N-(methyl) -1h-pyrazol-3-amine, n-(methyl)-pyridin-2-amine and n-(methyl)-thiazol-2-amine derivatives for the treatment of diseases associated with amyloid or amyloid-like proteins, like e.g. alzheimer's

Abstract

The present invention relates to novel compounds of formula (II) that can be employed in the treatment of a group of disorders and abnormalities associated with amyloid protein, such as Alzheimer's disease, and of diseases or conditions associated with amyloid-like proteins. The compounds of the present invention can also be used in the treatment of ocular diseases associated with pathological abnormalities/changes in the tissues of the visual system. The present invention further relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the preparation of medicaments for treating, or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins. A method of treating or preventing diseases or conditions associated with amyloid and/or amyloid-like proteins is also disclosed.

1 . A compound of the general formula (II) 
       
         
           
           
               
               
           
         
         wherein 
            independently represents a single bond or a double bond; 
         p is 1, 2 or 3; 
         each linker K is independently C 1-3  alkylene which is optionally substituted by one or more C 1-4  alkyl groups; 
         each B is independently a 5- or 6-membered saturated or unsaturated heterocyclic ring, wherein the heterocyclic ring B is optionally substituted by one or more substituents selected from C 1-4  alkyl, C 1-4  alkoxy, mono- and di-C 1-4  alkyl amino, C 3-7  cycloalkyl amino, and 5- or 6-membered saturated heterocyclyl, or two substituents may be joined to form a saturated, unsaturated or aromatic 5- to 7-membered ring which is fused with the heterocyclic ring B, and wherein the heterocyclic ring B may contain in addition to the units V and W one or more heteroatoms, selected from N, NR, S and O, wherein R is selected from H and C 1-4  alkyl; 
         each unit W is independently a H-bond acceptor; 
         each unit V is independently optional and, if present, is independently a H-bond donor; 
         R 1  is selected from —H, -halogen, —C 1-4  alkyl, —NH 2 , —NH—C 1-4  alkyl, —C 1-4  alkylene-NH 2 , —C 1-4  alkylene-NH—C 1-4  alkyl, -aryl, -aryl-R 3 , —C 1-4  alkylene-aryl, —C 1-4  alkylene-aryl-R 3 , -heteroaryl, -heteroaryl-R 3 , —NH—C 1-4  alkylene-aryl, —NH—C 1-4  alkylene-aryl-R 3 , —OH and —O—C 1-4  alkyl; and 
         R 3  is C 1-4  alkyl, halogen, OH or O—C 1-4  alkyl; 
         R 2  is —H, —C 1-4  alkyl, -aryl or a group of the formula 
       
       
         
           
           
               
               
           
         
         wherein B, V, W and K are as defined above, q is 0 or 1 and r is 0 or 1. 
       
     
     
         2 . The compound of  claim 1 , wherein the each unit W is independently N or C═O. 
     
     
         3 . The compound of  claim 1 , wherein each unit V is NH. 
     
     
         4 . The compound of  claim 1 , wherein each linker K is —CH 2 —, —CH 2 CH 2 — or —CH 2 CH 2 CH 2 . 
     
     
         5 . The compound of  claim 1 , wherein each heterocyclic ring B is independently selected from optionally substituted pyrazolylene, optionally substituted pyridinylene, optionally substituted 2-pyridinonylene, optionally substituted 2-piperidonylene, optionally substituted thiazolylene and optionally substituted isothiazolylene. 
     
     
         6 . The compound of  claim 1 , wherein R 1  is —H, —CH 3 , —NH—C 1-4  alkyl or —CH 2 —NH—CH 3 . 
     
     
         7 . The compound of  claim 1 , wherein R 2  is H or aryl. 
     
     
         8 . A pharmaceutical composition comprising a compound of  claim 1 . 
     
     
         9 - 14 . (canceled) 
     
     
         15 . A method of treating or preventing a disease or condition associated with an amyloid and/or amyloid-like protein comprising administering to a subject in need of such treatment an effective amount of a compound of  claim 1 . 
     
     
         16 . The method of  claim 15 , wherein the disease is a neurological disorder selected from Alzheimer's Disease (AD), Lewy body dementia (LBD), Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type), the Guam Parkinson-Dementia complex mild cognitive impairment (MCI), progressive supranuclear palsy, multiple sclerosis, inclusion-body myositis (IBM), Creutzfeld Jacob disease, Parkinson's disease, HIV-related dementia, amyotropic lateral sclerosis (ALS), inclusion-body myositis (IBM), adult onset diabetes, senile cardiac amyloidosis, endocrine tumors, glaucoma, ocular amyloidoses, primary retinal degeneration, macular degeneration, optic nerve drusen, optic neuropathy, optic neuritis, or lattice dystrophy. 
     
     
         17 - 24 . (canceled) 
     
     
         25 . A mixture comprising a compound according to  claim 1  and at least one further biologically active compound optionally in combination with a pharmaceutically acceptable carrier, a diluent, or an excipient. 
     
     
         26 - 41 . (canceled) 
     
     
         42 . A method of collecting data for the diagnosis of an amyloid-associated disease or condition in a sample or a patient comprising:
 (a) bringing a sample or a specific body part or body area suspected to contain an amyloid protein into contact with a compound according to  claim 1 ;   (b) allowing the compound to bind to the amyloid protein;   (c) detecting the compound bound to the protein; and   (d) optionally correlating the presence or absence of compound binding with the amyloid protein with the presence or absence of amyloid protein in the sample or specific body part or body area.   
     
     
         43 . A method of determining the extent of amyloidogenic plaque burden in a tissue or a body fluid comprising:
 (a) providing a sample representative of the tissue or body fluid under investigation;   (b) testing the sample for the presence of amyloid protein with a compound according to  claim 1 ;   (c) determining the amount of compound bound to the amyloid protein; and   (d) calculating the plaque burden in the tissue or body fluid.   
     
     
         44 . (canceled) 
     
     
         45 . A method of collecting data for determining a predisposition to an amyloid-associated disease or condition in a patient comprising detecting the specific binding of a compound according to  claim 1  to an amyloid protein in a sample or in situ which comprises the steps of:
 (a) bringing the sample or a specific body part or body area suspected to contain the amyloid protein into contact with a compound according to  claim 1 , which compound specifically binds to the amyloid protein;   (b) allowing the compound to bind to the amyloid protein to form a compound/protein complex;   (c) detecting the formation of the compound/protein complex;   (d) optionally correlating the presence or absence of the compound/protein complex with the presence or absence of amyloid protein in the sample or specific body part or body area; and   (e) optionally comparing the amount of the compound/protein complex to a normal control value.   
     
     
         46 . A method of collecting data for monitoring minimal residual disease in a patient following treatment with an antibody or a vaccine composition, wherein the method comprises:
 (a) bringing a sample or a specific body part or body area suspected to contain an amyloid protein into contact with a compound according to  claim 1 , which compound specifically binds to the amyloid protein;   (b) allowing the compound to bind to the amyloid protein to form a compound/protein complex;   (c) detecting the formation of the compound/protein complex;   (d) optionally correlating the presence or absence of the compound/protein complex with the presence or absence of amyloid protein in the sample or specific body part or body area; and   (e) optionally comparing the amount of the compound/protein complex to a normal control value.   
     
     
         47 . A method of collecting data for predicting responsiveness of a patient being treated with an antibody or a vaccine composition comprising:
 (a) bringing a sample or a specific body part or body area suspected to contain an amyloid protein into contact with a compound according to  claim 1 , which compound specifically binds to the amyloid protein;   (b) allowing the compound to bind to the amyloid protein to form a compound/protein complex;   (c) detecting the formation of the compound/protein complex;   (d) optionally correlating the presence or absence of the compound/protein complex with the presence or absence of amyloid protein in the sample or specific body part or body area; and   (e) optionally comparing the amount of the compound/protein complex to a normal control value.   
     
     
         48 . A test kit for detection and/or diagnosis of an amyloid-associated disease or condition comprising a compound according to  claim 1 . 
     
     
         49 - 51 . (canceled) 
     
     
         52 . A method of treating or preventing an ocular disease or condition associated with a pathological abnormality/change in the tissue of the visual system, particularly associated with an amyloid-beta-related pathological abnormality/change in the tissue of the visual system comprising administering to a subject in need of such treatment an effective amount of a compound of  claim 1 . 
     
     
         53 . The method of  claim 52 , wherein the ocular disease or condition is selected from the group consisting of neuronal degradation, cortical visual deficits, glaucoma, cataract due to beta-amyloid deposition, ocular amyloidoses, primary retinal degeneration, macular degeneration, for example age-related macular degeneration, optic nerve drusen, optic neuropathy, optic neuritis, and lattice dystrophy. 
     
     
         54 - 55 . (canceled) 
     
     
         56 . The method of  claim 16 , wherein the macular degeneration is age related macular degeneration (AMD).