2,4-diaminoquinazolines for spinal muscular atrophy

#The invention relates to a genus of 2,4-diaminoquinazolines that are useful for treating spinal muscular atrophy (SMA).

#Spinal muscular atrophy (SMA) is a currently untreatable, autosomal recessive genetic disease caused by a deficiency of full-length survival motor neuron (SMN) protein. The symptoms are the result of progressive degeneration of motor neurons in the anterior horn of the spinal cord resulting in weakness and wasting of the voluntary muscles.

#Type I (Acute) SMA is also called Werdnig-Hoffmann Disease. SMA type I is evident before birth or within the first few months of life. There may be a reduction in fetal movement in the final months of pregnancy. There is a general weakness in the intercostals and accessory respiratory muscles. The chest may appear concave. Symptoms include floppiness of the limbs and trunk, feeble movements of the arms and legs, swallowing and feeding difficulties, and impaired breathing. Affected children never sit or stand and usually die before the age of 2.

#As summarized above, the invention relates to novel 2,4-diaminoquinazoline compounds having formulae I-IV and VI, which are useful in the treatment of SMA.

#Compounds of formula III include novel ethers, thioethers, and amines. In these 2,4-diaminoquinazolines the substituent at the 5 position is defined as -G1-CH2-Q, wherein G1 is —O—, —NR6—, —S— or —OCH(CH3)—, and R6 is hydrogen or C1-C6 alkyl. In these compounds, residue Q is one of —CH2OCH3, —CH2OCH2CH═CH2, C6-C20 hydrocarbon, heterocyclyl, and heteroaryl; substituted C6-C20 hydrocarbon, substituted heterocyclyl, and substituted heteroaryl; and —CH(OH)Ar2, wherein Ar is substituted or unsubstituted phenyl. Examples of substituted and unsubstituted C6-C20 hydrocarbons, include, but are not limited to, substituted and unsubstituted cycloalkyls, cycloalkenyls, aryls, and fused cycloalkylaryls. In some embodiments of formula III, G1 is —O— or —S—. However, it should be noted that when G1 is —O— or —S—, then Q must be other than 4-chlorophenyl.

#Compounds of formula II include 2,4-diaminoquinazolines in which the substituent at the 5 position is defined as -G-R2. In this genus, G is —NR6—, —CH2—, —SO2— or —CH2O—, and R2 is cycloalkyl, aryl, fused cycloalkylaryl, heterocyclyl, and heteroaryl; substituted cycloalkyl, substituted aryl, substituted fused cycloalkylaryl, substituted heterocyclyl, or substituted heteroaryl. However, when G is —CH2— then R2 must be other than phenyl or substituted phenyl.