D-proline derivatives

Details D-proline derivatives D-proline derivatives

2002-07-01

2004-05-25

Ramsuer, Robert W. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06740760

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field
The invention relates to D-prolines and their use in treating diseases associated with amyloidosis.
2. Description
The compounds (R)-1-[(R)-3-mercapto-2-methyl-propionyl]-pyrrolidine-2-carboxylic acid and (R)-1-[(S)-3-mercapto-2-methyl-propionyl]-pyrrolidine-2-carboxylic acid are disclosed in WO 97/10225 as having antibacterial activity against
B. fragilis
. These compounds are also disclosed in
J. Comput.
-
Aided Mol. Des.,
1(2): 133-42 (1987) in a theoretical study of angiotensin-converting enzyme inhibitors. However, the use of these compounds for treating or preventing central and systemic amyloidosis was not known before the subject invention.
The subject invention provides unique D-proline derivatives that can be used to treat or prevent central and systemic amyloidosis. Amyloidosis is a disorder of protein metabolism in which normally soluble autologous proteins are deposited in tissues as abnormal insoluble fibrils that can cause structural and functional disruption. Disorders associated with amyloidosis include Alzheimer's disease and maturity onset diabetes mellitus.
SUMMARY OF THE INVENTION
The invention relates to D-prolines of the formula:
wherein
R is SH; benzyl; benzyl substituted by hydroxy or lower alkoxy; phenyl; phenyl substituted by hydroxy or lower alkoxy; or the group
R
1
is hydrogen or halogen;
X is —(CH
2
)
n
—; —CH(R
2
)(CH
2
)n—; —CH
2
O(CH
2
)
n
—; —CH
2
NH—; benzyl; —C(R
2
)═CH—; —CH
2
CH(OH)—; or thiazol-2,5-diyl;
Y is —S—S—; —(CH
2
)
n
—; —O—; —NH—; —N(R
2
)—; —CH═CH—; —NHC(O)NH—; —N(R
2
)C(O)N(R
2
)—; —N[CH
2
C
6
H
3
(OCH
3
)
2
]—; —N(CH
2
C
6
H
5
)—; —N(CH
2
C
6
H
5
)C(O)N(CH
2
C
6
H
5
)—; —N(alkoxyalkyl)—; —N(cycloalkyl-methyl)—; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl; biphenyl; 1,2-phenylen; 1,3-phenylen; 1,4-phenylen; 1,2-phenylen substituted by 1 to 4 substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, —COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid-pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimidoyl, 5-oxo-[1,2,4]oxadiazolyl, 2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl, and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl; 1,3-phenylen substituted by 1 to 4 substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, —COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid-pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimidoyl, 5-oxo-[1,2,4]oxadiazolyl, 2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl, and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl; and 1,4-phenylen substituted by 1 to 4 substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, —COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid-pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimidoyl, 5-oxo-[1,2,4]oxadiazolyl, 2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl, and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl;
X′ is —(CH
2
)
n
—; —(CH
2
)
n
CH(R
2
)—; —(CH
2
)
n
OCH
2
—; —NHCH
2
—; benzyl; —CH═C(R
2
)—; —CH(OH)CH
2
; or thiazol-2,5-diyl;
R
2
is lower alkyl, lower alkoxy, or benzyl;
is a single or a double bond; and
n is 0-3,
and to pharmaceutically acceptable salts and mono- and diesters thereof, with the exception of (R)-1-[(R)-3-mercapto-2-methyl-propionyl]pyrrolidine-2-carboxylic acid and (R)-1-[(S)-3-mercapto-2-methyl-propionyl]pyrrolidine-2-carboxylic acid.
A method of using these compounds for treating diseases associated with amyloidosis by administering to a subject in need of such treatment an effective amount of one of the above-identified compounds or (R)-1-[(R)-3-mercapto-2-methyl-propionyl]pyrrolidine-2-carboxylic acid or (R)-1-[(S)-3-mercapto-2-methyl-propionyl]pyrrolidine-2-carboxylic acid is also provided.
DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The invention provides compounds of the formulas:
wherein
R is SH, benzyl or phenyl, optionally substituted by hydroxy or lower alkoxy or the group
R
1
is hydrogen or halogen;
X is —(CH
2
)
n
—; —CH(R
2
)(CH
2
)n—; —CH
2
O(CH
2
)
n
—; —CH
2
NH—; benzyl, —C(R
2
)═CH—; —CH
2
CH(OH)—; or thiazol-2,5-diyl;
Y is —S—S—; —(CH
2
)
n
—; —O—; —NH—; —N(R
2
)—; —CH═CH—; —NHC(O)NH—; —N(R
2
)C(O)N(R
2
)—; —N[CH
2
C
6
H
3
(OCH
3
)
2
]—; —N(CH
2
C
6
H
5
)—; —N(CH
2
C
6
H
5
)C(O)N(CH
2
C
6
H
5
)—; —N(alkoxyalkyl)—; —N(cycloalkyl-methyl)—; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl; biphenyl; or 1,2-phenylen, 1,3-phenylen and 1,4-phenylen, wherein the phenylen groups are optionally substituted by 1-4 substituents, selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, —COO-lower alkyl, nitrilo, 5-tetrazol, (2-carboxylic acid-pyrrolidin-1-yl)-2-oxo-ethoxy, N-hydroxycarbamimidoyl, 5-oxo-[1,2,4]oxadiazolyl, 2-oxo-[1,2,3,5]oxathiadiazolyl, 5-thioxo-[1,2,4]oxadiazolyl and 5-tert-butylsulfanyl-[1,2,4]oxadiazolyl;
X′ is —(CH
2
)
n
—; —(CH
2
)
n
CH(R
2
)—; —(CH
2
)
n
OCH
2
—; —NHCH
2
—; benzyl, —CH═C(R
2
)—; —CH(OH)CH
2
; or thiazol-2,5-diyl;
R
2
is lower alkyl, lower alkoxy or benzyl and
n is 0-3,
and pharmaceutically acceptable salts or mono- and diesters thereof, with the exception of (R)-1-[(R)— and (R)-1-[(S)-3-mercapto-2-methyl-propionyl]-pyrrolidine-2-carboxylic acid.
The compounds of formulas I-A or I-B may contain 4 or 2 asymmetric carbon atoms. Accordingly, the present invention includes all sterioisomeric forms of the compounds of formula I-A or I-B, including each of the individual enantiomers and mixtures thereof.
It has been surprisingly found that the D-prolines of formula I-A and I-B can be used in the treatment or prevention of all forms of central and systemic amyloidosis, which is a disorder of protein metabolism in which normally soluble autologous proteins are deposited in the tissues as abnormal insoluble fibrils, which cause structural and functional disruption. The most common disorders associated with amyloidosis are Alzheimer's disease (AD), maturity onset diabetes mellitus, or amyloidosis
as a significant cause of non-ischaemic heart failure,
as complication of long term haemodialysis in renal failure,
as complication of monoclonal gammopathies,
from chronic inflammatory disorders,
from chronic infections or
from certain types of cancer.
Furthermore, amyloidosis comprises many different diseases such as forms of hereditary amyloidosis most common familial amyloid polyneuropathy (FAP), scrapie and Kreuzfeld-Jakob disease.
The common pathological feature is extracellular deposition of so called amyloid proteins in B-structured fibers and the same staining characteristics.
Serum amyloid P component (SAP) is a normal plasma protein and the precursor of amyloid component, a universal constituent of the abnormal tissue deposits in amyloidosis. It is resistant to proteases and therefore plays a key role in the persistance of amyloid in vivo. For therapy pharmaceutically active compounds have to be found which would prevent the interaction of SAP with amyloid fibrils. This interaction has been demonstrated to be a protein fiber interaction, rather than an interaction with more general fiber components such as glycosaminoglycans. SAP consists as a pentamer of 5 identical non-covalently associated subunits. Two pentamers can non-covalently associate to a decamer with the two pentameric disk-like rings interacting face to face. SAP is a calcium-dependent ligand binding protein. It is produced and degraded excl

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