.45 - 4.35 (IH, m), 4.20 - 4.18 (IH, d, J = 3.90), 3.78 (3H, s), 3.75 - 3.65 (2H, m), 3.34 (3H, s), 3.25 - 3.10 (IH, m), 3.08 - 3.00 (IH, m), 2.98 - 2.84 (5H, m), 1.80 - 1.75 (2H, m), 1.41 - 1.36 (2H, m), 1.01 (3H, t, J = 7.29) FAB MS (m/e) = 566 [M+H]+
[Example 108]
Preparation of 3 - [(ethylsulfonyP(methypamino1 -N-UlS)-l-\(5R)-3-(3 -methoxybenzvP- l,3-oxazolidin-5-yl]-2-phenylethyl}benzamide A process was conducted in the same manner as in Example 107, except for using the compound obtained in Preparation Example 46 instead of the compound obtained in Preparation Example 56, whereby 16 mg of the title compound was obtained at 49% yield.
IH-NMR (300 MHz, CDC13); 7.76 - 7.54 (2H, m), 7.45 - 7.40 (2H, m), 7.30 - 7.21 (5H, m), 6.92 - 6.90 (2H, m), 6.85 - 6.75 (2H, m), 4.56 - 4.54 (IH, d, J = 3.87), 4.45 - 4.35 (IH, m), 4.20 - 4.18 (IH, d, J = 3.90), 3.78 (3H, s), 3.75 - 3.65 (2H, m), 3.35 (3H, s), 3.25 - 3.10 (IH, m), 3.08 - 3.00 (IH, m), 3.00 - 2.86 (4H, m), 2.79 (IH, s), 1.34 (3H, t, .7 = 7.39) FAB MS (m/e) = 538 [M+H]+
[Example 109]
Preparation of N-{(lS)-l-[(5i? -3-(3-methoxybenzvP-1.3-oxazolidin-5-yl]-2- phenylethyl } -3 - [methvKmethylsulfonyPamino] benzamide A process was conducted in the same manner as in Example 107, except for using 3-[methyl(methylsulfonyl)amino]benzoic aicd instead of the compound obtained in Preparation Example 56, whereby 12 mg of the title compound was obtained at 40% yield.
1H-ΝMR (300 MHz, CDC13); 7.75 (IH, s), 7.56 - 7.54 (IH, m), 7.49 - 7.41 (3H, m),
7.37 - 7.22 (5H, m), 6.92 - 6.90 (2H, m), 6.83 - 6.81 (IH, m), 4.56 - 4.54 (IH, d, J =
3.87), 4.45 - 4.35 (IH, m), 4.20 - 4.18 (IH, d, J = 3.90), 3.78 (3H, s), 3.75 - 3.65 (3H, m), 3.33 (3H, s), 3.25 - 3.10 (IH, m), 3.08 - 3.00 (IH, m), 2.98 - 2.84 (2H, m), 2.82
(3H, s)
FAB MS (m/e) = 524 [M+H]+
[Preparation Example 153] Preparation of tert-butyl (lS,2i?V3-azido-l-benzyl-2-hydroxypropylcarbamate 500 mg (1.90 mmol) of the compound obtained in Preparation Example 132 was dissolved in 8.6 ml of methanol and 1.1 ml of distilled water, then 221 mg (4.13 mmol) of ammoniumchloride and 610 mg (9.39 mmol) of sodiumazide were added thereto at room temperature. After stirring for 16 hours at 40°C, the mixture was diluted with water and then extracted with ethyl acetate. After removing solvent by distillation under reducd pressure, the product was purified by column chromatography to obtain
523 mg of compound at 90% yield.
IH-NMR (300 MHz, CDC13); 7.33 - 7.11 (5H, m), 4.60 (IH. d, J = 8.07), 3.92 - 3.69 (2H, m), 3.43 - 3.30 (2H, m), 2.96 - 2.72 (2H, m), 1.37(9H, s)
[Preparation Example 154]
Preparation of. N-[(lS,2J? -3-azido-l-benzyl-2-hvdroxypropyl]-3-
[(benzylsulfonyP(methyPamino]benzamide 44 mg (0.144 mmol) of the compound obtained in Preparation Example 153 was dissolved in ethyl acetate diluted with 4.0 Ν hydrochloride solution and stirred for 2 hours. After distillation under reduced pressure for concentration, the residue was dissolved in 2 ml of Ν,Ν-dimethylformamide and cooled to 0°C, then 37 mg (0.12 mmol) of the compound obtained in Preparation Example 56 and 55 mg (0.144 mmol) of HATU were added thereto. 0.5 ml (excess amount) of N,N-diisopropylethylamine was then added thereto and heated to room temperature, followed by stirring for 4 hours. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and then washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography to obtain 47 mg of the title compound at 80% yield.
IH-NMR (300 MHz, CDC13); 7.51 - 7.16 (14H, m), 6.45 (IH, d, J= 7.82), 4.42 - 4.25 (IH, m), 4.27 (2H, s), 4.00 - 3.86 (2H, m), 3.52 - 3.35 (2H, m), 3.11 (3H, s), 3.05 - 2.95 (IH, m)
[Preparation Example 155]
Preparation of N- ( 1 S,2 R)-3 -amino- 1 -benzyl -2-hydroxypropyl] -3 - (benzylsulfonvP(methyPaminolbenzamide A process was conducted in the same manner as in Example 39, except for using the compound obtained in Preparation Example 154 instead of the compound obtained in example 38, whereby 40 mg of the title compound was obtained at 90% yield.
1H-ΝMR (300 MHz, CDC13); 7.56 (IH, s), 7.54 - 7.10 (14H, m), 5.31 (3H, bs), 4.45 - 3.85 (4H, m), 3.20 - 2.78 (4H, m), 2.98 (3H, s)
[Example 110]
Preparation of N- { ( 1 S.2R)- 1 -benzyl-2-hydroxy-3 - [(3 -methoxybenzovPamino] propyl 1 - 3 - [(benzylsulfonvP(methyPamino1 benzamide 20 mg (0.0428 mmol) of the compound obtained in Preparation Example 155 was dissolved in 1 ml of dichloromethane and cooled to 0°C, then 11.9 ml (0.0856 mmol) of triethylamine and 6.3 ml (0.0449 mmol) of 3-methoxybenzoyl chloride was added thereto. After stirring for 4 hours, the mixture was diluted with dichloromethane and then washed with 0.5 Ν hydrochloride solution, saturated sodium bocarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography to obtain 15 mg of the title compound at 58%) yield.
IH-NMR (300 MHz, CDC13); 7.89 - 7.76 (IH, m), 7.52 - 7.18 (17H, m), 7.10 - 6.98 (IH, m), 6.34 - 6.21 (IH, m), 4.78 - 4.51 (IH, m), 4.48 - 4.32 (IH, m), 4.27 (2H, s), 4.19 - 4.12 (IH, m), 3.86 (3H, s), 3.82 - 3.76 (IH, m), 3.29 - 3.08 (6H, m) FAB MS (m/e) = 602 [M+H]+
[Example 111] Preparation of N- ( ( 1 S,2 R)- 1 -benzyl-2-hydroxy-3 - [(phenylsulfonyPaminol propyl } -3 -
[(benzylsulfonvP(methvPaminolbenzamide A process was conducted in the same manner as in Example 110, except for using benzenesulfonylchloride instead of 3-methoxybenzoylchloride, whereby 14 mg of the title compound was obtained at 48% yield. 1H-ΝMR (300 MHz, CDCI3); 7.92 - 7.79 (2H, m), 7.58 - 7.17 (17H, m), 6.30 (IH, d, J
= 8.19), 6.08 - 5.91 (IH, m), 4.39 - 4.18 (IH, m), 4.27 (2H, s), 3.88 - 3.73 (IH, m),
3.24 - 2.86 (4H, m), 3.12 (3H, s)
FAB MS (m/e) = 608 [M+H]+
[Example 112]
Preparation of N-((lS.2i-Vl-benzyl-2-hvdroχy-3-(r2-
(trifluoromethyPbenzyl1amino}propyP-3-[(benzylsulfonvP(methyl)amino]benzamide 20 mg (0.0428 mmol) of the compound obtained in Preparation Example 155 and 6 mg (0.0342 mmol) of 2-trifluorobenzaldehyde were dissolved in 0.5 ml of 1,2- dichloroethane. 11 mg (0.0514 mmol) of sodium triacetoxyborohydride was added thereto and stirred for 16 hours. The mixture was diluted with ethyl acetate and then washed with saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reducd pressure, the product was purified by column chromatography to obtain 16 mg of compound at 60% yield. IH-NMR (300 MHz, CDC13); 7.71 - 7.08 (17H, m), 6.75 (IH, d, J= 7.68), 4.49 - 4.30 (IH, m), 4.26 (2H, s), 3.99 (2H, s), 3.78 - 3.62 (IH, m), 3.13 (3H, s), 3.12 - 2.93 (2H, m), 2.90 - 2.78 (2H, m), 2.33 (2H, bs) FAB MS (m/e) = 626 [M+H]+
[Example 113]
Preparation of N-(dS.2^-l-benzyl-2-hydroxy-3- -
(trifluoromethvPbenzyll amino } propyp-3 - [(benzylsulfonvP(methvPamino] benzamide A process was conducted in the same manner as in Example 112, except for using 3-trifluorobezaldehyde instead of 2-trifluorobezaldehyde, whereby 15 mg of the title compound was obtained at 58% yield.
1H-ΝMR (300 MHz, CDC13); 7.69 - 7.17 (17H, m), 6.72 (IH, d, J= 8.58), 4.43 - 4.28 (IH, m), 4.27 (2H, s), 3.93 - 3.78 (2H, m), 3.73 - 3.61 (IH, m), 3.13 (3H, s), 3.02 - 2.90 (2H, m), 2.80 - 2.71 (2H, m), 2.39 (2H, bs) FAB MS (m/e) = 626 [M+H]+
[Example 114]
Preparation of N- { ( 1 S.2R)- 1 -benzyl-3 - [(3 -bromobenzvPamino] -2-hydroxyprop yl } -3 - [(benzylsulfonyP(methvPamino]benzamide A process was conducted in the same manner as in Example 112, except for using 3-bromobezaldehyde instead of 2-trifluorobezaldehyde, whereby 18 mg of the title compound was obtained at 65% yield.
IH-NMR (300 MHz, CDC13); 7.60 - 7.11 (17H, m), 6.81 (IH, d, J= 8.38), 4.46 - 4.30 (IH, m), 4.27 (2H, s), 3.89 - 3.61 (3H, m), 3.13 (3H, s), 3.09 - 2.97 (2H, m), 2.83 - 2.72 (2H, m), 2.45 (2H, bs) FAB MS (m/e) = 636 [M+H]+
[Preparation Example 156] Preparation of. N- [( 1 S,2R)-3 -azido- 1 -benzyl-2-hydroxypropyll -3 -
[methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Preparation Example 154, except for using the compound obtained in Preparation Example 29 instead of the compound obtained in Preparation Example 56, whereby 45 mg of the title compound was obtained at 85% yield.
1H-ΝMR (300 MHz, CDC13); 7.64 (IH, s), 7.53 (IH, d, J= 7.42), 7.42 - 7.14 (7H, m),
6.38 (IH, d, J = 7.59), 4.43 - 4.30 (IH, m), 3.99 - 3.83 (IH, m), 3.76 - 3.66 (IH, m),
3.49 - 3.35 (2H, m), 3.32 (3H, s), 3.04 - 2.82 (4H, m), 1.89 - 1.71 (2H, m), 1.03 (3H, t,
J= 7.43)
[Preparation Example 157]
Preparation of N- [( 1 S,2R)-3 -amino- 1 -benzyl-2-hydroxyprop yll -3 -
[methvKpropylsulfonvPaminolbenzamide A process was conducted in the same manner as in Example 39, except for using the compound obtained in Preparation Example 156 instead of the compound obtained in Example 38, whereby 35 mg of the title compound was obtained at 91% yield.
IH-NMR (300 MHz, CDC13); 7.64 (IH, s), 7.56 - 7.40 (2H, m), 7.39 - 7.05 (7H, m), 4.48 - 4.39 (IH, m), 3.65 - 3.50 (IH, m), 3.31 (3H, s), 3.10 - 2.78 (6H, m), 2.70 (3H, bs), 1.91 - 1.71 (2H, m), 1.01 (3H, t, J= 7.44)
[Example 115]
Preparation of; N-((lS.2i?)-l-benzyl-2-hvdroxy-3-{r3- (trifluoromethoxy)benzyl1amino}propyP-3-[methyl(propylsulfonvPamino]benzamide 20 mg (0.0477 mmol) of the compound obtained in Preparation Example 157 and 7 mg (0.0342 mmol) of 3-trifluoromethoxybenzaldehyde were dissolved in 0.5 ml of 1,2-dichloroethane. 11 mg (0.0514 mmol) of sodium triacethoxyborohydride was added thereto and stirred for 16 hours. After dilution with ethyl acetate, the resulting mixture was washed with saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reducd pressure, the product was purified by column chromatography to obtain 20 mg of the title compound at 71%> yield. 1H-ΝMR (300 MHz, CDC13); 7.71 - 7.61 (IH, m), 7.56 - 7.09 (13H, m), 6.99 - 6.89 (IH, m), 4.48 - 4.30 (IH, m), 3.91 - 3.60 (3H, m), 3.33 (3H, s), 3.07 - 2.81 (4H, m), 2.80 - 2.71 (2H, m), 2.71 (2H, bs), 1.91 - 1.71 (2H, m), 1.02 (3H, t, J= 7.45) FAB MS (m/e) = 594 [M+H]+
[Example 116]
Preparation of N- { ( 1 S.2.K)- 1 -benzyl-2-hydroxy-3 - [(3 -phenoxybenzvPaminolpropyl I -3 - [methyl(propylsulfonyPamino]benzamide A process was conducted in the same manner as in Example 115, except for using 3-phenoxybenzaldehyde instead of 3-trifluoromethoxybezaldehyde, whereby 20 mg of the title compound was obtained at 10% yield. IH-NMR (300 MHz, CDC13); 7.68 (IH, s), 7.58 - 7.39 (2H, m), 7.38 - 7.15 (13H, m), 7.14 - 6.82 (3H, m), 4.48 - 4.32 (IH, m), 3.85 - 3.59 (3H, m), 3.32 (3H, s), 3.09 - 2.83 (4H, m), 2.82 - 2.74 (2H, m), 2.47 (2H, bs), 1.89 - 1.72 (2H, m), 1.01 (3H, t, J= 7.42) FAB MS (m/e) = 602 [M+H]+
[Example 117]
Preparation of N- { ( 1 S2R)- 1 -benzyl-2-hydroxy-3 - [(3 -hvdroxybenzvDamino] propyl } -3 -
[methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 115, except for using 3-hydroxybenzaldehyde instead of 3-trifluoromethoxybezaldehyde, whereby 17 mg of the title compound was obtained at 71% yield.
1H-ΝMR (300 MHz, CDC13); 7.65 (IH, s), 7.52 - 7.37 (2H, m), 7.36 - 7.06 (8H, m),
6.89 - 6.68 (3H, m), 4.45 - 4.29 (IH, m), 3.80 - 3.58 (3H, m), 3.60 (2H, bs), 3.48 (IH, s), 3.29 (3H, s), 2.99 - 2.84 (4H, m), 2.83 - 2.72 (2H, m), 1.89 - 1.70 (2H, m), 1.01 (3H, t, J= 7.41) FAB MS (m/e) = 526 [M+H]+
[Example 118]
Preparation of N- { ( 1 S2R)- 1 -benzyl-2-hydroxy-3 - r(4-methoxybenzvPamino]propyl } -3 - [methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 115, except for using 4-methoxybenzaldehyde instead of 3-trifluoromethoxybezaldehyde, whereby 16 mg of the title compound was obtained at 65% yield.
IH-NMR (300 MHz, CDC13); 7.69 (IH, s), 7.55 - 7.08 (11H, m), 6.91 - 6.78 (2H, m), 4.45 - 4.29 (IH, m), 3.86 - 3.59 (3H, m), 3.79 (3H, s), 3.32 (3H, s), 3.12 - 2.79 (8H, m), 1.90 - 1.69 (2H, m), 1.01 (3H, t, J= 7.41) FAB MS (m/e) = 540 [M+H]+
[Example 119] Preparation of N- ( ( 1 S2R)- 1 -benzyl-2-hydroxy-3 - [(2-methoxybenzyPamino] propyl } -3 -
[methyl(propylsulfonyPamino]benzamide A process was conducted in the same manner as in Example 115, except for using 2-methoxybenzaldehyde instead of 3-trifluoromethoxybezaldehyde, whereby 17 mg of the title compound was obtained at 68% yield. 1H-ΝMR (300 MHz, CDC13); 7.70 (IH, s), 7.62 - 7.49 (2H, m), 7.48 - 7.12 (9H, m),
7.01 - 6.82 (2H, m), 4.52 - 4.36 (IH, m), 3.93 - 3.63 (3H, m), 3.80 (3H, s), 3.31 (3H, s),
3.18 - 2.71 (8H, m), 1.90 - 1.68 (2H, m), 1.01 (3H, t, J= 7.38)
FAB MS (m/e) = 540 [M+H]+
[Preparation Example 158]
Preparation of 3-Ethoxybenzaldehyde 1.0 g(8.19 mmol) of 3-hydroxybenzaldehyde was dissolved in 40 ml of Ν,Ν- dimethylformaldehyde, and 1.29 g(16.31 mmol) of potassium carbonates and 1.95 ml (9.00 mmol) of iodoethane were added thereto. After stirring for 16 hours at room temperature, the solvent was removed by distillation under reduced pressure. Concentrated solution was dissolved in ethyl acetate and washed with water and sodium chloride solution. After removing the solvent by distillation under reducd pressure, the concentrated solution was purified by column chromatography to obtain 1.05 g of the title compound at 85% yield.
IH-NMR (300 MHz, CDC13); 9.62 (IH, s), 7.50 - 7.31 (3H, m), 7.22 - 7.10 (IH, m), 4.09 (2H, q, J= 6.97), 1.44 (3H, t, J= 6.99)
[Example 120] Preparation of N- ( ( 1 S2R)- 1 -benzyl-3 - [(3 -ethoxybenzyPamino] -2-hydroxypropyl } -3 - [methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 115, except for using the compound obtained in Preparation Example 158 instead of 3- trifluoromethoxybezaldehyde, whereby 17 mg of the title compound was obtained at 65% yield.
1H-ΝMR (300 MHz, CDC13); 7.69 (IH, s), 7.58 - 7.02 (10H, m), 6.92 - 6.71 (3H, m), 4.48 - 4.31 (IH, m), 3.40 (2H, q, J = 6.87), 3.87 - 3.56 (3H, m), 3.33 (3H, s), 3.07 - 2.69 (6H, m), 2.62 (2H, bs), 1.90 - 1.70 (2H, m), 1.40 (3H, t, J= 6.93), 1.02 (3H, t, J = 7.35) FAB MS (m/e) = 554 [M+H]+
[Preparation Example 159]
Preparation of 3-(allyloxy')benzaldehvde A process was conducted in the same manner as in Preparation Example 158, except for using allylbromide instead of iodoethane, whereby 1.14 g of the title compound was obtained at 86%> yield.
IH-NMR (300 MHz, CDC13); 9.97 (IH, s), 7.49 - 7.31 (3H, m), 7.24 - 7.11 (IH, m),
6.14 - 5.95 (IH, m), 5.48 - 5.19 (2H, m), 4.66 - 4.52 (2H, m)
[Example 121]
Preparation of N-(( 1 S2R)-3- { \3 -(allyloxy)benzyll amino } - 1 -benzyl-2-hvdroxypropyP-
3-[methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Preparation Example 115, except for using the compound obtained in Preparation Example 159 instead of 3- trifluoromethoxybenzaldehyde, whereby 19 mg of the title compound was obtained at
69% yield.
1H-ΝMR (300 MHz, CDC13); 7.69 (IH, s), 7.58 - 7.01 (10H, m), 6.94 - 6.70 (3H, m),
6.12 - 5.92 (IH, m), 5.45 - 5.20 (2H, m), 4.55 - 4.31 (3H, m), 3.95 - 3.59 (3H, m), 3.32 (3H, s), 3.10 - 2.61 (8H, m), 1.01 (3H, t, J= 7.37)
FAB MS (m/e) = 566 [M+H]+
[Preparation Example 160] Preparation of 3-(benzyloxy)benzaldehyde A process was conducted in the same manner as in Preparation Example 158, except for using benzylbromide instead of iodoethane, whereby 1.46 g of the title compound was obtained at 84%) yield. 1H-ΝMR (300 MHz, CDC13); 9.95 (IH, s), 7.50 - 7.18 (9H, m), 5.10 (2H, s) [Example 122]
Preparation of N-(( 1 S,2i?)- 1 -benzyl-3 - { [3 -(benzyloxylbenzyll amino } -2- hvdroxypropyP-3-rmethyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Preparation Example 115, except for using the compound obtained in Preparation Example 160 instead of 3- trifluoromethoxybenzaldehyde, whereby 19 mg of the title compound was obtained at
69% yield.
1H-ΝMR (300 MHz, CDC13); 7.69 (IH, s), 7.53 - 7.07 (15H, m), 7.02 - 6.81 (3H, m),
5.04 (2H, s), 4.48 - 4.30 (IH, m), 3.88 - 3.61 (3H, m), 3.30 (3H, s), 3.09 - 2.62 (8H, m), 1.90 - 1.72 (2H, m), 1.40 (3H, t, J= 6.93), 1.01 (3H, t, J= 7.41)
FAB MS (m/e) = 616 [M+H]+
[Preparation Example 161]
Preparation of 3-formylphenyl benzoate A process was conducted in the same manner as in Preparation Example 158, except for using benzoylchloride instead of iodoethane, whereby 1.24 g of the title compound was obtained at 61% yield. IH-NMR (300 MHz, CDC13); 10.04 (IH, s), 8.24 - 7.93 (2H, m), 7.82 - 7.40 (7H, m)
[Example 123]
Preparation of 3-({r(2J.,3S -2-hydroxy-3-((3-
[methyl(propylsulfonyPamino]benzoyl}amino')-4-phenylbutyl]amino}methvPphenyl benzoate A process was conducted in the same manner as in Preparation Example 115, except for using the compound obtained in Preparation Example 161 instead of 3- trifluoromethoxybenzaldehyde, whereby 21 mg of the title compound was obtained at 70% yield.
IH-NMR (300 MHz, CDC13); 8.20 - 8.16 (2H, m), 7.70 - 6.96 (17H, m), 4.48 - 4.32 (IH, m), 3.88 (IH, d, .7 =14.51), 3.84 (IH, d, J= 14.49), 3.72 - 3.60 (IH, m), 3.31 (3H, s), 3.11 - 2.78 (6H, m), 2.00 (2H, bs), 1.89 - 1.73 (2H, m), 1.01 (3H, t, J= 7.44) FAB MS (m/e) = 630 [M+H]+
[Preparation Example 162] Preparation of 3-(dimethylamino)benzaldehyde 0.3 g (1.98 mmol) of 3-dimethylaminobenzylalcohol was dissolved in 10 ml of dichloromethane, and 1.11 g (2.97 mmol) of pyridium dicromate was added thereto at room temperature. After stirring for 20 hours, the mixture was diluted with ether, and precipitant was filtered. After concentration of the filtate by distillation under reduced pressure, the concentrated solution was purified by column chromatography to obtain 221 mg of the title compound at 75%> yield.
IH-NMR (300 MHz, CDC13); 9.95 (IH, s), 7.38 (IH, t, J = 7.89), 7.20 - 7.18 (2H, m), 6.99 - 6.96 (IH, m), 3.01 (6H, s)
[Example 124]
Preparation of N-((lS,2i? -l -benzyl-3-l [3-(dimethylamino)benzyl]amino}-2- hvdroxypropyP-3-[methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Preparation Example 115, except for using the compound obtained in Preparation Example 162 instead of 3- trifluoromethoxybenzaldehyde, whereby 13 mg of the title compound was obtained at 50% yield.
IH-NMR (300 MHz, CDC13); 7.69 (IH, s), 7.57 - 7.49 (IH, m), 7.45 - 7.40 (IH, m), 7.35 - 7.19 (7H, m), 6.67 - 6.66 (3H, m), 4.50 - 4.35 (IH, m), 3.85 - 3.71 (3H, m), 3.32 (3H, s), 3.12 - 2.86 (6H, m), 2.92 (6H, s), 1.84 - 1.81 (2H, m), 1.01 (3H, t, J = 7.41) FAB MS (m/e) = 553 [M+H]+
[Example 125] Preparation of N-[( 1 S2R)- 1 -benzyl-2-hydroxy-3 -(phenethylamino propyl] -3 -
[methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 115, except for using phenylacetaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 15 mg of the title compound was obtained at 60% yield. 1H-ΝMR (300 MHz, CDC13); 7.68 - 7.67 (IH, m), 7.55 - 7.52 (IH, m), 7.43 - 7.38
(2H, m), 7.30 - 7.17 (9H, m), 6.93 - 6.91 (IH, m), 4.45 - 4.35 (IH, m), 3.71 - 3.67 (IH, m), 3.33 (3H, s), 3.06 - 3.00 (2H, m), 2.96 - 2.91 (4H, m), 2.85 - 2.80 (4H, m), 1.87 -
1.81 (2H, m), 1.01 (3H, t, J = 7.41)
FAB MS (m/e) = 524 [M+H]+
[Example 126]
Preparation of N-((lS.2i?)-l-benzyl-3-{r(5-ethyl-2-furvPmethyllaminol-2- hydroxypropyP-3 - [methyl (propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 115, except for using 5-ethylfurane-2-carbaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 17 mg of the title compound was obtained at 68% yield. IH-NMR (300 MHz, CDC13); 7.72 (IH, s), 7.58 - 7.42 (2H, m), 7.41 ~ 7.14 (7H, m), 6.10 (IH, d, J= 2.96), 5.90 (IH, d, J= 2.99), 4.49 - 4.32 (IH, m), 3.84 - 3.63 (3H, m), 3.33 (3H, s), 3.09 - 2.74 (6H, m), 2.58 (2H, q, J= 7.48), 2.48 (2H, bs), 1.90 - 1.72 (2H, m), 1.18 (3H,t, J= 7.54), 1.02 (3H, t, J= 7.44) FAB MS (m/e) = 528 [M+H]+
[Example 127] Preparation of N-((lS2R)-l -benzyl-3 - { (5 -ethyl-2-thienyl)methvn amino ) -2- hydroxypropyP-3 - [methvKpropylsulfonvPaminolbenzamide A process was conducted in the same manner as in Preparation Example 115, except for using 5-ethylthiopen-2-carbaldehyde instead of 3- trifluoromethoxybenzaldehyde, whereby 18 mg of the title compound was obtained at 71% yield.
IH-NMR (300 MHz, CDC13); 7.71 (IH, s), 7.58 - 7.40 (2H, m), 7.39 - 7.16 (7H, m), 7.58 - 7.40 (2H, m), 6.74 (IH, d, J= 3.24), 6.61 (IH, d, J= 3.30), 4.49 - 4.32 (2H, m), 3.76 - 3.61 (IH, m), 3.33 (3H, s), 3.12 - 2.56 (6H, m), 2.68 (2H, bs), 1.90 - 1.69 (2H, m), 1.28 (3H, t, J= 7.50), 1.02 (3H, t, J= 7.41) FAB MS (m/e) = 544 [M+H]+
[Example 128]
Preparation of N-r(lS.2i? -l-benzyl-2-hvdroxy-3-({r5-(hvdroxymethvP-2- furyllmethyl } amino)propyl] -3 - [methvKpropylsulfonvPamino] benzamide A process was conducted in the same manner as in Example 115, except for using 5-hydroxymethylfurane-2-carbaldehyde instead of 3- trifluoromethoxybenzaldehyde, whereby 15 mg of the title compound was obtained at
62% yield. IH-NMR (300 MHz, CDC13); 7.68 (IH, s), 7.55 - 7.40 (2H, m), 7.39 - 7.14 (6H, m),
7.02 (IH, d, J= 8.30), 6.18 (IH, d, J= 3.09), 6.13 (IH, d, J= 3.12), 4.50 (2H, s), 4.42 - 4.38 (IH, m), 3.84 (IH, d, J= 14.50), 3.74 (IH, d, J= 14.49), 3.64 - 3.51 (IH, m), 3.33 (3H, s), 3.09 - 2.87 (4H, m), 2.85 - 2.72 (2H, m), 2.57 (3H, bs), 1.89 - 1.72 (2H, m),
1.03 (3H, t, J= 7.44) FAB MS (m/e) = 530 [M+H]+
[Example 129]
Preparation of N-((lS,2J?)-l-benzyl-3-{[(5-bromo-2-thienvPmethyl]amino}-2- hydroxypropyP-3 - [methvKpropylsulfonvPamino] benzamide A process was conducted in the same manner as in Example 115, except for using 5-bromothiopen-2-carbaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 17 mg of the title compound was obtained at 63%) yield.
1H-ΝMR (300 MHz, CDC13); 7.69 (IH, s), 7.59 - 7.28 (8H, m), 6.91 - 6.82 (2H, m),
6.69 (IH, d, J = 3.64), 4.47 - 4.31 (IH, m), 3.96 (IH, d, J = 14.50), 3.92 (IH, d, J = 14.49), 3.72 - 3.60 (IH, m), 3.34 (3H, s), 3.10 - 2.86 (4H, m), 2.85 - 2.76 (2H, m),
1.99 (2H, bs), 1.89 - 1.73 (2H, m), 1.02 (3H, t, J= 7.46)
FAB MS (m/e) = 594 [M+H]+
[Example 130] Preparation of N- { ( 1 S2R)- 1 -benzyl-3 - [(3 -chlorobenzvPamino] -2-hydroxypropyl } -3 - [methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 115, except for using 3-chlorobenzaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 17 mg of the title compound was obtained at 67% yield.
1H-ΝMR (300 MHz, CDC13); 7.68 (IH, s), 7.55 - 7.12 (12H, m), 6.98 - 6.88 (IH, m), 4.46 - 4.32 (IH, m), 3.84 - 3.60 (3H, m), 3.33 (3H, s), 3.09 - 2.82 (4H, m), 2.81 - 2.70 (2H, m), 2.02 (2H, s), 1.90 - 1.73 (2H, m), 1.02 (3H, t, J= 7.41) FAB MS (m/e) = 544 [M+H]+
[Example 131]
Preparation of N- { ( 1 S2R)- 1 -benzyl-3 - [(3 -bromobenzvPamino] -2-hydroxypropyl } -3 - [methyl(propylsulfonyPamino]benzamide A process was conducted in the same manner as in Example 115, except for using 3-bromobenzaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 16 mg of the title compound was obtained at 60% yield.
1H-ΝMR (300 MHz, CDC13); 7.68 (IH, s), 7.56 - 7.13 (12H, m), 6.98 - 6.89 (IH, m), 4.46 - 4.32 (IH, m), 3.84 - 3.59 (3H, m), 3.33 (3H, s), 3.09 - 2.88 (4H, m), 2.81 - 2.71 (2H, m), 2.21 (2H, bs), 1.90 - 1.70 (2H, m), 1.02 (3H, t, J= 7.42) FAB MS (m/e) = 588 [M+H]+
[Example 132]
Preparation of N- { ( 1 S2R)- 1 -benzyl-2-hydroxy-3 - [(3 -iodobenzvPaminolpropyl } -3- [methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 115, except for using 3-iodobenzaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 18 mg of the title compound was obtained at 61% yield.
IH-NMR (300 MHz, CDC13); 7.74 - 7.14 (12H, m), 7.09 - 6.89 (2H, m), 4.47 - 4.31 (IH, m), 3.86 - 3.62 (3H, m), 3.33 (3H, s), 3.08 - 2.86 (4H, m), 2.82 - 2.72 (2H, m), 2.12 (2H, bs), 1.91 - 1.72 (2H, m), 1.02 (3H, t, J= 7.42) FAB MS (m/e) = 636 [M+H]+
[Example 133] Preparation of. N-(( 1 S2R )- 1 -benzyl-2-hydroxy-3- ( \3 -
(trifluoromethvPbenzyl] amino } propyP-3 - [methyKpropylsulfonyPaminolbenzamide A process was conducted in the same manner as in Example 115, except for using 3-trifluoromethylbenzaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 19 mg of the title compound was obtained at 70% yield. IH-NMR (300 MHz, CDC13); 7.76 - 7.16 (13H, m), 6.96 (IH, d, J= 8.52), 4.48 - 4.31
(IH, m), 3.99 - 3.62 (3H, m), 3.33 (3H, s), 3.10 - 2.72 (6H, m), 2.78 (2H, bs), 1.91 -
1.71 (2H, m), 1.02 (3H, t, J= 7.41)
FAB MS (m/e) = 578 [M+H]+
[Example 134]
Preparation of N- { ( 1 S2R)- 1 -benzyl-2-hydroxy-3 - [(3 -methylbenzyPamino] propyl } -3 - [methvKpropylsulfonvPaminolbenzamide A process was conducted in the same manner as in Example 115, except for using 3-methylbenzaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 17 mg of the title compound was obtained at 69% yield.
IH-NMR (300 MHz, CDC13); 7.70 (IH, s), 7.60 - 7.02 (13H, m), 4.49 - 4.35 (IH, m), 3.90 - 3.70 (3H, m), 3.32 (3H, s), 3.12 - 2.62 (8H, m), 2.33 (3H, s), 1.91 - 1.73 (2H, m), 1.02 (3H, t, J= 7.36) FAB MS (m/e) = 524 [M+H]+
[Example 135]
Preparation of N- { (1 S2R)-3 - [d ,3 -benzodioxol-5 - ylmethvPamino] - 1 -benzyl-2- hvdroxypropyl}-3-[methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 115, except for using pyperonal instead of 3-trifluoromethoxybenzaldehyde, whereby 17 mg of the title compound was obtained at 66%> yield.
1H-ΝMR (300 MHz, CDC13); 7.69 (IH, s), 7.61 - 7.12 (9H, m), 6.83 (IH, s), 6.79 -
6.70 (2H, m), 5.94 (2H, s), 4.46 - 4.33 (IH, m), 3.81 - 3.60 (2H, m), 3.33 (3H, s), 3.07 - 2.88 (4H, m), 2.87 - 2.72 (2H, m), 2.52 (2H, bs), 1.89 - 1.72 (2H, m), 1.02 (3H, t, J=
7.42)
FAB MS (m/e) = 554 [M+H]+
[Example 136] Preparation of N- { ( 1 S,2i? - 1 -benzyl-3 - [(3 ,5-dimethoxybenzvPamino] -2- hvdroxypropyl}-3-[methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 115, except for using 3,5-dimethoxybenzaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 20 mg of the title compound was obtained at 76% yield IH-NMR (300 MHz, CDC13); 7.69 (IH, s), 7.59 - 7.13 (10H, m), 6.58 - 6.31 (3H, m), 4.46 - 4.30 (IH, m), 3.88 - 3.62 (3H, m), 3.76 (6H, s), 3.32 (3H, s), 3.07 - 2.69 (8H, m), 1.90 - 1.70 (2H, m), 1.01 (3H, t, J= 7.38) FAB MS (m/e) = 570 [M+H]+
[Example 137]
Preparation of N- 1 ( 1 S2R)- 1 -benzyl-2-hydroxy-3 - [(2-hvdroxy-3 - methoxybenzvPamino]propyl}-3-rmethyl(propylsulfonyPamino]benzamide A process was conducted in the same manner as in Example 115, except for using 2-hydroxy-3-methoxybenzaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 16 mg of the title compound was obtained at 61%> yield 1H-ΝMR (300 MHz, CDC13); 7.66 (IH, s), 7.59 - 7.46 (2H, m), 7.40 - 7.15 (m, 6H), 7.17 - 6.97 (IH, m), 6.85 - 6.69 (3H, m), 4.38 - 4.25 (IH, m), 4.09 - 3.89 (3H, m), 3.84 (3H, s), 3.82 (3H, bs), 3.32 (3H, s), 3.05 - 2.78 (IH, m), 1.89 - 1.72 (2H, m), 1.02 (3H, t, J= 7.41)
FAB MS (m/e) = 556 [M+H]+
[Example 138]
Preparation of. N-{(lS,2i?)-l-benzyl-3-[(2,3-dimethoxybenzyPamino]-2- hydroxypropyl } -3 - [methy KpropylsulfonyPamino] benzamide A process was conducted in the same manner as in Example 115, except for using 2,3-dimethoxybenzaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 19 mg of the title compound was obtained at 75%) yield 1H-ΝMR (300 MHz, CDC13); 7.71 (IH, s), 7.56 - 7.46 (IH, m), 7.45 - 7.14 (8H, m), 7.06 - 6.98 (IH, m), 6.90 - 6.81 (2H, m), 4.49 - 4.35 (IH, m), 3.88 - 3.78 (8H, m), 3.77 - 3.68 (IH, m), 3.32 (3H, s), 3.09 - 2.82 (6H, m), 2.65 (2H, bs), 1.91 - 1.75 (2H, m), 1.02 (3H, t, J= 7.41) FAB MS (m/e) = 570 [M+H]+
[Example 139]
Preparation of N- ( (1 S,2i?)- 1 -benzyl-2-hydroxy-3 - [(2-hydroxy-5 - methoxybenzvPamino]propyl}-3-[methyl(propylsulfonyPamino1benzamide A process was conducted in the same manner as in Example 115, except for using 2-hydroxy-5-methoxybenzaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 17 mg of the title compound was obtained at 62%) yield 1H-ΝMR (300 MHz, CDC13); 7.64 (IH, s), 7.57 - 7.17 (9H, m), 6.84 - 6.68 (2H, m), 6.67 - 6.52 (2H, m), 4.35 - 4.21 (IH, m), 4.05 (IH, d, J = 14.52), 3.97 (IH, d, J = 14.48), 3.88 - 3.78 (8H, m), 3.75 (3H, s), 3.77 - 3.68 (IH, m), 3.34 (3H, s), 3.14 (3H, bs), 3.12 - 2.75 (6H, m), 1.91 - 1.72 (2H, m), 1.04 (3H, t, J= 7.49) FAB MS (m/e) = 556 [M+H]+
[Example 140]
Preparation of N- { ( 1 S,2i?)- 1 -benzyl-3 - [(2,5 -dimethoxybenzvPamino] -2- hvdroxypropyl}-3-[methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 115, except for using 2,5-dimethoxybenzaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 19 mg of the title compound was obtained at 71% yield 1H-ΝMR (300 MHz, CDC13); 7.69 (IH, s), 7.53 (IH, d, J= 7.93), 7.45 (IH, d, J= 7.76), 7.40 - 7.12 (7H, m), 6.84 - 6.71 (3H, m), 4.61 (2H, bs), 4.50 - 4.37 (IH, m), 3.95 (IH, d, J = 13.52), 3.86 (IH, d, J = 13.01), 3.77 (3H, s), 3.74 (3H, s), 3.31 (3H, s), 3.77 - 3.68 (IH, m), 3.11 - 2.78 (6H, m), 1.90 - 1.73 (2H, m), 1.02 (3H, t, J= 7.40) FAB MS (m/e) = 570 [M+H]+
[Example 141]
Preparation of N- { ( 1 S2R)- 1 -benzyl-2-hydroxy-3 - f(l -naphthylmethvPamino] ropyl } -3 -
[methvKpropylsulfonyPaminolbenzamide A process was conducted in the same manner as in Example 115, except for using naphthalene- l-carbaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 18 mg of the title compound was obtained at 69% yield
1H-ΝMR (300 MHz, CDC13); 8.15 - 8.10 (IH, m), 7.90 - 7.88 (IH, m), 7.85 - 7.78 (IH, m), 7.66 - 7.65 (IH, m), 7.51 - 7.41 (5H, m), 7.30 - 7.05 (7H, m), 4.50 - 4.45 (IH, m), 4.28 - 4.25 (2H, m), 3.85 - 3.78 (IH, m), 3.33 (3H, s), 2.98 - 2.89 (6H, m), 1.87 - 1.81 (2H, m), 1.00 (3H, t, J = 7.41) FAB MS (m/e) = 560 [M+H]+
[Example 142]
Preparation of N- { ( 1 S,2i?V 3 -[( 1 ,3 -benzodioxol-4-ylmethvPamino] - 1 -benzyl -2- hydroxypropyl)-3-[methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 115, except for using 2,3-(methylenedioxy)benzaldehyde instead of 3-trifluoromethoxybenzaldehyde, whereby 17 mg of the title compound was obtained at 64% yield 1H-ΝMR (300 MHz, CDC13); 7.69 (IH, s), 7.55 - 7.49 (IH, m), 7.47 - 7.43 (IH, m), 7.40 - 7.20 (6H, m), 6.79 - 6.75 (3H, m), 5.8 9(2H, s), 4.50 - 4.45 (IH, m), 3.89 - 3.76 (2H, m), 3.75 - 3.69 (IH, m), 3.32 (3H, s), 2.98 - 2.89 (6H, m), 1.87 - 1.81 (2H, m), 1.02 (3H, t, J = 7.38) FAB MS (m/e) = 554 [M+H]+
[Example 143]
Preparation of N-[( 1 S2R)- 1 -benzyl -2-hydroxy-3 -( 1 H-pyrazol- 1 -vPpropyl] -3 -
[methyl(propylsulfonvPamino]benzamide 19 mg (0.07 mmol) of the compound obtained in Preparation Example 132 and 0.07 mmol of pyrazol were dissolved in 1 ml of isopropanol, then 0.10 mmol of triethylamine was added thereto, followed by stirring for 12 hours at 70°C. The reaction solution was diluted using ethyl acetate and washed with 1 Ν hydrochloride solution, saturated sodium bicarbonate and sodium chloride solution. After removing solvent by distillation under reduced pressure, the concentrated solution was dissolved in 1 ml of dichloromethane, then 100 ml of trifluoroacetic acid was added thereto. After stirring for 1 hour at room temperature, the reaction solution was concentrated under reduced pressure. The concentrated solution and 16 mg (0.06 mmol) of the compound obtained in Preparation Example 29 were dissolved in 1 ml of Ν,Ν-dimethylformamide and cooled to 0°C, then 11.5 mg (0.06 mmol) of EDC, 8.1 mg (0.06 mmol) of HOBT and 0.06 mmol of triethylamine were added thereto, followed by stirring for 10 hours. The reaction solution was diluted with ethyl acetate and washed with 1 N hydrochloride solution, saturated sodium bicarbonate and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography to obtain 13 mg of the title compound at 40%o yield. IH-NMR (300 MHz, CDC13); 7.76 (IH, s), 7.41 - 7.61 (4H, m), 7.11 - 7.32 (5H, m),
6.67 (IH, d, J= 8.64), 6.23 (IH, m), 4.68 (IH, bs), 4.42 (IH, m), 4.26 (2H, d, J= 5.59),
4.05 (IH, m), 3.31 (3H, s), 2.94 (4H, m), 1.81 (2H, m), 1.12 (3H, t, J= 7.36)
FAB MS (m/e) = 471 [M+H]+
[Example 144]
Preparation of N- [( 1 S2R)- 1 -benzyl-3-(3 -benzyl- 1 H-pyrazol- 1 -vP-2-hydroxypropyl]-3 -
[methvKpropylsulfonyPaminolbenzamide A process was conducted in the same manner as in Example 143, except for using 3-benzylpyrazole instead of pyrazole, whereby 17 mg of the title compound was obtained at 45%> yield.
1Η-ΝMR (300 MHz, CDCI3); 7.78 (IH, s), 7.21 - 7.73 (12H, m), 7.04 (IH, m), 6.64
(IH, m), 6.05 (IH, m), 4.52 (2H, bs), 4.34 (IH, m), 4.21 (2H, m), 3.98 (2H, m), 3.34
(3H, s), 3.01 (4H, m), 1.78 (2H, m), 1.12 (3H, t, J= 7.43) FAB MS (m/e) = 561 [M+H]+
[Example 145]
Preparation of N-[(lS,2i?)-l-benzyl-2-hvdroxy-3-(3-isopropyl-lH-pyrazol-l-vPpropyl]- 3-[methyl(propylsulfonvPamino1benzamide A process was conducted in the same manner as in Example 143, except for using 3-isopropylpyrazole instead of pyrazole, whereby 14 mg of the title compound was obtained at 41% yield.
1H-ΝMR (300 MHz, CDCI3); 7.68 (IH, m), 7.55 (IH, m), 7.39 (2H, m), 7.25 (5H, m), 6.52 (IH, d, J= 8.74), 6.05 (IH, m), 4.92 (IH, bs), 4.43 (IH, m), 4.21 (2H, d, J= 5.27), 4.13 (IH, m), 3.32 (3H, s), 2.93 (5H, m), 1.85 (2H, m), 1.20 (6H, m), 1.05 (3H, t, J =
7.43)
FAB MS (m/e) = 513 [M+H]+
[Example 146]
Preparation of N-(( 1 S2RY 1 -benzyl-2-hydroxy-3 - { 3 -[(E)-2-phenylethenyl] - 1 H-pyrazol- l-yl}propyP-3-[methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 143, except for using 3-styrenepyrazole instead of pyrazole, whereby 18 mg of the title compound was obtained at 44%o yield.
1H-ΝMR (300 MHz, CDC13); 7.65 (IH, m), 7.16 - 7.58 (14H, m), 7.05 (IH, s), 6.48
(IH, d, J= 8.70), 6.41 (IH, m), 4.80 (IH, bs), 4.45 (IH, m), 4.32 (2H, d, J= 5.38), 4.08
(IH, m), 3.28 (3H,s), 2.89 (4H, m), 1.83 (2H, m), 0.95 (3H, m)
FAB MS (m/e) = 573 [M+H]+
[Example 147]
Preparation of N- [(1 S2R)- 1 -benzyl-2-hydroxy-3 -(3 -phenethyl- 1 H-pyrazol- 1 -yPpropyl] -
3-[methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 143, except for using 3-phenethylpyrazol instead of pyrazole, whereby 18 mg of the title compound was obtained at 45%) yield.
1Η-ΝMR (300 MHz, CDC13); 7.80 (IH, m), 7.55 (IH, m), 7.43 (2H, m), 7.12 - 7.33
(9H, m), 7.01 (IH, m), 6.42 (IH, d, J= 8.70), 6.05 (IH, d, J= 2.20), 4.70 (IH, bs), 4.35
(IH, m), 4.16 (IH, d, J= 5.20), 3.93 (2H, m), 3.33 (3H, s), 2.88 (8H, m), 1.82 (2H, m), 1.03 (3H, m)
FAB MS (m/e) = 575 [M+H]+
[Preparation Example 163] Preparation of. tert-butyl (lS,2J?Vl-benzyl-2-hydroxy-3-[(3- methoxybenzvP(methvPaminolpropylcarbamate 0.5 ml (12.53 mmol) of 40% methylamine solution and 100 mg (0.38 mmol) of the compound obtained in Preparation Example 132 were dissolved in 3 ml of isopropanol, then the resulting mixture was stirred for 16 hours at room temperature. After removing solvent by distillation under reduced pressure, the concentrated solution and 41 mg (0.34 mmol) of 3-methoxybenzaldehyde were dissolved in 2 ml of 1,2- dichloroethane. 108 mg (0.51 mmol) of sodium triacethoxyborohydride was added thereto and stirred for 16 hours at room temperature. The resulting mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography to obtain 118 mg of the title compound at 75% yield.
IH-NMR (300 MHz, CDC13); 7.29 - 7.18 (6H, m), 6.87 - 6.78 (3H, m), 5.70 - 5.60 (IH, m), 3.80 (3H, s), 3.79 - 3.74 (IH, m), 3.63 - 3.59 (2H, m), 3.44 - 3.40 (IH, m), 2.95 - 2.85 (2H, m), 2.42 - 2.32 (2H, m), 2.21 (3H, s), 1.34 (9H, s)
[Example 148]
Preparation of N-((lS.2i?)-l-benzyl-2-hvdroxy-3-[(3- methoxybenzvP(methvPamino]propyl}-3-[methyl(propylsulfonvPamino]benzamide 20 mg (0.0482 mmol) of the compound obtained in Preparation Example 163 was dissolved in 1 ml of 4.0 N hydrochloride solution diluted with ethyl acetate, and stirred for 2 hours. After distillation under reduced pressure for concentration, the residue was dissolved in 1 ml of N,N-dimethylformamide and cooled to 0°C, then 13 mg (0.0482 mmol) obtained in Preparation Example 29 and 20 mg (0.0530 mmol) of HATU were added thereto. 0.2 ml (excess amount) of diisopropylamine was further added thereto, then heated to room temperature, followed by stirring for 4 hours. After removing solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, 0.5 N hydrochloride solution, saturated sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography to obtain 20 mg of the title compound at 75% yield.
IH-NMR (300 MHz, CDC13); 7.65 - 7.64 (IH, m), 7.55 - 7.50 (IH, m), 7.40 - 7.39 (2H, m), 7.36 - 7.21 (5H, m), 6.88 - 6.82 (3H, m), 6.56 - 6.50 (IH, m), 4.49 - 4.45 (IH, m), 3.85 - 3.78 (IH, m), 3.79 (3H, s), 3.65 - 3.60 (IH, m), 3.47 - 3,42 (IH, m), 3.32 (3H, s), 2.99 - 2.90 (4H, m), 2.65 - 2.46 (2H, m), 2.26 (3H, s), 1.87 - 1.79 (2H, m), 1.02 (3H, t, J= 7.44) FAB MS (m/e) = 554 [M+H]+
[Preparation Example 164]
Preparation of tert-butyl (!S.2./?)-3-[acetyl(3-methoxybenzvPamino1-l-benzyl-2- hvdroxypropylcarbamate 65 mg (0.249 mmol) of the compound obtained in Preparation Example 132 was dissolved in 2 ml of isopropanol, then 35 ml (0.274 mmol) of 3- methoxybenzylamine was added thereto at room temperature. After reflux for 16 hours, the solvent was removed by distillation under reduced pressure. The concentrated solution was dissolved in 2 ml of dichloromethane and cooled to 0°C. 70 ml (0.498 mmol) of triethylamine and 21 ml (0.274 mmol) of acetic anhydride were added thereto, then stirred for 1 hour. The reaction solution was diluted with ethyl acetate and washed with 0.5 N hydrochloride solution, sodium bicarbonate solution and sodium chloride solution. After removing solvent by distillation under reduced pressure, the product was purified by column chromatography to obtain 90 mg of the title compound at 76% yield. IH-NMR (300 MHz, CDC13); 7.28 - 7.13 (6H, m), 6.82 - 6.65 (3H, m), 4.55 (3H, m), 3.78 (3H, s), 3.71 - 3.62 (2H, m), 3.40 - 3.36 (IH, m), 2.99 - 2.81 (2H, m), 2.16 (3H, s), 1.30 (9H, s) FAB MS (m/e) = 443 [M+H]+
[Example 149] Preparation of. N-{(lS.2i?)-3-[acetyl(3-methoxybenzyPamino]-l-benzyl-2- hvdroxypropyl}-3-[methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 148, except for using the compound obtained in Preparation Example 164 instead of the compound obtained in Preparation Example 163, whereby 20 mg of the title compound was obtained at 75%> yield.
1H-ΝMR (300 MHz, CDC13); 7.78 (IH, s), 7.56 - 7.53 (IH, d, J = 7.44), 7.43 - 7.34 (2H, m), 7.27 - 7.22 (5H, m), 6.81 - 6.64 (4H, m), 4.75 - 4.65 (IH, m), 4.60 - 4.55 (2H, m), 4.40 - 4.30 (IH, m), 3.97 - 3.87 (IH, m), 3.76 (3H, s), 3.45 - 3.44 (IH, m), 3.32 (3H, s), 3.03 - 3.02 (2H, d, J = 5.53), 2.95 - 2.90 (2H, m), 2.14 (3H, s), 1.86 - 1.81 (2H, m), 1.01 (3H, t, J = 7.36). FAB MS (m/e) = 582 [M+H]+
[Preparation Example 165]
Preparation of tert-butyl (lS)-3-methyl-l-[(2S)oxiranyl]butylcarbamate According to the known method (Tetrahedron Letters 36(31), 1999, 5453- 5456), the title compound from t-butoxycarbonyl-(S)-leucine could be synthesized. IH NMR (500 MHz, CDC13); 4.38 (IH, br), 3.52 (IH, br), 2.85 (IH, m), 2.77 (2H, d), 1.75 (IH, m), 1.45 (9H, s), 1.45-1.32 (2H, m), 0.95 (3H, d), 0.92 (3H, d)
[Preparation Example 166]
Preparation of benzyl (2i?,3S)-3-[(tert-butoxycarbonvPamino1-2-hvdroxy-5- methylhexyl(3-methoxybenzvPcarbamate A process was conducted in the same manner as in Preparation Example 133, except for using the compound obtained in Preparation Example 165 instead of the compound obtained in Preparation Example 132, whereby 98 mg of the title compound was obtained at 51% yield.
IH NMR (500 MHz, CDC13); 7.39-7.27 (5H, m), 7.21 (IH, t), 6.80 (IH, dd), 6.76 (IH, d), 6.71 (IH, s), 5.18 (2H, s), 4.56 (2H, dd), 3.97 (IH, br), 3.83-3.58 (5H, m), 3.40 (IH, m), 3.26 (IH, d), 2.63 (IH, m), 1.41 (9H, s), 1.48-1.24 (2H, m), 0.91 (3H, d), 0.88 (3H,
d)
[Preparation Example 167]
Preparation of. benzyl (2i?.3S)-2-hvdroxy-5-methyl-3-( ( 3 - [methyl(propylsulfonvPaminolbenzoyllamino)hexyl(3-methoxybenzvPcarbamate A process was conducted in the same manner as in Preparation Example 134, except for using the compound obtained in Preparation Example 166 instead of the compound obtained in Preparation Example 133, whereby 70 mg of the title compound was obtained at 56% yield.
IH NMR (400 MHz, CDC13); 7.85 (IH, s), 7.63 (2H, dd), 7.45 (IH, t), 7.38-7.23 (5H, m), 7.20 (IH, t), 6.84-6.65 (4H, m), 5.18 (2H, dd), 4.54 (2H, dd), 4.28 (IH, m), 3.93 (IH, br), 3.71 (3H, s), 3.50-3.30 (5H, m), 2.97 (2H,dd), 1.92-1.78 (2H, m), 1.68-1.48 (2H, m), 1.32 (IH, m), 1.02 (3H, t), 0.91 (6H, d)
[Example 150]
Preparation of N-(( 1 S)- 1 - { ( 1 i?)- 1 -hydroxy-2- [(3 -methoxybenzvDamino] ethyl } -3 - methylbutvD-3-[methyl(propylsulfonyDamino]benzamide A process was conducted in the same manner as in Example 88, except for using the compound obtained in Preparation Example 167 instead of the compound obtained in Preparation Example 134, whereby 51 mg of the title compound was obtained at 92% yield.
IH ΝMR (400 MHz, CDCI3); 7.85 (IH, t), 7.58 (2H, dd), 7.39 (IH, t), 7.26 (IH, m),
7.08 (IH, d), 6.94-6.88 (2H, m), 6.83 (IH, dd), 4.30 (IH, m), 3.92-3.71 (6H, m), 3.37 (3H, s), 3.02-2.88 (3H, m), 2.80 (IH, dd), 1.92-1.80 (2H, m), 1.67 (IH, m), 1.57-1.40
(2H, m), 1.03 (3H, t), 0.95 (6H, d)
ESI MS (m/e) = 506 [M+H]+
[Preparation Example 168] Preparation of tgrt-butyl ( 1 S - 1 -l(2i?)oxiranyll -2-phenylethylcarbamate According to the known method (Tetrahedron 55(49), 1999, 14145-14160), the title compound from tert-butyl (lS,2S)-l-benzyl-2,3-dihydroxypropylcarbamate could be synthesized. IH NMR (400 MHz, CDC13); 7.35-7.16 (5H, m), 4.47 (IH, br), 4.12 (IH, dd), 3.05-2.82 (3H, m), 2.69 (IH, t), 2.59 (IH, br), 1.39 (9H, s)
[Preparation Example 169]
Preparation of benzyl (2S,3S)-3-[(tert-butoxycarbonyDamino]-2-hydroxy-4- phenylbutyl(3-methoxybenzyDcarbarnate A process was conducted in the same manner as in Preparation Example 133, except for using the compound obtained in Preparation Example 168 instead of the compound obtained in Preparation Example 132, whereby 611 mg of the title compound was obtained at 94% yield. IH NMR (400 MHz, CDC13); 7.40-7.13 (1 IH, m), 6.83-6.56 (3H, m), 5.16 (2H, s), 4.93
(lH,br), 4.43 (2H, dd), 4.01 (IH, br), 3.70-3.55 (5H, m), 3.06 (IH, d), 2.92-2.72 (2H, m), 1.37 (9H, s)
[Preparation Example 170] Preparation of benzyl (2S,3S)-2-hydroxy-3-({3-
[methyl(propylsulfonvDamino]benzoyl}amino)-4-phenylbutyl(3- methoxybenzyPcarbamate A process was conducted in the same manner as in Preparation Example 134, except for using the compound obtained in Preparation Example 169 instead of the compound obtained in Preparation Example 133, whereby 117 mg of the title compound was obtained at 87% yield.
IH NMR (400 MHz, CDC13); 7.73 (IH, s), 7.59 (IH, d), 7.53 (IH, d), 7.41 (IH, t), 7.36-7.18 (10H, m), 7.14 (IH, t), 6.80-6.59 (4H, m), 5.16 (2H, s), 4.43 (2H, s), 4.16 (IH, dd), 3.81 (IH, m), 3.69 (3H, s), 3.62 (IH, m), 3.35 (3H, s), 3.14 (IH, d), 3.07-2.87 (4H, m), 1.90-1.78 (2H, m), 1.02 (3H, t)
[Example 151]
Preparation of N- { (1 S2S)- 1 -benzyl-2-hydroxy-3 -[(3 -methoxybenzypamino]propyl } -3 - [methyl(propylsulfonvDamino]benzamide A process was conducted in the same manner as in Example 88, except for using the compound obtained in Preparation Example 170 instead of the compound obtained in Preparation Example 134, whereby 73 mg of the title compound was obtained at 86% yield. IH ΝMR (400 MHz, CDC13); 7.76 (IH, t), 7.58 (IH, m), 7.51 (IH, d), 7.41 (IH, t),
7.33-7.17 (6H, m), 6.84-6.76 (3H, m), 6.71 (IH, d), 4.27 (IH, m), 3.81-3.63 (6H, m),
3.36 (3H, s), 3.11-2.91 (4H, m), 2.73 (IH, dd), 2.58 (IH, dd), 1.91-0.78 (2H, m), 1.03
(3H, t)
ESI MS (m/e) = 540 [M+H]+
[Example 152]
Preparation of N-{(lS)-l-[(5S)-3-(3-methoxybenzvP-l,3-oxazolidin-5-yl]-2- phenylethyl } -3 - [methyKpropylsulfony Pamino] benzamide A process was conducted in the same manner as in Example 89, except for using the compound obtained in Example 151 instead of the compound obtained in Example 88, whereby 14 mg of the title compound was obtained at 82%» yield. IH NMR (400 MHz, CDC13); 7.84 (IH, t), 7.63-7.57 (2H, m), 7.45 (IH, t), 7.35-7.18 (5H, m), 7.14 (IH, t), 6.94 (IH, d), 6.82-6.73 (3H, m), 4.53 (IH, d), 4.29 (IH, m), 4.19 (IH, d), 4.16 (IH, m), 3.72 (3H, s), 3.62 (2H, dd), 3.37 (3H, s), 3.14 (IH, dd), 3.01-2.90 (3H, m), 2.80 (2H, d), 1.90-1.78 (2H, m), 1.02 (3H, t) ESI MS (m/e) = 552 [M+H]+
[Preparation Example 171] Preparation of tert-butyl ( 1 S2S)- 1 -benzyl-2-hydroxy-3 - [(3 - methoxybenzvP(methvPamino]propylcarbamate A process was conducted in the same manner as in Preparation Example 163, except for using the compound obtained in Preparation Example 168 instead of the compound obtained in Preparation Example 132, whereby 110 mg of the title compound was obtained at 70% yield.
IH-NMR (300 MHz, CDC13); 7.35 - 7.18 (6H, m), 6.85 - 6.78 (3H, m), 5.00 - 4.90 (IH, m), 3.85 - 3.78 (3H, s), 3.78 - 3.58 (3H, m), 3.45 - 3.38 (IH, m), 2.98 - 2.85 (2H, m), 2.65 - 2.46 (IH, m), 2.21 - 2.15 (IH, m), 2.18 (3H, s), 1.43 (9H, s)
[Example 153]
Preparation of N- { ( 1 S2S)- 1 -benzyl -2-hydroxy-3 - [(3- methoxybenzvP(methvPamino]propyl}-3-[methyl(propylsulfonvPamino]benzamide A process was conducted in the same manner as in Example 148, except for using the compound obtained in Preparation Example 171 instead of the compound obtained in Preparation Example 163, whereby 16 mg of the title compound was obtained at 70% yield.
IH-NMR (300 MHz, CDC13); 7.75 (IH, s), 7.57 - 7.56 (IH, m), 7.38 (IH, t, J = 7.89), 7.30 - 7.26 (5H, m), 7.18 - 7.13 (IH, m), 6.81 - 6.73 (3H, m), 6.60 - 6.55 (IH, m), 4.30 - 4.10 (IH, m), 3.85 - 3.78 (IH, m), 3.74 (3H, s), 3.64 - 3.60 (IH, d, J = 12.96), 3.37 - 3.33 (IH, m), 3.35 (3H, s), 3.04 - 2.92 (4H, m), 2.52 (IH, m), 2.25 - 2.21 (IH, m), 2.22 (3H, s), 1.87 - 1.81 (2H, m), 1.02 (3H, t, J = 7.45) FAB MS (m/e) = 554 [M+H]+
[Experimental Example 1]
Determination of bioactivity of beta-secretase inhibitor.
(1) Construction of expression vector for recombinant beta-secretase cDNA of BACE gene was cloned from Human placental cDNA library (Clonetech) by PCR using primers synthesized based on human BACE gene sequence (accession^ AF190725) disclosed in the public Genebank data base. Only ectodomain which corresponds to the region of 1st - 460th amino acid sequence excluding transmembrane domain and cytoplasmic domain in the above whole BACE gene was re-cloned, then the base sequence of Fc region which corresponds to 230 amino acids (1st - 460th amino acid sequece) of human Immunoglobulin G (hlgG) was linked to the 3' end thereof. The above BACE (ectodomain)-IgG Fc (hereinafter, referred to as "BACE-Fc") was ligated between BamHI and EcoR I sites of pCDNA3 (Invitrogen) as a mammalian expression vector to construct BACE-Fc protein expression vector (hereinafter, referred to as "pCDNA3 BACE Fc"). (2) Preparation of mammalian cell line for expression of BACE-Fc fusion protein HEK (human embryonic kidney) 293T cells (ATCC Accession CRL1573) were cultured in DMEM (Dulbecco's minimum essential medium) (GIBCO-BRL) supplemented with 10% fetal bovine serum (FBS) (GIBCO-BRL), then moved to 6- well culture plate. When the cells reached confluence, they were transfected with pCDNA3 BACE Fc using Lipofectamine Plus (Life Technologies). Selection was carried out using media containing 1 mg/ml of Geneticin(G418 sulfate) (GIBCO-BRL), replaced every 4 days, then 60 clones were isolated and cultured again in 6-well culture plates. Among these isolated clones, 13 clones showing acceptable growth rates were subcultured in 24-well culture plates for 3 days at equal cell density (2 x 105 cells/ml/24-well). The amount of BACE-Fc protein secreted to the media was quantified by ELISA method using Goat anti-human IgG (Pierce). As a result, clone #8-3 showing the highest growth rate and expression of BACE-Fc (20 mg / IL culture) was selected.
(3) Production and purification of BACE-Fc fusion protein HEK 293T BACE-Fc #8-3 cell lines were inoculated into a roller bottle containing 250 ml of DMEM media supplemented with 10% FBS to a density of 2 x 105 cells/ml, and cultured in a Roll-In cell incubator (Bellco) at 37°C for 4 days at 40 rpm. When cells reached confluence, they were washed once with 250 ml of serum-free medium (SFII; GIBCO-BRL), then a serum-free media containing 500 ml of insulin (0.5 μg/ml) (SIGMA) was added and they were again cultured for 3 days. After the culture media was harvested, 500 ml of serum free media was again added thereto and then they were cultured for 3 days, which was repeated two times. All conditioned media harvested was centrifuged at 7000 rpm for 20 minutes (Beckman, JA 10 rotor) to isolate only washing solution. The washing solution was filtered by a 0.45 μm filter, then the resulting solution was passed through a Protein A Sepharose Chromatography Column (Pharmacia) equilibrated with 20 mM sodium phosphate buffer (pH 7.0), and washed with 20 mM sodium phosphate buffer (pH 7.0), thereby removing all non- adsorbed proteins. 100 mM sodium acetate buffer (pH 3.5) was added to elute the adsorbed proteins, thereby the BACE-Fc protein (M.W 100 kDa) of over 90% purity was obtained. The BACE-Fc fusion protein thus prepared is in the fully glycosylated form, different from protein obtained by refolding after expression in E.coli. It has been reported that such protein exhibits the identical characteristics in view of the substrate specificity to BACE protein purified and isolated from in vivo (Citron et al., Neuron 14: 661-670 (1999)).
(4) Determination of beta-secretase activity using fluorescence-labeled specific substrate To determine the enzyme activity of beta-secretase and inhibition efficiency of synthesized compounds, a Fluorescence Resonance Energy Transfer (FRET) enzyme activity assay using the purified BACE-Fc fusion protein and fluorescence-labeled beta secretase specific substrate was used. This method is briefly illustrated in the following. From the amino acid sequence of Amyloid Precursor Protein (APP), known as the beta secretase-specific substrate in cells, a peptide corresponding to a 10-amino acid region including beta-secretase cleavage site was synthesized, and included EDANS as a fluorophore and DABCYL as a quenching group linked thereto. When this fluorescence-labeled substrate was reacted with BACE-Fc, the BACE functional region is cut and the quenching group is detached, and EDANS emits fluorescence at 510 nm upon excitation with 350 nm light, whereby the level of fluorescence is measured to accurately and conveniently determine the extent of the cleavage reaction. Each synthesized compound is dissolved in DMSA at a concentration of 10 mM and then held at 20°C. For determination of degree of activity, 100 μM of DMSO solution is first added to the right row of a 96 well plate, then doubling dilutions are carried out through nine steps with the same volume of DMSO. 5 μl of the diluted compound solution is added into 96-well assay plate, containing 600 μM of fluorescence-labeled BACE substrate dissolved in 15 μl of reaction buffer (100 mM sodium acetate, pH 5.0, 0.05% CHAPS) and 10 μl of 50% DMSO, so that the final concentration of DMSO is adjusted to 10%, and the inhibitor is carried through nine doubling dilutions from 5 μM. 70 μl of the purified BACE-Fc fusion protein solution is added to a final concentration of 0.2 μM, and reacted at room temperature for 1 hour. The amount of reaction product is measured by fluorescence using 350 nm excitation light and 510 nm emission light using a fluorescent plate reader (SpectraMax Gemini XS, Molecular Device). The concentration of synthesized compound inhibiting beta-secretase activity up to 50%, i.e., IC50 and Ki axe determined by comparing the measurement value with that of a control group with no synthesized compounds added thereto. From the experimental result, it was ascertained that IC50 value of the sulfone amide derivatives of Formula 1 according to the present invention has activity in the range of 0.1 - 50 μM, and the Ki value is in the range of 0.01 - 50 μM.
[Experimental Example 2]
Determination of beta-secretase activity in cells. The inhibition degree of beta-secretase activity in cells by the synthesized compound can be determined by using human cell lines producing beta-amyloid peptide from amyloid precursor protein (APP).
(1) Construction of eternal cell lines producing beta-secretase and amyloid precursor The whole BACE gene was cloned to pcDNA3.1(+)Zeo (Invitrogen) which is a mammalian expression vector, and the Swedish mutant type (APPswe KK) amyloid precursor (APPswe) gene in which two lysines are added to the C-terminal was cloned to pcDNA3.1(+)Neo (Invitrogen). HEK (human embryonic kidney) 293T cells (ATCC Accession# CRL1573) were cultured in DMEM (Dulbecco's minimum essential medium) (GIBCO-BRL) media supplemented with 10% FBS, and then transferred to 6- well culture plates. When the cells reached confluence, they were transfected with pcDNA3.1(+)Zeo BACE and pcDNA3 (+)Neo APPswe KK expression vector using Lipofectamine 2000 (Life Technologies). Selection was carried out using media containing 1 mg/ml of Geneticin (G418 sulfate) (GIBCO-BRL) changed every four days, and each clone was isolated, then cultured again on 6-well culture plates. Among the selected clones, 76 clones showing acceptable growth rates were cultured on 24-well culture plates with the number of cells (2 x 105 cells/ml/24-well) being adjusted for 2 days, then the cells were added with OPTI-MEM (GIBCO-BRL) media supplemented with 10% of fetal bovine serum (FBS) (GIBCO-BRL) and cultured for 48 hours to quantify the amount of beta-amyloid peptide secreted to media, using an ELISA method using antibody specific to beta-amyloid peptide. As a result, clone #28, showing the highest growth rate and expression of beta-amyloid peptide was selected. (2) Determination of ELISA method for beta-amyloid peptide HEK BACE APPswe KK #28 cell, which is an eternal cell line expressing the BACE and Swedish mutant amyloid precursor with two lysines added at the C-terminal, was added to a 24-well culture plate at a concentration of 1 x 105 cells per well and cultured in an incubator under 6% CO2 at 37°C for 48 hours. When the cells reached confluence, Opti-MEM (GIBCO-BRL) media supplemented with 300 μl of 10% FBS was added, and the cells were again cultured for 48 hours. The expression level of beta- amyloid peptide secreted to the media was measured by a sandwich ELISA method using two types of antibodies specific to beta-amyloid peptide, which is briefly illustrated in below. First, monoclonal antibody 4G8 (Signet) specifically reacting with beta- amyloid peptide amino acids 17 - 24 was diluted with PBS to a concentration of 10 μg/ml, and added to each well of Maxisorp 96 well immuno plates (NUNC) at 100 μl, then left for more than 2 hours at room temperature (or overnight at 4°C) to coat the surface of wells. The plate was treated with 200 μl of Superblock (PIERCE) at room temperature for 1 hour to prevent the non-specific absorption, then beta-amyloid peptide
1 - 40 diluted in 100 μl of the cell culture media adjusted to 1 x RIP A was added thereto and reacted at room temperature for 2 hours. After washing 5 times with washing solution (PBS, 0.05% Tween 20), 100 μl of anti-Ab 1-40 or anti-Ab 1-42 (Biosource International), which is a polymerizing clonal antibody 500-times diluted with 1 x Superblock (PIERCE), was added thereto and reacted at room temperature for 2 hours. After washing 5 times with washing solution, 100 μl of goat anti-rabbit IgG antibody conjugated with HRP (horse radish peroxidase) (Amersham) which was 2,000-times diluted with Superblock (PIERCE) was added thereto and reacted at room temperature for 1 hour. After washing 5 times with washing solution, 100 μl of O-phenylenediamine dihydrochloride (SIGMA) dissolved in 100 mM sodium citrate (pH 4.5) was added thereto and reacted at room temperature for 30 minutes, then the optical density (absorbance) was measured at 450 nm using a microplate reader (SpectraMax 340, Molecular Device). The concentration of synthesized compound inhibiting 50% of beta- secretase activity, i.e., IC50 was determined by comparing the measured value thereof with that of control group treated only with 0.5% DMSO with no synthesized compounds added thereto. From the results, it was ascertained that the IC50 value of sulfone amide derivatives of Formula 1 according to the present invention is in the range of 0.5 - 50 μM.
[Experimental Example 3] Pharmacokinetic test in mouse. The drugs used in the present test are N-{(lS,2i?)-l-benzyl-2-hydroxy-3-[(3- methoxybenzyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide (hereinafter, referred to as "Compound 1") as the compound obtained in Example 88 and N-{(1S)-1- [(5i?)-3 -(3 -methoxybenzyl)- 1 ,3 -oxazolidin-5-yl] -2-phenylethyl } -3 - [methyl(propylsulfonyl)amino]benzamide (hereinafter, referred to as "Compound 2") as the compound obtained in Example 89. In addition, as a compound for comparison test, Ν ' - { 1 -benzyl-2-hydroxy-3- [(3 -methoxybenzyl)amino]propyl } -Ν3,Ν3- dipropylisophthalamide (hereinafter, referred to as "Compound 3") from PCT international application WO 02/098849 by Elan Pharmaceutical was used. Mice (250 - 300 g, KR, BIOGENOMICS) which were fasted for 18 hours prior to drug administration were administered with 20 mg/kg of the drug dissolved in PEG400 using a hard palate. About 200 μl of blood was collected from the tail vein of each mouse before drug administration (control) and 30, 60, 120, 240 and 360 minutes after drug administration, respectively, using a heparin treated syringe. The collected blood was centrifuged to isolate plasma, and after proteinization, it was again centrifuged to obtain supernatant, followed by analysis using HPLC. A calibration curve was constructed in the range of 0.10 - 5.0 g/ml of drug concentration. The drug was analyzed by Shiseido Capcell-Pak C18 reverse phase column. The HPLC consisted of Class-LCI 0 AD system control software, CBM-10A communication bus module, two LC-10AD pumps, SIL- 10AXL autoinjector with sample cooler, SPD-10AV ultraviolet detector (Shimadzu, Tokyo, Japan) and GLP-2050+ laser printer (LG Electronics, Seoul, Korea). The Compound 3 was analyzed by ultra-violet light at 210 nm, and the flow rate was 1 ml per minute. The mobile phase was 36% acetonitrile and 64% of 0.1% trifluoroacetic acid solution, respectively. Retention time of the drug was approximately 11 minutes. The Compound 1 and Compound 2 were analyzed at 228 nm using an ultraviolet lamp, and the flow rate was 1 ml per minute. The mobile phase was 35%) acetonitrile and 65% of 0.1% trifluoroacetic acid solution, respectively. Retention time of the drug was approximately 8 minutes. Data is presented as the concentration of drug in plasma according to time (FIG. 1), and the pharmacokinetic parameter was calculated by applying it to non-compartment model using Win-Nonlin program (Scientific Consultion Company, USA). When the maximum concentration of the drug in plasma after drug administration (Cmax), the time at the maximum concentration (Tmax), the area under the plasma concentration vs. time curve assumed to tend to infinity (AUCjnf), and the area under the plasma concentration vs. time curve from drug administration to 6 hours (AUC0-6hr) were calculated, Compounds 1 and 2 showed higher values than the Compound 3 in all of Cmax, AUCjnf and AUC0-6hr, whereby it was confirmed that oral absorption in mice was accomplished successfully. [Table 1] (Pharmacokinetic parameter values after oral administration of the Compound 1, Compound 2 and Compound 3 to mice)
Figure imgf000223_0001
CONCLUSIONS As described in Examples and Experimental Examples, the drug of the present invention is structurally specific to and highly active versus beta-secretase, and can also be used as a drug for oral administration, in view of pharmacokinetics. One skilled in the art to which the present invention pertains having a conventional knowledge would be able to contrive various applications and modifications within the scope of the invention, on the basis of the description provided herein.

Claims

WHAT IS CLAIMED IS:
1. A sulfone amide derivative as represented by Formula I below.
Figure imgf000224_0001
wherein, (I) A which is a substituent of the benzene ring is hydrogen, halogen, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted ester, substituted or unsubstituted amide, substituted or unsubstituted amine, substituted or unsubstituted alkoxy group; (II) Ri is a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl (-SAC-Ar) substituted with aromatic, or hydrogen; (III) R2 is a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl (-SAC-Ar) substituted with aromatic, or hydrogen, and Ri and R2 may form a ring structure as a simple alkyl group; (IV) R3 is a -SAC, alkyl substituted with double bond including allyl, -SCAC, -
Ar, -SAC-Ar or hydrogen, and includes side chain residues of all native amino acids, and where the adjacent position becomes a stereo center depending upon the kind of R3, both kinds of stereo isomers are included in the range of R3 definition, and where R3 is of carboxylie acid or base being side chain residues of amino acids, it also includes the case that a protective group such as simple ester group is bonded thereto and the case that it is in the form of pharmaceutically acceptable salts; (V) X is one of substituents of Formula 2 or Formula 4 below;
Figure imgf000225_0001
wherein, n is 0 or 1. R4 is each independently -SAC, alkyl substituted with double bond including allyl, -SCAC, -Ar, -SAC-Ar or hydrogen, and includes side chain residues of all native amino acids, and where the adjacent position becomes a stereo center depending upon the kind of R4, both kinds of stereo isomers are included in the range of R4 definition, and where R4 is of carboxylie acid or base being side chain residues of amino acids, it also includes the case that a protective group such as simple ester group is bonded thereto and the case that it is in the form of pharmaceutically acceptable salts, and it also includes - (CH2)nOR (R = -SAC, -SCAC, -Ar, -SAC-Ar: n = 1, 2) or -(CH2)nOC(=O)R (R = -SAC, -SCAC, -Ar, -SAC-Ar: n=l, 2); R5 is a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar), or hydrogen; RQ is a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar), or hydrogen, and includes a substituent as represented by
Formula 5 or 6 below;
Figure imgf000226_0001
wherein, R is each independently a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar), or hydrogen, and includes side chain residue of all native amino acids, and where the adjacent position becomes a stereo center depending upon the kind of R7, both kinds of stereo isomers are included in the range of Rγ definition, and where R is of carboxylie acid or base being side chain residues of amino acids, it also includes the case that a protective group such as simple ester group is bonded thereto and the case that it is in the form of pharmaceutically acceptable salts; Rs and R9 are each independently simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar), alkyl substituted with aromatic substituted with carboxylie acid, or hydrogen; Rio is each independently a simple alkyl group (-SAC), alkyl substituted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), alkyl substituted with aromatic (-SAC-Ar), or hydrogen; Rn is each independently a simple alkyl group (-SAC), alkyl substimted with double bond including allyl, cycloalkyl (-SCAC), aromatic (-Ar), aromatic substituted with alkyl or alkoxy, heteroaromatic substituted with alkyl or alkoxy, or heterocycloalkyl substituted with alkoxy.
2. The sulfone amide derivative according to claim 1, wherein Ri is an alkyl group substimted with aromatic, R2 is a simple alkyl, R5 is a simple alkyl, and Rio is a simple alkyl group.
3. The sulfone amide derivative according to claim 1, wherein said derivative is a compound as represented by Formula 7 below.
Figure imgf000227_0001
wherein, n, A, Ri, R2, R3, R4, R5 and RQ are the same as defined in Formula 1.
4. The sulfone amide derivative according to claim 1 , wherein said derivative is a compound as represented by Formula 8 below.
Figure imgf000227_0002
wherein, n, A, Ri, R2, R3, R4, Rio and Rπ are the same as defined in Formula 1.
5. The sulfone amide derivative according to claim 1, wherein said derivative is a compound as represented by Formula 9 below.
Figure imgf000228_0001
wherein, n, A, Ri, R2, R3, Rio and Rπ are the same as defined in Formula 1.
6. The sulfone amide derivative according to claim 1, wherein said derivative is selected from compounds below. (1) 4-[({(2S)-2-[((2i-,4S,5S)-5-{[3-(l,l-dioxo-116-isothiazolidin-2- yl)benzoyl]amino}-4-hydroxy-2,7- dimethyloctanoyl)amino]propanoyl}amino)methyl]benzoic acid
(2) N-((lS,2S,4i?)-5-{[(lS)-2-(benzylamino)-l-methyl-2-oxoethyl]amino}-2- hydroxy- 1 -isobutyl -4-methyl-5-oxopentyl)- 1 -methyl-2,2,4-trioxo- 1 ,2,3 ,4-tetrahydro- 2λ6,l-benzothiazine-7-carboxamide.
(3) 4-{ [((2S)-2- { [(2i?,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3- [(propylsulfonyl)amino] benzoyl } amino)octanoyl] amino } propanoyl)amino]methyl } benz oic acid
(4) 4-{[((2S)-2-{[(2i?,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3- [(pheny lsulfonyl)amino] benzoyl } amino)octanoyl] amino } propanoy l)amino]methyl } benz oic acid.
(5) 4-{[((2S)-2-{[(2i?,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3-[(2- thienylsulfonyl)amino]benzoyl}amino)octanoyl]amino}propanoyl)amino]methyl}benzo ic acid
(6) 4-{[((2S)-2-{[(2i?,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3-
[methyl(propylsulfonyl)amino]benzoyl}amino)octanoyl]amino}propanoyl)amino]meth yl} benzoic acid (7) 4-{[((2S)-2-{[(2i?,4S,5S)-5-({3-[ethyl(propylsulfonyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}propanoyl)amino]methyl}benzoic acid
(8) 4-{[((2S)-2-{[(2i?,4S,5S)-4-hydroxy-2,7-dimethyl-5-({3-
[propyl(propylsulfonyl)amino] benzoyl } amino)octanoyl] amino } propanoy l)amino] methy
1} benzoic acid. (9) 4-{[((2S)-2-{[(2i?,4S,5S)-5-({3-[benzyl(propylsulfonyl)amino]benzoyl}amino)-
4-hydroxy-2,7-dimethyloctanoyl]amino}propanoyl)amino]methyl}benzoic acid
(10) 4-{[((2S)-2-{[(2i?,4S,5S)-5-({3-[(ethylsulfonyl)(methyl)amino]benzoyl}amino)- 4-hydroxy-2,7-dimethyloctanoyl]amino}propanoyl)amino]methyl}benzoic acid
(11) 4-{[((25)-2-{[(2i?,4S,5S)-5-({3- [(butylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7- dimethyloctanoyl] amino } propanoy l)amino]methyl } benzoic acid
(12) 4-{[((2S)-2-{[(2i?,4S,5S)-5-({3-
[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7- dimethyloctanoyl] amino } propanoyl)amino] methyl } benzoic acid (13) 4-[({(2S)-2-[((2i?,4S,5S)-4-hydroxy-2,7-dimethyl-5-{[3-(methyl{[2-(l- naphthyl)ethyl] sulfonyl } amino)benzoyl] amino } octanoyl)amino]propanoyl } amino)meth yl]benzoic acid
(14) N-((lS,2S,4J?)-5-{[(lS)-2-(benzylamino)-l-methyl-2-oxoethyl]amino}-2- hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl)-3-[methyl(2- thienylsulfonyl)amino]benzamide
(15) N-((lS,2S,4i?)-5-{[(lS)-2-(benzylamino)-l-methyl-2-oxoethyl]amino}-2-hydroxy- 1 -isobutyl-4-methyl-5 -oxopentyl)-3 - [methyl(phenylsulfonyl)amino]benzamide
(16) N-((lS,2S,4i?)-5-{[(lS)-2-(benzylamino)-l-methyl-2-oxoethyl]amino}-2-hydroxy- l-isobutyl-4-methyl-5-oxopentyl)-3-[methyl(l-naphthylsulfonyl)amino]benzamide
( 17) N-(( 1 S,2S,4i?)-5 - { [( 1 S)-2-(benzylamino)- 1 -methyl-2-oxoethyl] amino} -2-hydroxy- l-isobutyl-4-methyl-5-oxopentyl)-3-[methyl(2-naphthylsulfonyl)amino]benzamide
(18) N-(( 1 S,2S,4i?)-5- { [( 1 S)-2-(benzylamino)- 1 -methyl-2-oxoethyl] amino } -2-hydroxy- l-isobutyl-4-methyl-5-oxopentyl)-3-[{[5-(dimethylamino)-l- naphthyl] sulfonyl } (methy l)amino] benzamide
(19) 3 - [ { [2-(acetylamino)-4-methyl- 1 ,3 -thiazol-5-yl] sulfonyl} (methyl)amino]-N- (( lS,2S,4i?)-5- { [(1 S)-2-(benzylamino)- 1 -methyl-2-oxoethyl]amino} -2-hydroxy- 1 - isobutyl-4-methyl-5-oxopentyl)benzamide
(20) N-((lS,2S,4i?)-5-{[(lS)-2-(benzylamino)-l-methyl-2-oxoethyl]amino}-2- hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl)-3-
[(benzylsulfonyl)(methyl)amino]benzamide
(21) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonyl)(methyl)amino]benzamide (22) N-[(lS,2S,4S)-4-({[(lS)-2-(benzylamino)-l-methyl-2- oxoethyl]amino}carbonyl)-2-hydroxy- 1 -isobutyl-5-methylhexyl]-3-
[(benzylsulfonyl)(methyl)amino]benzamide
(23) N-{(lS,2S,4S)-4-[({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl}amino)carbonyl]-2-hydroxy-l-isobutyl-5-methylhexyl}-3- [(benzylsulfonyl)(methyl)amino]benzamide (24) N-[(lS,2S,4i?)-4-({[(lS)-2-(benzylamino)-l-methyl-2- oxoethyl]amino}carbonyl)-2-hydroxy-l-isobutyl-6-heptenyl]-3- [(benzylsulfonyl)(methyl)amino]benzamide (25) N-{(lS,2S,4i-)-4-[({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl}amino)carbonyl]-2-hydroxy-l-isobutyl-6-heptenyl}-3- [(benzylsulfonyl)(methyl)amino]benzamide
(26) 4-({[(2S)-2-({(2i?)-2-[(2S,3S)-3-({3- [(benzylsulfonyl)(methyl)amino]benzoyl}amino)-2-hydroxy-5-methylhexyl]-4- pentenoyl } amino)propanoyl] amino } methy l)benzoic acid.
(27) 4-({ [(2S)-2-({(2i?)-2-[(2S,3S)-3-({3-
[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-2-hydroxy-5-methylhexyl]-4- pentenoyl } amino)propanoyl] amino } methy l)benzoic acid.
28) 4-{[((2S)-2-{[(2 ?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}-3-methylbutanoyl)amino]methyl}benzoic acid
(29) 4-{[((2S)-2-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)- 4-hydroxy-7-methyl-2-propyloctanoyl]amino}propanoyl)amino]methyl}benzoic acid
(30) N-{(lS,2S,4i-)-4-[({(lS)-l-[(benzylamino)carbonyl]-2- methy Ipropyl } amino)carbonyl] -2-hydroxy- 1 -isobuty lheptyl } -3 - [(benzylsulfonyl)(methyl)amino]benzamide
(31) 4-{[((2S)-2-{[(2i?>4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)- 4-hydroxy-7-methyl-2-propyloctanoyl]amino } -3 - methylbutanoyl)amino]methyl}benzoic acid
(32) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[methyl(2- thienylsulfonyl)amino] benzamide
(33) N-(( 1 S,2S,4i?)-5 - { [( 1 S)-2-(benzylamino)- 1 -methyl-2-oxoethyl] amino } -2-hydroxy- l-isobutyl-4-methyl-5-oxopentyl)-3-[methyl(propylsulfonyl)amino]benzamide (34) N-[( 1 S,2S,4R)-5 -( {(IS)-1 -[(benzylamino)carbonyl] -2-methylpropyl} amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[methyl(propylsulfonyl)amino]benzamide (35) N-[(lS,2S,4Λ)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylproρyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-5-[(benzylsulfonyl)(methyl)amino]-2- chlorobenzamide (36) N-[( 1 S,2S,4i?)-5-( { ( 1 S)- 1 - [(benzylamino)carbonyl] -2-methylpropyl } amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5- (trifluoromethyl)benzamide
(37) N-[( 1 S,2S,4R)-5-( {( S)-1- [(benzylamino)carbonyl] -2-methylpropyl } amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5- bromobenzamide
(38) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5- nitrobenzamide
(39) 3-amino-N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl}amino)-2-hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-5-
[(benzylsulfonyl)(methyl)amino]benzamide
(40) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5- cyanobenzamide (41) N- [( 1 S,2S,4R)- 5 -( { ( 1 S)- 1 - [(benzylamino)carbonyl] -2-methylpropyl } amino)-2- hydroxy- 1 -isobuty l-4-methyl-5 -oxopentyl] -3 - [(benzylsulfonyl)(methyl)amino] -5 - methylbenzamide
(42) N- [( 1 S,2S,4J?)-5 -( { ( 1 S)- 1 - [(benzylamino)carbonyl] -2-methylpropyl } amino)-2- hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-5- chlorobenzamide
(43) N-[(lS,2S,4i-)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy- 1 -isobutyl -4-methyl-5-oxopentyl]-5- [(benzylsulfonyl)(methyl)amino]isophthalamide (44) methyl 3-({[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl } amino)-2-hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl] amino } carbonyl)-5 - [(benzylsulfonyl)(methyl)amino]benzoate
(45) benzyl 3-({[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl}amino)-2-hydroxy-l-isobutyl-4-methyl-5-oxopentyl]amino}carbonyl)-5- [(benzylsulfonyl)(methyl)amino]benzoate
(46) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-4- methoxybenzamide
(47) N-[(lS,2S,4Λ)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-4- fluorobenzamide
(48) N-[(lS,2S,4Λ)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]-4- chlorobenzamide (49) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-5-[(benzylsulfonyl)(methyl)amino]-2- methoxybenzamide
(50) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-{methyl[(2- nitrobenzyl)sulfonyl]amino}benzamide
(51) 3-[[(2-aminobenzyl)sulfonyl](methyl)amino]-N-[(lS,2S,4i?)-5-({(lS)-l- [(benzylamino)carbonyl]-2-methylpropyl}amino)-2-hydroxy-l-isobutyl-4-methyl-5- oxopentyl] benzamide (52) N-[(lS,2S,4^)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylρroρyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-{methyl[(2- methylbenzyl)sulfonyl]amino}benzamide
(53) N-[(lS,2S,4Λ)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-{methyl[(3- methylbenzyPsulfonyl] amino } benzamide
(54) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3-{methyl[(4- methylbenzyl)sulfonyl]amino}benzamide
(55) N-{(lS,2S,4i-)-4-[({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl } amino)carbonyl] -2-hydroxy- 1 -isobutyl-6-heptynyl} -3 - [(benzylsulfonyl)(methyl)amino]benzamide
(56) N-{(lS,2S,4Z)-4-[({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl} amino)carbonyl]-2 -hydroxy- 1 -isobutyl-4-hexenyl} -3- [(benzylsulfonyl)(methyl)amino]benzamide (57) N-{(1S,2S,4Λ or 4S)-4-[({(lS)-l-[(benzylamino)carbonyl]-2- methy Ipropyl } amino)carbonyl] -2-hydroxy- 1 -isobuty lhexyl } -3 - [(benzylsulfonyl)(methyl)amino]benzamide
(58) N-{(lS,2S,4i? or 4S)-4-[({(lS)-l-[(benzylamino)carbonyl]-2- methylpropyl}amino)carbonyl]-2-hydroxy-l-isobutylhexyl}-3-
[(benzylsulfonyl)(methyl)amino]benzamide
(59) methyl (2S)-2-{[(2i?,4S,5S)-5-({3- [(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7- dimethyloctanoyl]amino}-3-methylbutanoate. (60) (2S)-2-{ [(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}-3-methylbutanoic acid
(61 ) N-(( 1 S,2S,4i?)-5- { [( 1 S 1 -(aminocarbonyl)-2-methylproρyl] amino } -2-hydroxy- l-isobutyl-4-methyl-5-oxopentyl)-3[(benzylsulfonyl)(methyl)amino]benzamide
(62) (2S)-2-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4- hydroxy-2 ,7-dimethyloctanoy 1] amino } butanoic acid
(63) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]propyl}amino)-2-hydroxy-l- isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide
(64) (2S,3i?)-2-{[(2i?,4S,5S)-5-({3- [(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7- dimethyloctanoyl]amino}-3-methylpentanoic acid
(65) N-[(lS,2S,4i?)-5-({(lS,2i?)-l-[(benzylamino)carbonyl]-2-methylbutyl}amino)- 2-hydroxy- 1 -isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonyl)(methyl)amino]benzamide
(66) methyl (2S)-2-{[(2i?,4S,5S)-5-({3- [(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7- dimethyloctanoyl] amino } -3 ,3 -dimethylbutanoate
(67) (2S)-2-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}-3,3-dimethylbutanoic acid (68) N-[(lS,2S,4i?)-5-({(lS)-l-[(benzylamino)carbonyl]-2,2- dimethylpropyl}amino)-2-hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonyl)(methyl)amino]benzamide
(69) N-[(lS,2S,4i-)-5-({(lS)-l-[(benzylamino)carbonyl]-2,2- dimethylpropyl}amino)-2-hydroxy-l-isobutyl-4-methyl-5-oxopentyl]-3- [(benzylsulfonyl)(methyl)amino]benzamide
(70) N- [( 1 S,2S,4R)-5 -( { 1 - [(benzylamino)carbonyl] cyclopentyl } amino)-2-hydroxy- 1 - isobutyl-4-methyl-5-oxopentyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide
(71) (2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4-hydroxy-2,7- dimethyloctanoic acid (72) 3-[(benzylsulfonyl)(methyl)amino]-N-((lS,2S,4i?)-2-hydroxy-l-isobutyl-4- methyl-5-oxo-5-{[(3i? or 3S)-2-oxopiperidinyl]amino}pentyl)benzamide
(73) 3 - [(benzylsulfonyl)(methyl)amino]-N-(( 1 S,2S,4i?)-2-hydroxy- 1 -isobutyl-4- methyl-5-oxo-5-{[(3i? or 3S)-2-oxopiperidinyl] amino }pentyl)benzamide
(74) methyl 4-({[(2#,4S,5S)-5-({3- [(benzylsulfonyl)(methyl)amino]benzoyl} amino)-4-hydroxy-2,7- dimethyloctanoyl] amino } methy l)cyclohexanecarboxylate
(75) 4-({[(27?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}methyl)cyclohexanecarboxylic acid
(76) methyl 4-{[(2i-,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)- 4-hydroxy-2,7-dimethyloctanoyl]amino}cyclohexanecarboxylate
(77) 4- { [(2R,4S,5S)-5-( { 3 -[(benzylsulfonyl)(methyl)amino]benzoyl } amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}cyclohexanecarboxylic acid
(78) methyl 3-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)- 4-hydroxy-2,7-dimethyloctanoyl]amino}cyclohexanecarboxylate
(79) 3-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}cyclohexanecarboxylic acid
(80) methyl 5-{ [(2/?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)- 4-hydroxy-2,7-dimethyloctanoyl]amino}pentanoate (81) 5-{[(2i?,4S,5S)-5-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-4- hydroxy-2,7-dimethyloctanoyl]amino}pentanoic acid
(82) ethyl 3-((lS)-l-{[(2i?,4S,5S)-5-({3-
[(benzylsulfonyl)(methyl)amino]benzoyl } amino)-4-hydroxy-2,7- dimethyloctanoyl]amino}-2-methylpropyl)-4,5-dihydro-5-isoxazolecarboxylate (83) 3-[(benzylsulfonyl)(methyl)amino]-N-((lS,2S,4i-)-5-{[(lS)-l-cyano-2- methy Ipropyl] amino} -2-hydroxy- 1 -isobutyl -4-methyl-5-oxopentyl)benzamide (84) methyl (2S)-2-{[(3S,4S)-4-({3-
[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-3-hydroxy-6- methylheptanoyl]amino}-3-methylbutanoate (85) (2S)-2-{ [(3S,4S)-4-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)-3- hydroxy-6-methylheptanoyl]amino}-3-methylbutanoic acid
(86) N-[(lS,2S)-4-({(lS)-l-[(benzylamino)carbonyl]-2-methylpropyl}amino)-2- hydroxy-l-isobutyl-4-oxobutyl]-3-[(benzylsulfonyl)(methyl)amino]benzamide
(87) 4-{[((2S)-2-{[(3S,4S)-4-({3-[(benzylsulfonyl)(methyl)amino]benzoyl}amino)- 3-hydroxy-6-methylheptanoyl]amino}-3-methylbutanoyl)amino]methyl}benzoic acid
(88) N- { ( 1 S,2i?)- 1 -benzyl-2-hydroxy-3 -[(3-methoxybenzyl)amino]propyl } -3 - [methyl(propylsulfonyl)amino]benzamide
(89) N-{(15)-l-[(5i?)-3-(3-methoxybenzyl)-l,3-oxazolidin-5-yl]-2-phenylethyl}-3- [methyl(propylsulfonyl)amino]benzamide
(90) N- { ( 1 S,2R)- 1 -benzyl-2-hydroxy-3 -[(3-methylbenzyl)amino]propyl } -3 - [methyl(propylsulfonyl)amino]benzamide
(91) N-{(lS)-l-[(5i?)-3-(3-methylbenzyl)-l,3-oxazolidin-5-yl]-2-phenylethyl}-3- [methyl(propylsulfonyl)amino]benzamide (92) N- { ( 1 S,2R)- 1 -benzyl-2-hydroxy-3 -[(2-pyridinylmethyl)amino]propyl } -3 - [methyl(propylsulfonyl)amino]benzamide
(93) N- { ( 1 S,2R)- 1 -benzyl-3 - [(3-ethylbenzyl)amino] -2-hydroxypropyl } -3- [methyl(propylsulfonyl)amino]benzamide
(94) N-{(lS)-l-[(5i?)-3-(3-ethylbenzyl)-l,3-oxazolidin-5-yl]-2-phenylethyl}-3- [methyl(propylsulfonyl)amino] benzamide
(95) N-[( 1 S,2R)- 1 -benzyl-3 -(benzylamino)-2-hydroxypropyl] -3 - [methyl(propylsulfonyl)amino]benzamide
(96) N-{(lS)-l-[(5i?)-3-benzyl-l,3-oxazolidin-5-yl]-2-phenylethyl}-3- [methyl(propylsulfonyl)amino]benzamide (97) N-((lS,2i?)-l-benzyl-2-hydroxy-3-{[(li?)-l-phenylproρyl]amino}proρyl)-3- [methyl(propylsulfonyl)amino]benzamide
(98) 3-[methyl(propylsulfonyl)amino]-N-((lS)-2-phenyl-l-{(5i?)-3-[(li?)-l- phenylpropyl] - 1 ,3 -oxazolidin-5-yl } ethyl)benzamide
(99) N-((lS,2i-)-l-benzyl-2-hydroxy-3-{[(lS)-l-phenylpropyl]amino}propyl)-3- [methyl(propylsulfonyl)amino]benzamide
(100) 3-[methyl(propylsulfonyl)amino]-N-((lS)-2-phenyl-l-{(5Λ)-3-[(lS)-l- phenylpropyl] - 1 ,3 -oxazolidin-5-yl } ethyl)benzamide
(101) N-((lS,2i?)-l-benzyl-2-hydroxy-3-{[(li?)-l-(3- methoxyphenyl)ethyl] amino } propyl)-3 - [methyl(propylsulfonyl)amino]benzamide
(102) N-((lS)-l-{(57?)-3-[(li?)-l-(3-methoxyphenyl)ethyl]-l,3-oxazolidin-5-yl}-2- phenylethyl)-3 - [methyl(propylsulfonyl)amino]benzamide
(103) N-((lS,2Λ)-l-benzyl-2-hydroxy-3-{[(lS)-l-(3- methoxyphenyl)ethyl]amino}propyl)-3-[methyl(propylsulfonyl)amino]benzamide (104) N-((lS)-l-{(5i?)-3-[(lS)-l-(3-methoxyphenyl)ethyl]-l,3-oxazolidin-5-yl}-2- phenylethyl)-3-[methyl(propylsulfonyl)amino]benzamide
(105) N- {( 1 S,2R)- 1 -benzyl-2-hydroxy-3 -[(3 -methoxybenzyl)amino]propyl } -3 - [(benzylsulfonyl)(methyl)amino]benzamide
(106) 3-[(benzylsulfonyl)(methyl)amino]-N-{(lS)-l-[(5i?)-3-(3-methoxybenzyl)-l,3- oxazolidin-5-yl]-2-phenylethyl}benzamide
(107) 3-[(butylsulfonyl)(methyl)amino]-N-{(lS)-l-[(5i-)-3-(3-methoxybenzyl)-l,3- oxazolidin-5 -yl] -2-phenylethyl } benzamide
(108) 3-[(ethylsulfonyl)(methyl)amino]-N-{(lS)-l-[(57?)-3-(3-methoxybenzyl)-l,3- oxazolidin-5 -yl] -2-phenylethyl } benzamide (109) N-{(lS)-l-[(5i-)-3-(3-methoxybenzyl)-l,3-oxazolidin-5-yl]-2-phenylethyl}-3- [methyl(methylsulfonyl)amino]benzamide
(110) N- { ( 1 S,2R)- 1 -benzyl-2-hydroxy-3 - [(3 -methoxybenzoyl)amino]propy 1 } -3 - [(benzylsulfonyl)(methyl)amino]benzamide
(111) N-{(lS,2i?)-l-benzyl-2-hydroxy-3-[(phenylsulfonyl)amino]propyl}-3- [(benzylsulfonyl)(methyl)amino]benzamide
(112) N-(( 1 S,2R)- 1 -benzyl-2-hydroxy-3 - { [2-(trifluoromethyl)benzyl] amino } propyl)-3 - [(benzylsulfonyl)(methyl)amino]benzamide
(113) N-((lS,2i?)-l-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl)-3- [(benzylsulfonyl)(methyl)amino]benzamide
(114) N- { ( 1 S,2i?)- 1 -benzyl-3 - [(3 -bromobenzyl)amino] -2-hydroxypropyl } -3 - [(benzylsulfonyl)(methyl)amino]benzamide
(115) N-((lS,2i?)-l-benzyl-2-hydroxy-3-{[3- (trifluoromethoxy)benzyl]amino}propyl)-3-[methyl(propylsulfonyl)amino]benzamide (116) N-{(lS,2i?)-l-benzyl-2-hydroxy-3-[(3-phenoxybenzyl)amino]propyl}-3- [methyl(propylsulfonyl)amino]benzamide
(117) N- { ( 1 S,2i?)- 1 -benzyl-2-hydroxy-3-[(3 -hydroxybenzyl)amino]propyl } -3 - [methyl(propylsulfonyl)amino]benzamide
(118) N- { ( 1 S,2R)- 1 -benzyl-2-hydroxy-3- [(4-methoxybenzyl)amino]propyl } -3- [methyl(propylsulfonyl)amino]benzamide
(119) N-{(lS,2i?)-l-benzyl-2-hydroxy-3-[(2-methoxybenzyl)amino]propyl}-3- [methyl(propylsulfonyl)amino]benzamide
(120) N- { ( 1 S,2R)- 1 -benzyl-3 - [(3 -ethoxybenzyl)amino] -2-hydroxypropyl } -3 - [methyl(propylsulfonyl)amino]benzamide (121) N-(( 1 S,2i?)-3 - { [3 -(allyloxy)benzyl]amino } - 1 -benzyl-2-hydroxypropyl)-3- [methyl(propylsulfonyl)amino]benzamide
(122) N-(( 1 S,2R)- 1 -benzyl-3 - { [3 -(benzyloxy)benzyl] amino } -2-hydroxypropyl)-3 - [methyl(propylsulfonyl)amino]benzamide
(123) 3-({[(2i?,3S)-2-hydroxy-3-({3-[methyl(propylsulfonyl)amino]benzoyl}amino)- 4-phenylbutyl] amino } methy l)phenyl benzoate
( 124) N-((IS,2R)- 1 -benzyl-3- { [3-(dimethylamino)benzyl]amino} -2-hydroxypropyl)- 3-[methyl(propylsulfonyl)amino]benzamide
(125) N-[( 1 S,2R)- 1 -benzyl-2-hydroxy-3-(phenethylamino)propyl] -3 - [methyl(propylsulfonyl)amino] benzamide
(126) N-((lS,2i?)-l-benzyl-3-{[(5-ethyl-2-furyl)methyl]amino}-2-hydroxypropyl)-3- [methyl(propylsulfonyl)amino]benzamide
(127) N-((lS,2/?)-l-benzyl-3-{[(5-ethyl-2-thienyl)methyl]amino}-2-hydroxypropyl)- 3-[methyl(propylsulfonyl)amino]benzamide (128) N-[(lS,2i?)-l-benzyl-2-hydroxy-3-({[5-(hydroxymethyl)-2- furyl]methyl } amino)propyl] -3 - [methyl(propylsulfonyl)amino]benzamide
(129) N-(( 1 S,2R)- 1 -benzyl-3 - { [(5-bromo-2-thienyl)methyl] amino } -2-hydroxypropyl)- 3-[methyl(propylsulfonyl)amino]benzamide
(130) N- { ( 1 S,2R)- 1 -benzyl-3 - [(3 -chlorobenzyl)amino] -2-hydroxypropyl } -3 - [methyl(propylsulfonyl)amino] benzamide
(131) N- { ( 1 S,2i?)- 1 -benzyl-3 - [(3 -bromobenzyl)amino] -2-hydroxypropyl } -3 - [methyl(propylsulfonyl)amino]benzamide
(132) N-{(lS,2i?)-l-benzyl-2-hydroxy-3-[(3-iodobenzyl)amino]propyl}-3- [methyl(propylsulfonyl)amino]benzamide (133) N-(( 1 S,2R)- 1 -benzyl-2-hydroxy-3 - { [3-(trifluoromethyl)benzyl] amino } propyl)- 3-[methyl(propylsulfonyl)amino]benzamide
(134) N-{(lS,2i?)-l-benzyl-2-hydroxy-3-[(3-methylbenzyl)amino]propyl}-3- [methyl(propylsulfonyl)amino]benzamide
(135) N-{(lS,2Λ)-3-[(l,3-benzodioxol-5-ylmethyl)amino]-l-benzyl-2- hydroxypropyl}-3-[methyl(propylsulfonyl)amino]benzamide
(136) N-{(lS,2i?)-l-benzyl-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxypropyl}-3- [methyl(propylsulfonyl)amino]benzamide
(137) N-{(lS,2i?)-l-benzyl-2-hydroxy-3-[(2-hydroxy-3- methoxybenzyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide
(138) N- { ( 1 S,2R)- 1 -benzyl-3 - [(2,3 -dimethoxybenzyl)amino] -2-hydroxypropyl } -3 - [methyl(propylsulfonyl)amino]benzamide
(139) N-{(lS,2i?)-l-benzyl-2-hydroxy-3-[(2-hydroxy-5- methoxybenzyl)amino]propyl}-3-[methyl(propylsulfonyl)amino]benzamide (140) N- { ( 1 S,2R)- 1 -benzyl-3 - [(2,5 -dimethoxybenzy l)amino] -2-hydroxypropyl } -3 - [methyl(propylsulfonyl)amino]benzamide
(141) N- { ( 1 S,2R)- 1 -benzyl-2-hydroxy-3 -[( 1 -naphthylmethyl)amino]propyl} -3 - [methyl(propylsulfonyl)amino]benzamide
( 142) N- {( 1 S,2i?)-3 - [( 1 ,3-benzodioxol-4-ylmethyl)amino]- 1 -benzyl-2- hydroxypropyl } -3 - [methyl(propylsulfonyl)amino] benzamide
(143) N-[(lS,2i?)-l-benzyl-2-hydroxy-3-(lH-pyrazol-l-yl)propyl]-3- [methyl(propylsulfonyl)amino]benzamide
(144) N-[(lS,2Λ)-l-benzyl-3-(3-benzyl-lH-pyrazol-l-yl)-2-hydroxypropyl]-3- [methyl(propylsulfonyl)amino]benzamide (145) N-[( 1 S,2 ? 1 -benzyl-2-hydroxy-3-(3 -isopropyl- 1 H-pyrazol- 1 -yPpropyl] -3 - [methyl(propylsulfonyl)amino]benzamide
(146) N-((lS,2i?)-l-benzyl-2-hydroxy-3-{3-[(E)-2-phenylethenyl]-lH-pyrazol-l- yl } propyl)-3 - [methyl(propylsulfonyl)amino] benzamide
(147) N-[(lS,2i?)-l-benzyl-2-hydroxy-3-(3-phenethyl-lH-pyrazol-l-yl)propyl]-3- [methyl(propylsulfonyl)amino]benzamide
(148) N-{(lS,2J?)-l-benzyl-2-hydroxy-3-[(3-methoxybenzyl)(methyl)amino]propyl}- 3 - [methyl(propylsulfonyl)amino] benzamide
(149) N-{(1 S,2i?)-3 - [acetyl (3 -methoxybenzyl)amino] - 1 -benzyl-2-hydroxypropyl } -3 - [methyl(propylsulfonyl)amino]benzamide
(150) N-((lS)-l-{(li?)-l-hydroxy-2-[(3-methoxybenzyl)amino]ethyl}-3-methylbutyl)- 3-[methyl(propylsulfonyl)amino]benzamide
(151) N-{(1 S,2S)- 1 -benzyl-2-hydroxy-3 - [(3 -methoxybenzyl)amino]propyl } -3 - [methyl(propylsulfonyl)amino]benzamide (152) N-{(lS)-l-[(5S)-3-(3-methoxybenzyl)-l,3-oxazolidin-5-yl]-2-phenylethyl}-3- [methyl(propylsulfonyl)amino]benzamide
(153) N-{(1 S,2S)- 1 -benzyl-2-hydroxy-3 - [(3 -methoxybenzyl)(methyl)amino]propyl } - 3-[methyl(propylsulfonyl)amino]benzamide
7. A process for preparation of the sulfone amide derivative according to claim 1.
8. The process according to claim 7, wherein the sulfone amide derivative
(derivative of Formula 7) in which X in Formula 1 is the substituent of Formula 2 is prepared by the procedure comprising: (i) a step of obtaining a lactone compound (1) using an amino group- protected (BocΝH-) amino acid; (ii) a step of reacting the compound (1) with lithium bis(trimethylsilyl)amide and iodomethane in anhydrous tetrahydrofurane solution to obtain an alkyl-substituted lactone (2); (iii) a step of treating the lactone (2) with lithium hydroxide solution and then reacting with imidazole and t-butyldimethylsilylchloride to obtain O-protected carboxylie acid compound (3); (iv) a step of coupling the compound (3) with amine to obtain a compound (4); (v) a step of removing the protective group of the compound (4) and coupling with a sulfoneamide-substituted benzoic acid to obtain a compound (5); and (vi) a step of removing O-protective group of the compound (5) to obtain a compound (6) (the derivative of Formula 7).
Figure imgf000244_0001
5
Figure imgf000244_0002
6 (Formula 7)
9. The process according to claim 8, wherein among said sulfoneamide- substituted benzoic acids, the sulfoneamide-substituted benzoic acid for preparation of cyclized sulfoneamide derivative is prepared by the procedure comprising: (vii) a step of reacting ethyl-3-aminobenzoate (7) with 3- chloropropanesulfonyl chloride to obtain 3-{bis[(3- chloropropyl)sulfonyl] amino } benzoate (8) (viii) a step of reacting the compound (8) with sodium hydroxide solution under the solvent N,N-dimethylformamide to obtain a cyclic compound (9); and (ix) a step of reacting the compound (9) with sodium hydroxide solution in a mixture of tetrahydrofurane and methanol solvent to obtain a cyclic compound (10).
Figure imgf000245_0001
Figure imgf000245_0002
9 10
10. The process according to claim 8, wherein among said sulfoneamide- substituted benzoic acids, the sulfoneamide-substituted benzoic acid for preparation of non-cyclized sulfoneamide derivative is prepared by the procedure comprising: (vii) a step of obtaining ethylalkylsulfonylaminobenzoate using a compound (7) and alkylsulfonylchloride; and (viii) a step of hydrolyzing ethyl alkylsulfonylaminobenzoate in lithium hydroxide solution to obtain a sulfoneamide-substituted benzoic acid.
11. The process according to claim 7, wherein the sulfone amide derivative (the derivative of Formula 8 or 9) in which X in Formula 1 is the substituent of Formula 3 or 4 is prepared by the procedure comprising: (i) a step of obtaining an epoxide compound (11) using amino group- protected (BocNH-) amino acid; (ii) a step of reacting the compound (11) with the corresponding amine in isopropanol solution to obtain a compound (12); (iii) a step of removing the protective group from compound (12) and then coupling with the corresponding alkyl sulfonylamino benzoic acid to obtain a compound (14) (the derivative of compound 8); and (iv) a step of reacting the compound (14) with formaline in tetrahydrofurane solution to obtain a compound (15) (the derivative of compound 9) in which some substituents (between -OH and =N-Rt) of the compound (14) are cyclized.
Figure imgf000246_0001
1
Figure imgf000246_0002
13 14 (Formula 8)
Figure imgf000246_0003
15 (Formula 9)
12. A pharmaceutical composition for inhibiting BACE comprising a physiologically acceptable carrier and a therapeutically effective amount of sulfone amide derivatives of Formula 1 according to claim 1.
13. The composition according to claim 12, wherein said composition is formulated as a drug for oral administration, parenteral administration or intradermal administration.
14. A method for treatment or prevention diseases caused by production of beta- amyloid, inhibiting the activity of BACE (or beta-secretase) by using the sulfone amide derivative of compound 1 according to claim 1 as an active agent.
15. The method according to claim 14, wherein the disease caused by production of said beta-amyloid is Alzheimer's disease.
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