WO2005030709A1 - Nouveaux derives sulfonamide capables d'inhiber bace - Google Patents

Nouveaux derives sulfonamide capables d'inhiber bace Download PDF

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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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Prior art keywords
amino
methyl
hydroxy
benzamide
benzylsulfonyl
Prior art date
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PCT/KR2004/002523
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English (en)
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/fr

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    • 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
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    • 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
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    • 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
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    • 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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    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
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    • 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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    • C07C311/38—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

L'invention concerne de nouveaux dérivés sulfonamide représentés par la formule générale (I) définie dans le descriptif, inhibant l'activité de BACE (ou bêta-sécrétase). Lesdits dérivés sulfonamide servent au traitement et à la prévention, par inhibition de l'activité de BACE, de la maladie d'Alzheimer et de maladies associées dues à la production de bêta-amyloïde,
PCT/KR2004/002523 2003-10-01 2004-10-01 Nouveaux derives sulfonamide capables d'inhiber bace WO2005030709A1 (fr)

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006508166A (ja) * 2002-11-27 2006-03-09 イーラン ファーマスーティカルズ、インコーポレイテッド 置換尿素及びカルバメート
WO2006086923A1 (fr) * 2005-02-18 2006-08-24 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences 4-hydroxypentanamides, leur synthèse et leurs applications
WO2009111278A2 (fr) * 2008-02-29 2009-09-11 Array Biopharma Inc. Composés inhibiteurs de kinases raf et procédés d'utilisation
WO2009111280A1 (fr) 2008-02-29 2009-09-11 Array Biopharma Inc. Dérivés de n-(6-aminopyridin-3-yl)-3-(sulfonamido) benzamide comme inhibiteurs de b-raf pour le traitement du cancer
WO2009131906A1 (fr) * 2008-04-23 2009-10-29 Merck & Co., Inc. Cyclobutylsulfones en tant qu'inhibiteurs de gamma-secrétase épargnant notch
WO2010023448A1 (fr) * 2008-08-29 2010-03-04 Xention Limited Nouveaux bloquants du canal potassique
WO2010139967A1 (fr) 2009-06-04 2010-12-09 Xention Limited Derives de dihydroindole et de tetrahydroisoquinoline utiles en tant qu'inhibiteurs des canaux potassiques
WO2010139953A1 (fr) 2009-06-04 2010-12-09 Xention Limited Composés
US8258138B2 (en) 2008-08-29 2012-09-04 Xention Limited Potassium channel blockers
US8299267B2 (en) 2007-09-24 2012-10-30 Comentis, Inc. (3-hydroxy-4-amino-butan-2-yl) -3- (2-thiazol-2-yl-pyrrolidine-1-carbonyl) benzamide derivatives and related compounds as beta-secretase inhibitors for treating
US8372840B2 (en) 2008-08-29 2013-02-12 Xention Limited Potassium channel blockers
CN103508957A (zh) * 2012-06-25 2014-01-15 中国科学院上海药物研究所 羟乙基吡唑类化合物或氨乙基吡唑类化合物及其制备方法和用途
US8859628B2 (en) 2003-02-27 2014-10-14 JoAnne McLaurin Method for preventing, treating and diagnosing disorders of protein aggregation
US9096593B2 (en) 2009-11-06 2015-08-04 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor

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JP2006508166A (ja) * 2002-11-27 2006-03-09 イーラン ファーマスーティカルズ、インコーポレイテッド 置換尿素及びカルバメート
US8859628B2 (en) 2003-02-27 2014-10-14 JoAnne McLaurin Method for preventing, treating and diagnosing disorders of protein aggregation
US9833420B2 (en) 2003-02-27 2017-12-05 JoAnne McLaurin Methods of preventing, treating, and diagnosing disorders of protein aggregation
WO2006086923A1 (fr) * 2005-02-18 2006-08-24 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences 4-hydroxypentanamides, leur synthèse et leurs applications
US9169250B2 (en) 2006-11-22 2015-10-27 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US9487515B2 (en) 2006-11-22 2016-11-08 Plexxikon Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
US8299267B2 (en) 2007-09-24 2012-10-30 Comentis, Inc. (3-hydroxy-4-amino-butan-2-yl) -3- (2-thiazol-2-yl-pyrrolidine-1-carbonyl) benzamide derivatives and related compounds as beta-secretase inhibitors for treating
US8338452B2 (en) 2008-02-29 2012-12-25 Array Biopharma Inc. Raf inhibitor compounds and methods of use thereof
WO2009111278A2 (fr) * 2008-02-29 2009-09-11 Array Biopharma Inc. Composés inhibiteurs de kinases raf et procédés d'utilisation
WO2009111280A1 (fr) 2008-02-29 2009-09-11 Array Biopharma Inc. Dérivés de n-(6-aminopyridin-3-yl)-3-(sulfonamido) benzamide comme inhibiteurs de b-raf pour le traitement du cancer
WO2009111278A3 (fr) * 2008-02-29 2010-07-15 Array Biopharma Inc. Composés inhibiteurs de kinases raf et procédés d'utilisation
WO2009131906A1 (fr) * 2008-04-23 2009-10-29 Merck & Co., Inc. Cyclobutylsulfones en tant qu'inhibiteurs de gamma-secrétase épargnant notch
US8759579B2 (en) 2008-04-23 2014-06-24 Merck Sharp & Dohme Corp. Cyclobutyl sulfones as notch sparing gamma secretase inhibitors
JP2014210787A (ja) * 2008-04-23 2014-11-13 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． ノッチスペアリングガンマセクレターゼ阻害剤としてのシクロブチルスルホン
US8372840B2 (en) 2008-08-29 2013-02-12 Xention Limited Potassium channel blockers
US8258138B2 (en) 2008-08-29 2012-09-04 Xention Limited Potassium channel blockers
WO2010023448A1 (fr) * 2008-08-29 2010-03-04 Xention Limited Nouveaux bloquants du canal potassique
US9073834B2 (en) 2008-08-29 2015-07-07 Xention Limited Potassium channel blockers
US8673901B2 (en) 2008-08-29 2014-03-18 Xention Limited Potassium channel blockers
US9447089B2 (en) 2009-04-03 2016-09-20 Plexxikon Inc. Compositions and uses thereof
US9663517B2 (en) 2009-04-03 2017-05-30 Plexxikon Inc. Compositions and uses thereof
US8426442B2 (en) 2009-06-04 2013-04-23 Xention Ltd Compounds
US8399481B2 (en) 2009-06-04 2013-03-19 Xention Ltd Compounds
WO2010139953A1 (fr) 2009-06-04 2010-12-09 Xention Limited Composés
WO2010139967A1 (fr) 2009-06-04 2010-12-09 Xention Limited Derives de dihydroindole et de tetrahydroisoquinoline utiles en tant qu'inhibiteurs des canaux potassiques
US9096593B2 (en) 2009-11-06 2015-08-04 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9624213B2 (en) 2011-02-07 2017-04-18 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US11337976B2 (en) 2011-02-07 2022-05-24 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
US9695169B2 (en) 2012-05-31 2017-07-04 Plexxikon Inc. Synthesis of heterocyclic compounds
CN103508957A (zh) * 2012-06-25 2014-01-15 中国科学院上海药物研究所 羟乙基吡唑类化合物或氨乙基吡唑类化合物及其制备方法和用途
CN103508957B (zh) * 2012-06-25 2017-02-08 中国科学院上海药物研究所 羟乙基吡唑类化合物或氨乙基吡唑类化合物及其制备方法和用途

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