Compounds to treat Alzheimer's disease

Details Compounds to treat Alzheimer's disease Compounds to treat Alzheimer's disease

2001-03-23

2004-05-18

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S058200, C544S059000, C544S106000, C544S358000, C544S359000, C546S192000, C548S400000, C548S561000, C549S074000, C549S426000, C549S491000, C549S497000, C564S153000, C564S156000, C564S167000, C514S218000, C514S231200, C514S451000, C514S461000, C514S471000, C514S618000, C514S619000, C514S227500, C514S315000, C514S317000, C514S330000, C514S331000, C540S492000

Reexamination Certificate

active

06737420

ABSTRACT:

FIELD OF THE INVENTION
The present invention is compounds useful in treating Alzheimer's disease and other similar diseases.
BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) is a progressive degenerative disease of the brain primarily associated with aging which results in loss of memory and orientation. As the disease progresses, motor, sensory and linguistic abilities are also affected until there is global impairment of multiple cognitive functions. These cognitive losses occur gradually, but typically lead to severe impairment and eventual death in the range of four to twelve years.
Alzheimer's disease is characterized by two major pathologic observations in the brain: neurofibrillary tangles and amyloid (or neuritic) plaques, particularly in those regions involved with memory and cognition (see, Selkoe D J, “Translating cell biology into therapeutic advances in Alzheimer's disease,” Nature ( ENGLAND ) Jun. 24, 1999, 399 (6738 Suppl) pA23-31). Smaller numbers of these lesions in a more restricted anatomical distribution are found in the brains of most aged humans who do not have clinical AD. Amyloid plaque and neurofibrillary tangles are comprised predominantly of an aggregate of a peptide fragment known as beta-amyloid peptide (A&bgr;).
Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
Neurofibrillary tangles are characterized as networks of microtubules and microfilaments which were once structural supports running symmetrically through the nerve cells transporting nutrients, but have degenerated into dysfunctional tangled masses. They can be described histologically as non-membrane bound bundles containing paired, helically wound filaments (PHF) that are approximately 10 nm in length and located in the perinuclear cytoplasm of certain neurons. Major components of paired helical filaments are highly phosphorylated tau proteins (PHF-tau) of 60 kDa, 64 kDa and 68 kDa. Tau belongs to the family of microtubule-associated proteins and plays a role in the microtubule assembly and stabilization. In certain other neurodegenerative disorders, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Pick's disease, hyperphosphorylated tau proteins also accumulate in brain tissue in association with abnormal filaments. Recent research indicates that the pattern of hyperphosphorylation and the resulting ultrastructure of the helical filaments are somewhat different in each type of disease.
At present there are no effective treatments for halting, preventing or reversing the progression of Alzheimer's disease; only treatments that palliate symptoms are thus far available. Therefore, there is an urgent need for pharmaceutical agents capable of slowing the progression of Alzheimer's disease and/or preventing it in the first place.
Of General Interest
United States Patents
1. U.S. Pat. No. 5,733,882
2. U.S. Pat. No. 4,880,781
3. U.S. Pat. No. 5,663,200
4. U.S. Pat. No. 5,807,891
5. U.S. Pat. No. 5,935,976
6. U.S. Pat. No. 4,668,770
7. U.S. Pat. No. 6,013,658
8. U.S. Pat. No. 5,162,538
International Patents and Patent Applications
1. WO 93/02057
2. WO 93/17003
3. EP 0320205
4. WO 87/02986
5. WO 89/01488
6. WO 92/17490
7. WO 89/00161
8. GB 2203740
9. EP 0337714
10. DE 3721855
11. EP 0209897
12. EP 0264106
13. WO 8704349
14. JP 7-126286
15. EP 0212903
16. JP 297664
17. EP 0372537
18. WO 97/30072
19. EP 0437729
Literature References
1. Sakurai, M., et al.,
Chem. Pharm. Bull
. (1993), 41, 8, 1378-1386.
2. Sakurai, M., et al.,
Tetrahedron Lett
. (1993), 34, 37, 5939-5942.
3. Diederich, A. M., et al.,
Tetrahedron Lett
. (1993), 34, 39, 6169-6172.
SUMMARY OF INVENTION
This invention is directed to the novel compounds of formula 1 that are useful in treating Alzheimer's disease and other similar diseases.
Disclosed are hydroxyethylene compounds of the formula (XII):
where R
1
is:
(I) C
1
-C
6
alkyl,
(II) C
1
-C
6
alkyl-S-alkyl
(III) C
1
-C
6
alkyl-(C
2
-C
6
alkenyl),
(IV) —(CH
2
)
0-6
-alkyl -(R
1-aryl
) where R
1-aryl
is unsubstituted or substituted with:
(A) C
1
-C
6
alkyl,
(B) —CF
3
,
(C) —F, Cl, —Br or —I,
(D) C
1
-C
3
alkoxy,
(E) —O—CF
3
,
(F) —NH
2
,
(G) —OH, or
(H) —C≡N,
(V) —(CH
2
)
0-6
-alkyl -(R
1-heteroatyl
) where R
1-heteroaryl
is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) inidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(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) &bgr;-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrofuranyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
 where the R
1-heteroaryl
group is bonded to -alkyl- by any ring atom of the parent R
N-heteroaryl
group substituted by hydrogen such that the new bond to the R
1-heteroaryl
group replaces the hydrogen atom and its bond, where R
1-heteroaryl
is unsubstituted or substituted with:
(1) C
1
-C
3
alkyl,
(2) —CF
3
,
(3) —F, Cl, —Br, or I,
(4) C
1
-C
3
alkoxy,
(5) —O—CF
3
,
(6) —NH
2
,
(7) —OH, or
(8) —C≡N,
(VI) —(R
1-heteroaryl
) where R
1-heteroaryl
is as defined above,
(VII) —C
1
-C
5
alkyl-(R
1-heterocycle
) where R
1-heterocycle
is:
(A) morpholinyl,
(B) thiomorpholinyl,
(C) thiomorpholinyl S-oxide,
(D) thiomorpholinyl S,S-dioxide,
(E) piperazinyl,
(F) homopiperazinyl,
(G) pyrrolidinyl,
(H) pyrrolinyl,
(I) tetrahydropyranyl,
(J) piperidinyl,
(K) tetrahydrofuranyl, or
(L) tetrahydrothiophenyl,
 where the R
1-heterocycle
group is bonded by any atom of the parent R
1-heterocycle
group substituted by hydrogen such that the new bond to the R
1
heteroaryl group replaces the hydrogen atom and its bond, where R
1-heterocycle
is unsubstituted or substituted with:
(1) ═O
(2) C
1
-C
3
alkyl,
(3) —CF
3
,
(4) —F, Cl, —Br or —I,
(5) C
1
-C
3
alkoxy,
(6) —O—CF
3
,
(7) —NH
2
,
(8) —OH, or
(9) —C≡N, or
(VIII) —R
1-heterocycle
with R
1-heterocycle
as defined above;
where R
2
is:
(I) —H,
(II) alkyl, or
(III) —C
1
-C
5
alkyl-R
2-1
where R
2-1
is cycloalkyl, R
1-aryl
or R
1-heteroaryl
where R
1-aryl
and R
1-heteroaryl
are as defined above,
where R
N
is:
(I) R
N-1
—X
N
— where X
N
is:
(A) —CO—,
(B) —SO
2
—,
(C) —(CR′R″)
1-6
where R′ and R″ are the same or different and are —H or C
1
-C
4
alkyl,
(D) —CO—(CR′R″)
1-6
—X
N-1
where X
N-1
is —O—, —S— or —NR′R″— and where R′ and R″ are as defined above, or
(E) a single bond;
where R
N-1
is:
(A) R
N-aryl
where R
N-aryl
is unsubstituted or substituted with:
(1) C
1
-C
6
alkyl,
(2) —F, —Cl, —Br, or —I,
(3) —OH,
(4) —NO
2
,
(5) —CO—OH,
(6) —C≡N,
(7) —CO—NR
N-2
R
N-3
where R
N-2
and R
N-3
are the same or different and are:
(a) —H,
(b) —C
1
-C
6
alkyl unsubstituted or substituted with
(i) —OH, or
(ii) —NH
2
,
(c) —C
1
-C
6
alkyl unsubstituted or substituted with —F, —Cl, —Br, or —I,
(d) —C
3
-C
7
cycloalkyl,
(e) —(C
1
-C
2
alkyl)-(C
3
-C
7
cycloalkyl),
(f) —(C
1
-C
6
alkyl)—O—(C
1
-C
3
alkyl),
(g) —C
1
-C
6
alkenyl with one or two double bonds,
(h) —C
1
-C
6
alkynyl with one or two

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