Pyrrolo[2,3-c]pyridines as Imaging Agents for Neurofibrilary Tangles

Title:	Pyrrolo[2,3-c]pyridines as imaging agents for neurofibrilary tangles
Patent Application Number:	WO 2015188368 A2	Publication date:	December 17th, 2015
Priority Application:	PCT/CN2014/079834	Priority date:	June 13th, 2014
Inventors:	Abbas, Walji; Hostetler, Eric; Greshock, Thomas; Li, Jing; Moore, Keith P.; Bennacef, Idriss; Mulhearn, James; Selnick, Harold; Wang, Yaode; Yang, Kun; Fu, Jianmin
Assignee Company:	Merck, Sharpe and Dohme, Inc.
Disease Area:	CNS Alzheimer’s disease	Biological Target:	Tau protein and tau aggregates
Summary:	Alzheimer’s disease (AD), a neurodegenerative disorder characterized by neuronal and synaptic loss, brain atrophy, and slow, progressive dementia first characterized by Dr. Alois Alzheimer in 1901, remains a major unmet medical need. Despite decades of research, a cure remains elusive and treatment options are limited. In 2015, approximately 5.3 million US citizens had Alzheimer’s disease, and the direct cost of AD patient care in the US was ∼$226 billion. In the absence of novel therapies, the US AD patient population is expected to exceed 13.8 million by 2050, and the cost of care will balloon to over $1.1 trillion.
	Although the pathogenesis of AD has not been determined, there are two major theories that describe its pathogenesis, the amyloid hypothesis and the tau theory. According to the amyloid hypothesis the neurodegeneration and loss of cognitive function associated with AD are caused by the buildup of β-amyloid plaques. These plaques are believed to be the result of improper amyloid precursor protein (APP) processing by β-secretase (BACE) and γ-secretase, which leads to a buildup of the Aβ-42 fragment of APP. Aβ-42 is prone to aggregation and plaque formation, and it has been hypothesized that preventing the formation and/or clearing these materials from the brain will arrest AD progression.
	The tau theory, however, hypothesizes that AD pathogenesis is caused by mishandling of tubulin-associated unit (tau) proteins. Under normal conditions, this highly soluble microtubule associated protein modulates the stability of axonal microtubules. In AD patients, however, tau becomes hyperphosphorylated, which substantially decreases its solubility. This leads to the formation of tau aggregates and neurofibrillary tangles inside nerve cells. This, in turn, causes neuron death, cognitive impairment, and other symptoms of AD.
	Diagnostic tools capable of detecting the presence of either β-amyloid plaques or tau aggregates could provide a method of diagnosing AD. The present disclosure describes a series of pyrrolo[2,3-c]pyridines useful as positron emission tomography (PET) imaging agents capable of binding to tau aggregates.
Important Compound Classes:
Definitions:	X represents CH, or N;
	R represents hydrogen, or −C1–6alkyl, said alkyl optionally substituted with 1 to 3 groups of Ra:
	R1 represents hydrogen, −C1–6alkyl, −CN, −(CH2)nNH(CH2)nN(R)2, −C2–6alkenyl, −(CH2)nOR, or −(CH2)nhalogen;
	R2 represents −C1–6 alkyl, −OC1–6 alkyl, −C2–6 alkenyIR3, −C2–6 alkynyIR3, −(CH2)nOR, −(CH2)nhalogen, −O(CH2)nhalogen, −C6–10 aryl, −C5–10 heterocyclyl, −N(R)2, −O(CH2)nRa, −N(CH3)(CH2)nOR, −NRC(O)R, −NH(CH2)nhalo, −NC(O)C6–10 aryl, −NC(O)C5–10 heterocyclyl, −N(CH3) (CH2)nhalogen, −C(O)NC6–10 aryl, said alkyl, aryl, and heterocyclyl optionally substituted with 1 to 3 groups of Ra;
	or an adjacent R1 can combine with R2 to form a nine- to 10-membered bicyclic ring together with the ring to which R1 and R2 are attached, said bicyclic ring optionally interrupted with N, S, and/or O, said ring optionally substituted with 1 to 3 groups of Ra;
	R3 represents hydrogen, −C1–6alkyl, −(CH2)nhalogen, −(CH2)nN(R)2, −(CH2)nNR(CH2)nN(R)2, −C6–10aryl, −C5–10heteroaryl, said alkyl, aryl, and heteroaryl optionally substituted with 1 to 3 group of Ra;
	Ra represents −CN, CF3, −Cl-6alkyl, −C2–6alkenyl, −C2–6alkynyl, C6–10aryl, −C5–10 heterocyclyl, −CN, NO2, (CH2)nhalogen, −O(CH2)nhalogen, (CH2)nOR, −O(CH2)nC6–10 aryl, −(CH2)nN(R)2, −C(O)N(R)2, −N(CH3) (CH2)nOR, −NRCOR, −COR, −NH(CH2)nhalo, −NC(O)C C6–10aryl, −N(CH3) (CH2)nhalogen, C(O)C6–10 aryl, or −CO2R;
	Rb represents -C1–6alkyl, -OR, or halogen; and n represents 0–4.
Key Structures:
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Biological Assay:	Tau binding assay using human brain samples.
	Amyloid binding assay using human brain samples.
Biological Data:
Claims:	27 total claims
	21 composition of matter claims
	6 method of use claims

The authors declare no competing financial interest.