Compounds to treat Alzheimer's disease Number:6,737,420 from the United States Patent and Trademark Office (PTO) owispatent The present invention is directed toward substituted hydroxyethylene compounds of formula (XII): ##STR1##useful in treating Alzheimer's disease and other similar diseases.<H Alzheimer, Compounds, Compounds, to, tr, 6737420.html, Patent, pto, 6737420

Title: Compounds to treat Alzheimer's disease

Abstract: The present invention is directed toward substituted hydroxyethylene compounds of formula (XII): ##STR1##useful in treating Alzheimer's disease and other similar diseases.

Patent Number: 6,737,420 Issued on 05/18/2004 to Hom, et al.

Inventors: Hom; Roy (San Francisco, CA), Mamo; Shumeye S. (Oakland, CA), Tung; Jay (Belmont, CA), Gailunas; Andrea (San Francisco, CA), John; Varghese (San Francisco, CA), Fang; Lawrence Y. (Foster City, CA)
Assignee: Elan Pharmaceuticals, Inc. (South San Francisco, CA)

Appl. No.: 09/815,960

Filed: March 23, 2001

Current U.S. Class: 514/218 ; 514/227.5; 514/231.2; 514/315; 514/317; 514/330; 514/331; 514/451; 514/461; 514/471; 514/618; 514/619; 540/492; 544/106; 544/358; 544/359; 544/58.2; 544/59; 546/192; 548/400; 548/561; 549/426; 549/491; 549/497; 549/74; 564/153; 564/156; 564/167

Current International Class: C07C 271/18 (20060101); C07C 237/22 (20060101); C07C 237/00 (20060101); C07C 271/00 (20060101); C07C 271/22 (20060101); C07C 271/14 (20060101); C07D 295/185 (20060101); C07D 295/00 (20060101); C07D 307/52 (20060101); C07D 307/00 (20060101); C07D 307/14 (20060101); C07D 307/33 (20060101); C07D 261/00 (20060101); C07D 261/20 (20060101); C07K 7/00 (20060101); C07K 7/02 (20060101); C07D 295/13 (20060101); C07K 5/00 (20060101); C07K 5/02 (20060101); A61K 38/00 (20060101)

Field of Search: 564/153,156,167 540/492 544/59,58.2,106,358,359 546/192 548/400,561 549/74,426,491,497 514/218,231.2,451,461,471,618,619,227.5,315,317,330,331

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Primary Examiner: Ford; John M.
Assistant Examiner: Tucker; Zachary C.
Attorney, Agent or Firm: McDonnell Boehnen Hulbert & Berghoff

Parent Case Text

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority of invention under 35 U.S.C. .sctn.119(e) from U.S. provisional application No. 60/191,528, filed Mar. 23, 2000.

Claims

We claim:

1. A compound of the formula: ##STR81##

or a pharmaceutically acceptable salt thereof wherein R.sub.1 is: (I) C.sub.1 -C.sub.6 alkyl, unsubstituted or substituted with one, two or three C.sub.1 -C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --NH.sub.2, --C.ident.N, --CF.sub.3, or --N.sub.3, (II) --(CH.sub.2).sub.1-2 --S--CH.sub.3, (III) --CH.sub.2 --CH.sub.2 --S--CH.sub.3, (IV) --CH.sub.2 --(C.sub.2 -C.sub.6 alkenyl) unsubstituted or substituted by one --F, (V) --(CH.sub.2).sub.0-3 --(R.sub.1-aryl) where R.sub.1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstituted or independently substituted on the aryl ring with one or two of C.sub.1 -C.sub.3 alkyl, --CF.sub.3, --F, Cl, --Br, --I, C.sub.1 -C.sub.3 alkoxy, --O--CF.sub.3, --NH.sub.2, --OH, or --C.ident.N; R.sub.2 is: (I) --H, (II) C.sub.1 -C.sub.6 alkyl, or (III) --(CH.sub.2).sub.0-4 --R.sub.2-1 where R.sub.2-1 is (C.sub.3 -C.sub.6)cycloalkyl, R.sub.1-aryl where R.sub.1-aryl is optionally substituted with R.sub.100, where R.sub.100 is (1) C.sub.1 -C.sub.6 alkyl, (2) --F, --Cl, --Br, or --I, (3) --OH, (4) --NO.sub.2, (5) --CO--OH, (6) --C.ident.N, (7) --CO--NR.sub.N-2 R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are the same or different and are: (a) --H, (b) --C.sub.1 -C.sub.6 alkyl unsubstituted or substituted with one --OH or --NH.sub.2, (c) --C.sub.1 -C.sub.6 alkyl unsubstituted or substituted with one to three --F, --Cl, --Br, or --I, (d) --C.sub.3 -C.sub.7 cycloalkyl, (e) --(C.sub.1 -C.sub.2 alkyl)--(C.sub.3 -C.sub.7 cycloalkyl), (f) --(C.sub.1 -C.sub.6 alkyl)--O--(C.sub.1 -C.sub.3 alkyl), (g) --C.sub.1 -C.sub.6 alkenyl with one or two double bonds, (h) --C.sub.1 -C.sub.6 alkynyl with one or two triple bonds, (i) --C.sub.1 -C.sub.6 alkyl chain with one double bond and one triple bond, (8) --CO--(C.sub.3 -C.sub.12 alkyl), (9) --CO--(C.sub.3 -C.sub.6 cycloalkyl), (11) --CO--R.sub.1-heterocycle where R.sub.1-heterocycle is morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S, S-dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl. tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, or tetrahydrothiophenyl, where the R.sub.1-heterocycle group is bonded by any atom of the parent R.sub.1-heterocycle group substituted by hydrogen such that the new bond to the R.sub.1-heterocycle group replaces the hydrogen atom and its bond, where heterocycle is unsubstituted or substituted with one or two .dbd.O, C.sub.l -C.sub.3 alkyl, --CF.sub.3, --F, Cl, --Br, --I, C.sub.1 -C.sub.3 alkoxy, --OCF.sub.3, --NH.sub.2, --OH, or --C.ident.N, (12) --CO--RN.sub.N-4 where R.sub.N-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C.sub.1 -C.sub.3 alkyl, (13) --CO--O--R.sub.N-4 where R.sub.N-5 is: (a) C.sub.1 -C.sub.6 alkyl, or (b) --(CH.sub.2).sub.0-2 --(R.sub.1-aryl) where R.sub.aryl is as defined above, (14) --SO.sub.2 --NR.sub.N-2 R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are as defined above, (15) --SO--(C.sub.1 -C.sub.8 alkyl), (16) --SO.sub.2 --(C.sub.3 -C.sub.12 alkyl), (17) --NH--CO--O--R.sub.N-5 where R.sub.N-5 is as defined above, (18) --NH--CO--N(C.sub.1 -C.sub.3 alkyl).sub.2, (19) --N--CS--N(C.sub.1 -C.sub.3 alkyl).sub.2, (20) --N(C.sub.1 -C.sub.3 alkyl)--CO--R.sub.N-5 where R.sub.N-5 is as defined above, (21) --NR.sub.N-2 R.sub.N-3 where R.sub.N-2 and R.sub.N-3 can be the same or different and are as defined above, (22) --R.sub.N-4 where R.sub.N-4 is as defined above, (23) --O--CO--(C.sub.1 -C.sub.6 alkyl), (24) --O--CO--N(C.sub.1 -C.sub.3 alkyl).sub.2, (25) --O--CS--N(C.sub.1 -C.sub.3 alkyl).sub.2, (26) --O--(C.sub.1 -C.sub.6 alkyl), (27) --O--(C.sub.2 -C.sub.5 alkyl)--COOH, (28) --S--(C.sub.1 -C.sub.6 alkyl), (29) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 --F, or (30) --O--(C.sub.1 -C.sub.6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 --F, or (31) --O-.phi.; R.sub.N-1 is phenyl that is independently substituted with one, two, three or four of R.sub.100 ; R.sub.a is hydrogen or C.sub.1 -C.sub.6 alkyl; R.sub.c is: --(C.sub.1 -C.sub.10)alkyl-K.sub.1-3 in which: (A) the alkyl chain is unsubstituted or substituted with one --OH, (B) the alkyl chain is unsubstituted or substituted with one C.sub.1 -C.sub.6 alkoxy unsubstituted or substituted with 1-5 --F, (D) the alkyl chain is unsubstituted or substituted with 1-5 --F, (F) each K is: (1) H, (2) C.sub.1 -C.sub.3 alkyl, (3) C.sub.1 -C.sub.3 alkoxy, (4) C.sub.1 -C.sub.3 alkylthioxy, (5) C.sub.1 -C.sub.6 alkylacylamino, (6) C.sub.1 -C.sub.6 alkylacyloxy, (7) amino (8) C.sub.1 -C.sub.6 alkylamino (9) phenylamino, (10) carbamyl (11) carboxyl (12) carboxy(C.sub.2 -C.sub.5)alkoxy, (13) carboxy(C.sub.2 -C.sub.5)alkylthioxy, (16) amino unsubstituted or substituted with C.sub.1 -C.sub.6 alkyl, (17) hydroxyl, or (18) carboxyl methyl ester.

2. A compound according to claim 1, which is N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-penty l]-5-methyl-N,N-dipropyl -isophthalamide.

3. A compound according to claim 1, which is 3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-et hyl-4-(S)-hydroxyhexanoylamino]-propionic acid.

4. A compound according to claim 1, which is 8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-et hyl-4-(S)-hydroxyhexanoylamino]-octanoic acid.

5. A compound according to claim 1, which is 8-[6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)- ethyl-4-(S)-hydroxy-hexanoylamino]-octanoic acid methyl ester.

6. A compound according to claim 1, which is N-[4-(R)-Butylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N ,N-dipropyl-isophthalamide.

7. A compound according to claim 1, which is N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-hexyl ]-N,N-dipropyl-isophthalamide.

8. A compound according to claim 1, which is N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]- N,N-dipropyl -isophthalamide.

9. A compound according to claim 1, which is N-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hy droxy-hexyl]-N,N-dipropyl-isophthalamide.

10. A compound according to claim 1, which is N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine-1-carbonyl) -hexyl]-N,N-dipropyl-isophthalamide.

11. A compound according to claim 1, which is N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S )-hydroxy-hexyl]-N,N-dipropyl-isophthalamide.

12. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.

13. A method of treating Alzheimer's Disease comprising administering to a subject in need of such treatment an effective amount of a compound according to claim 1.

Description

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.beta.).

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): ##STR2##

where R.sub.1 is: (I) C.sub.1 -C.sub.6 alkyl, (II) C.sub.1 -C.sub.6 alkyl-S-alkyl (III) C.sub.1 -C.sub.6 alkyl-(C.sub.2 -C.sub.6 alkenyl), (IV) --(CH.sub.2).sub.0-6 -alkyl -(R.sub.1-aryl) where R.sub.1-aryl is unsubstituted or substituted with: (A) C.sub.1 -C.sub.6 alkyl, (B) --CF