Prolylendopeptidase inhibitors

Details Prolylendopeptidase inhibitors Prolylendopeptidase inhibitors

1998-04-17

2001-02-20

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S465000

Reexamination Certificate

active

06191161

ABSTRACT:

This application is the national phase under 35 U.S.C. §371 of prior PCT International Application No. PCT/HU96/00041 which has an International filing date of Jul. 26, 1996 which designated the United States of America, the entire contents of which are hereby incorporated by reference.
The present invention relates to new compounds of the general Formula (I), to pharmaceutical compositions containing them, and to the process for the preparation of these compounds. A further aspect of our present invention is the use of the new compounds of the general formula I for the treatment of CNS diseases by inhibition of certain enzymes described later on on this page.
Because of the incidence and social consequences of diseases of the central nervous system accompanied with amnesia, dementia and the progressive decline of cognitive and intellectual functioning for example Alzheimer disease, AIDS dementia, senile dementias of various origin (hypoxia, ischaemia) there are significant demands for new pharmaceuticals for treating and preventing the diseases mentioned above.
Prolyl endopeptidase PE or PEP is a post-proline cleaving enzyme (PPCE). It is widespread in mammalian species and can be found in various organs of the body. The level of the enzyme is the highest in the brain, testis and skeletal muscle (Yoshimoto T., Ogita K., Walter, R., Koida M. and Tsuru D.: Biochim. Biophys. Acta, 569, (1979), 184-192).
PEP has some important role in memory process due to the fact that its substrates are biologically active neuropeptides (substance P, thyrotropin-releasing hormone, Arg
8
-Vasopressin). These neuropeptides exert characteristic pharmacological effects on the central nervous system: they are capable of changing the performance of animals and humans in learning and memory tasks (Toide K., Iwamoto Z., Fujiwara T., and Abe H.: J. Pharm. Exp. Therapeutics, 274, (1995), 1370-1378; Riedel W. and Jolles J. Drugs & Aging, 8, (1996), 245-274). The neuropeptide sustance P prevents &bgr;-amyloid-induced neuronal loss and expression of Alz-50 proteins in cerebral cortex (Kowall N., Beal M. F., Busciglio J., and Duffy L. K.: Proc. Natl. Acad. Sci., 88, (1991), 7247-7251). In brains of patients with Alzheimer's disease, it is well known that the cerebral ACh content decreased and the cerebral function suffers severe damage (O'Leary R. and O'Connor B.: J. Neurochem., 65, (1995), 953-963). A PEP inhibitor through the increasing the level of TRH could induce ACh release in the brain which should result in a better cognitive performance. It can be supposed that a highly specific PEP inhibitor could prove to be usefilul in the treatement of diseases of central nervous system in neurodegenerative illnesses.
The new PEP inhibitor as a new drug would be a
1. nootropic drug having memory enhancing and anti-amnestic effect and could be used in treatement of age-related cognitive decline;
2. neuropotective agent useful in therapy of
a., acute events (ischemia/hypoxia)
b., progressive neurodegenerative disorders
Alzheimer's disease
AIDS dementia
Huntington's disease
Senile dementia and Alzheimer's disease become serious and fastly outgrowing problem of the aging population and a PEP inhibitor could be useful for the general treatment of the above mentioned serious diseases.
We set ourselves the task of preparing new PEP-inhibitors displaying advantageous characteristics which could serve as active ingredients of new drugs. By advantages we mean over a strong PEP—inhibitory effect, selectivity, easily transfer through the blood-brain barrier, a long half-life, good oral resorption, enchanced chemical and biological stability and advantageous therepautical profile including lowser toxicity and low probability of side effects.
During the synthesis and biological examination of numerous new compounds we found that new compounds of the general formula (I) wherein A means an onefold or manifold substituted or unsubstituted organic cyclic group containing one nitrogen atom with one free valency and optionally one or more further heteroatom selected from a group consisting of nitrogen atom, sulfuratom or oxigenatom, especially a group having the general formula (1), (1a), (2), (2a), (3), (3a), (4), (5), (6), (7), (8), (9), (10), (11a), (11b), (12), (12a), (12b), (13), (13a), (14), (15), (16), (17), (18), (19), (19a), (20), (20a), (21), (22), (23), (23a), (23b), (24), (25), (25a), (26), (27), (28), (28a), (28b), (29), (29a), (30), (31), (32), (32a), (33), (34), (35), (36)—wherein
R means hydrogenatom alkyl group of 1-4 carbon atoms or aryl or aralkyl group of 6-12 carbon atoms;
R
1
, R
2
, R
3
and R
4
mean independently from each other hydrogen atom, halogen atom, hydroxyl group, straight chain or branched chain alkvl or alkenyl- or alkinyl or alkoxy- or alkenyloxy- or alkinyloxy groups containing 1-6 carbon atoms, nitro-group, amino group, monoalkylamino or monoacylamino group of 1-12 carbon atoms, dialkylamino- or diacylamino group of 2-24 carbon atoms—where the acyl group is an alkyl, aralkyl, cycloalkyl or aryl type-, cyano group, mercapto group, carboxyl group, esterified carboxyl group of 2-7 carbon atoms, hydroxyalkyl group of 1-6 carbon atoms, acyl group of 1-7 carbon atoms, acyloxy group of 1-7 carbon atoms, phenyl or benzyl group, anilino group, benzoyl group, phenoxy group, benzyloxy group, isocyanato group, isothiocyanato group, alkylthio group of 1-6 carbon atoms, sulfamino or sulfamoyl group, thiocyanato or cyanato group;
R
5
and R
6
mean independently from each other hydrogen atom, hydroxyl group phenyl group or alkyl group of 1-4 carbon atoms or R
5
and R
6
together mean oxo group;
R
7
means alkyl group of 1-6 carbon atoms;
R
8
means hydrogen atom or alkyl group of 1-6 carbon atoms or aralkyl group of 7-10 carbon atoms;
the dotted line means an optional chemical bond;
n is zero 1, 2 or 3;
X means —CH
2
— group, —NH— group, carbon atom, hydrogen atom, oxygen atom or amino group; or
A means an R—Y—N=group or
 group—wherein R′ means alkyl group of 1-6 carbon atoms, aralkyl group of 7-10 carbon atoms, diphenylmethyl group, alkoxy group, arylalkyloxy group of 7-10 carbon atoms, or phenyl- or phenoxy or phenylalkyl group containing 7-10 carbon atoms or phenylalkyloxy group containing 7-10 carbon atoms optionally substituted with halogen atoms or alkyl groups of 1-4 carbon atoms or nitro groups; Y means chemical bond or oxo-, sulfonyl- or sulfinyl group, R
9
means hydrogen atom or alkyl group of 1-4 carbon atoms; —with the proviso that in the case of formulas (20) and (33) X cannot mean —CH
2
— group, —NH— group, oxygen atom or sulfur atom and in the case of formulas (30) and (31) X cannot mean —CH
2
— group, oxygen atom or sulfur atom or amino group;
B means
 group—wherein m is an integer of 1 to 21; or
 group wherein p is an integer of 1 to 3; or
 group—wherein R
9
, R
10
, R
11
, R
12
, R
13
and R
14
mean independently from each other hydrogen alkyl or alkoxy group of 1-6 carbonatoms, halogen, amino group optionally substituted with one or two alkyl group of 1-6 carbonatoms; or
phenyl, phenoxy, aryl-alkyl group of 7-12 carbonatoms or aryl-alboxy group of 7-12 carbonatoms each of them optionally containing 1, 2 or 3 same or different substituents identical to R
1
, R
2
, R
3
or R
4
; or
two of R
9
, R
10
, R
11
, R
12
, R
13
and R
14
mean together an oxo or epoxy group or further chemical bond or four of them mean together two further chemical bonds and the remaining groups stand for hydrogen atoms; or
R
9
, R
10
, R
11
, R
12
, R
13
and R
14
mean together with the chain carbonatoms a saturated or unsaturated homocycle containing 3-8 carbon atoms or a saturated or unsaturated heterocycle containing 2-7 carbon atoms and a nitrogen or sulfur or oxygen atom, to which optionally an aromatic ring of 6-10 carbon atoms is condensed; and
w is zero or 1;
C means prolyl group or one of the groups of formula (37), (38), (39), (40) or (41)—where n is zero or 1 or 2, Hlg means fluorine, chlorine, bromine, or iodine atom;
R
5
and R
6

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