Compounds to treat Alzheimer's disease

• US 7,030,239 B2
• Filed: 05/18/2004
• Issued: 04/18/2006
• Est. Priority Date: 03/23/2000
• Status: Expired due to Fees

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: Tung, Jay, John, Varghese, Gailunas, Andrea, Fang, Lawrence Y., Hom, Roy, Mamo, Shumeye S.
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Tucker, Zachary C.
• Application Number:
  US10/847,819
• Publication Number:
  US 20040214846A1
• Time in Patent Office: 700 Days
• Field of Search: 544/244, 544/235, 544/237, 544/335, 544/336, 544/353, 546/146, 546/174, 546/334, 548/180, 548/204, 548/205, 548/214, 548/236, 548/247, 548/335.5, 548/375.1, 548/494, 548/561, 549/58, 549/74, 549/76, 549/469, 549/492, 549/494
• US Class Current: 544/224
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 237/22 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07C 271/14 to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 271/18 to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07D 261/20 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07D 307/14 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/33 in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 307/52 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07K 5/0207 containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link

Abstract

The present invention is directed toward substituted hydroxyethylene compounds of formula (XII)
useful in treating Alzheimer'"'"'s disease and other similar diseases.

Claims

1. A compound of the formula:

where R₁ is

—

CH₂phenyl, where phenyl is substituted with two —

F in the 3- and 5-positions giving 3,5-difluorophenyl, or

—

CH₂)_n1—

(R₁-heteroaryl), where n1 is 0, 1, 2, or 3, and R_1-heteroaryl is

(B) pyrimidinyl,

(C) quinolinyl,

(D) indenyl,

(E) indanyl,

(F) benzothiophenyl,

(H) inclolinyl,

(I) pyridazinyl,

(J) pyrazinyl,

(K) isoindolyl,

(L) isoguinolyl,

(N) quinazolinyl,

(N) quinoxalinyl,

(O) phthalazinyl,

(P) imidazolyl,

(Q) isoxazolyl,

(R) pyrazolyl,

(S) oxazolyl,

(U) indolizinyl,

(V) indazolyl,

(W) benzothiazolyl,

(X) benzimidazolyl,

(Y) benzofuranyl,

(BB) pyrrolyl,

(CC) oxadiazolyl,

(DD) thiadiazolyl,

(EE) triazolyl,

(FF) tetrazolyl,

(GG) 1,4-benzodioxan

(HH) purinyl,

(II) oxazolopyridinyl,

(JJ) imidazopyridinyl,

(KK) isothiazolyl,

(LL) naphthyridinyl,

(MM) cinnolinyl,

(NN) carbazolyl,

(OO) β

-carbolinyl,

(PP) isochromanyl,

(QQ) chromanyl,

(RR) furazanyl,

(SS) tetrahydroisoquinoline,

(TT) isoindolinyl,

(UU) isobenzotetrahydrofuranyl,

(VV) isobenzotetrahydrothienyl,

(WW) isobenzothiophenyl,

(XX) benzoxazolyl, or

(YY) pyridopyridinyl; and

PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobornyloxycarbonyl, -phenyl-C(═

N)—

H, or 1-piperidyloxycarbonyl.

2. A compound according to claim 1 where R₁ is —

CH₂-phenyl, where phenyl is substituted with two —

F in the 3- and 5-positions giving 3,5-difluorophenyl.

3. A compound according to claim 1 where PROTECTING GROUP is t-butoxycarbonyl.

4. A compound according to claim 1 where PROTECTING GROUP is benzyloxycarbonyl.

5. A compound according to claim 1 which is:

(L)-[2-(3,5-Difluorophenyl)-1-(methoxymethylcarbamoyl)ethyl]-carbamic acid tert-butyl ester,

(L)-[1-(3,5-Difluorobenzyl)-2-oxoethyl]-carbamic acid tert-butyl ester,

(L)-[1-(3,5-Difluorobenzyl)allyl]-carbamic acid tert-butyl ester,

(L)-[2-(3,5-Difluorophenyl)-1-(methoxymethylcarbamoyl)ethyl]-carbamic acid benzyl ester,

(L)-[1-(3,5-Difluorobenzyl)-2-oxoethyl]-carbamic acid benzyl ester, or

(L)-[1-(3,5-Difluorobenzyl)allyl]-carbamic acid benzyl ester.