InventorsR. Scott Bitner, Kaitlin E. Browman, Michael E. Brune, Yixian Chen, Jurgen Dinges, Karla Drescher, Peer Jacobson, Hwan-soo Jae, Ravi Kurukulasuriya, James T. Link, David J. Madar, Jyoti R. Patel, Marina A. Pliushchev, Jeffrey J. Rohde, Lynne E. Rueter, Qi Shuai, Bryan K. Sorensen, Jiahong Wang, Karsten M. Wicke, Martin Winn, Dariusz Wodka, Vince Yeh, Hong Yong
A method for treating a patient suffering from disorders and deficits of the central nervous system associated with diabetes, associated with aging and neurodegeneration, comprising attention deficit disorder in general, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild cognitive impairment, senile dementia, AIDS dementia, neurodegeneration, depression, and schizophrenia, comprising administering to a patient in need of such treatment an effective amount of a selective inhibitor of the 11-β-hydroxysteroid dehydrogenase Type 1 enzyme activity.
Drawings
Claims1
A pharmaceutical composition comprising a compound of formula (IV)
wherein:
n is 2;
R1 is
each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, haloalkyl, Cl, Br, F, I, —CN, —NO2, —ORb, —SRb, —S(O)RZ, —S(O)2RZ, —NRaRb, —C(O)Rb, —C(O)ORb, —C(O)NRaRb, —S(O)2NRaRb, —C(═NOH)NH2, —C(═NH)NH2, —Rc, —(CRdRe)m—CN, —(CRdRe)m—ORb, —(CRdRe)m—SRb, —(CRdRe)m—S(O)2RZ, —(CRdRe)m—NRaRb, —(CRdRe)m—C(O)Rb, —(CRdRe)m—C(O)ORb, —(CRdRe)m—S(O)2NRaRb, —(CRdRe)m—Re, —N(Ra)—(CRdRe)m—C(O)Rb, —N(Ra)—(CRdRe)m—C(O)ORb, —N(Ra)—(CRdRe)m—C(O)NRaRb, —O—(CRdRe)m—C(O)Rb, —O—(CRdRe)m—C(O)ORb, and —O—(CRdRe)m—C(O)NRaRb;
R2 and R3, at each occurrence, are each independently hydrogen or alkyl,
R4 is —(CRdRe)m-E-G, wherein E, at each occurrence, is independently O, or N(Re), and G, at each occurrence, is independently phenyl or pyridinyl, wherein each G is idenpendently unsubstituted or substituted with 1, or 2 substituents independently selected from the group consisting of alkyl, alkenyl, haloalkyl, Cl, Br, F, I, —CN, —NO2, —ORd, —S(Rd), —S(O)(alkyl), —S(O)(haloalkyl), —S(O)2(alkyl), —S(O)2(haloalkyl), —NRdRe, —C(O)(Rd), —C(O)ORd, —C(O)NRdRe, —S(O)2NRdRe, Rc, —(CRdRe)m—CN, —(CRdRe)m—NO2, —(CRdRe)m—ORd, —(CRdRe)m—S(Rd), —(CRdRe)m—S(O)(alkyl), —(CRdRe)m—S(O)(haloalkyl), —(CRdRe)m—S(O)2(alkyl), —(CRdRe), —S(O)2(haloalkyl), —(CRdRe), —NRdRe, —(CRdRe)m—C(O)(Rd), —(CRdRe)m—C(O)ORd, —(CRdRe), —C(O)NRdRe, —(CRdRe)m—S(O)2NRdRe, and —(CRdRe)m—Re;
Ra, at each occurrence, is independently hydrogen or alkyl;
Rb, at each occurrence, is independently hydrogen, alkyl, haloalkyl, Rc or —(CRdRe)m—Rc;
RZ, at each occurrence, is independently alkyl, haloalkyl, Rc or —(CRdRe)m—Rc;
Rc at each occurrence, is independently aryl, heteroaryl, cycloalkyl or heterocycle;
wherein each Rc is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of alkyl, alkenyl, haloalkyl, Cl, Br, F, I, —CN, —NO2, —ORd, —S(Rd), —S(O)(alkyl), —S(O)(haloalkyl), —S(O)2(alkyl), —S(O)2(haloalkyl), —NRdRe, —C(O)(Rd), —C(O)ORd, —C(O)NRdRe, —S(O)2NRdRe, —(CRdRe)m—CN, —(CRdRe)m—NO2, —(CRdRe)m—ORd, —(CRdRe)m—S(Rd), —(CRdRe)m—S(O)(alkyl), —(CRdRe)m—S(O)(haloalkyl), —(CRdRe), —S(O)2(alkyl), —(CRdRe), —S(O)2(haloalkyl), —(CRdRe)m—NRdRe, —(CRdRe)m—C(O)(Rd), —(CRdRe)m—C(O)ORd, —(CRdRe)m—C(O)NRdRe, and —(CRdRe)m—S(O)2NRdRe;
Rd and Re, at each occurrence, are independently hydrogen or alkyl;
and
m is 1;
and a pharmaceutically acceptable carrier to treat a disorder of the central nervous system wherein an inhibitor of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme activity is of therapeutic benefit;
wherein the disorder is selected from the group comprising decline in cognitive function in Alzheimer's and associated dementias, cognitive deficits associated with aging and neurodegeneration, dementia, senile dementia, AIDS dementia, major depressive disorder, psychotic depression, treatment resistant depression, anxiety, panic disorder, post traumatic stress disorder, depression in Cushing's syndrome, steroid-induced acute psychosis, cognitive deficits associated with diabetes, attention deficit disorder in general, attention deficit hyperactivity disorder (ADHD), mild cognitive impairment, and schizophrenia.
5 Apr 2027Estimated · howhide20 years from earliest known nonprovisional domestic filing plus recorded patent term adjustment. Maintenance-fee lapses, terminal disclaimers and statutory extensions have not been checked. The continuity chain may be incomplete; this is not an enforceability determination.
About 5 months of term left · ends 5 Apr 2027 (estimated)
Priority7 Apr 2006
Filed20 Jul 2012
Published7 Mar 2013
Granted27 Jan 2015
Today12 Oct 2026
Term ends5 Apr 2027
Priority7 Apr 2006
Granted27 Jan 2015
Term ends5 Apr 2027
Priority claimedParent application 60/790,141
Application filedUS 13/554,698
PublishedUS 2013/0059829 A1
Assigned to Abbvie Inc.assignment of assignor's interest
GrantedUS 8,940,902 B2
TodayWithin its term
Term endsEstimated
Description11,554 words
Summary660 words
#The present invention relates to a treatment of central nervous system disorders, cognitive deficits and dementias associated with a diversity of conditions, including age-related or glucocorticoid-related declines in cognitive function such as those seen in Alzheimer's and associated dementias, major depressive disorder, psychotic depression, anxiety, panic disorder, post traumatic stress disorder, depression in Cushing's syndrome, and treatment resistant depression, using 11β-HSD1 inhibitors.
#11-β-hydroxysteroid dehydrogenase Type 1 enzyme (11β-HSD-1) is a low affinity enzyme with Km for cortisone in the micromolar range that prefers NADPH/NADP+ (nicotinamide adenine dinucleotide phosphate) as cofactors. 11β-HSD-1 is widely expressed and particularly high expression levels are found in liver, brain, lung, adipose tissue, and vascular smooth muscle cells. In vitro studies indicate that 11β-HSD-1 is capable of acting both as a reductase and a dehydrogenase. However, many studies have shown that it functions primarily as a reductase in vivo and in intact cells. It converts inactive 11-ketoglucocorticoids (i.e., cortisone or dehydrocorticosterone) to active 11-hydroxyglucocorticoids (i.e., cortisol or corticosterone), and thereby amplifies glucocorticoid action in a tissue-specific manner.
#11β-HSD-1 is expressed in mammalian brain, and published data indicates that elevated levels of glucocorticoids may cause neuronal degeneration and dysfunction, particularly in the aged (de Quervain et al.; Hum Mol Genet. Vol. 13 pages 47-52, 2004; Belanoff et al. J. Psychiatr Res. Vol. 35, pages 127-35, 2001). Evidence in rodents and humans suggests that prolonged elevation of plasma glucocorticoid levels impairs cognitive function that becomes more profound with aging. (See, A. M. Issa et al., J. Neurosci. Vol. 10, pages 3247-3254, 1990; S. J. Lupien et. al., Nat. Neurosci., Vol. 1, pages 69-73, 1998; J. L. Yau et al. Neuroscience, Vol. 66, pages 571-581, 1995). Chronic excessive cortisol levels in the brain may result in neuronal loss and neuronal dysfunction. (See, D. S. Kerr et al., Psychobiology, Vol. 22 pages 123-133, 1994, C. Woolley, Brain Res. Vol. 531 pages 225-231, 1990, P. W. Landfield, Science, Vol. 272 pages 1249-1251, 1996). Furthermore, glucocorticoid-induced acute psychosis exemplifies a more pharmacological induction of this response, and is of major concern to physicians when treating patients with these steroidal agents (Wolkowitz et al.; Ann NY Acad Sci. Vol. 1032 pages 191-194, 2004). It has been recently shown that 11β-HSD-1 mRNA is expressed in human hippocampus, frontal cortex and cerebellum, and that treatment of elderly diabetic individuals with the non-selective 11β-HSD-1 and 11β-HSD-2 inhibitor carbenoxolone improved verbal fluency and memory (Thekkapat et al., Proc Natl Acad Sci USA. Vol. 101, pages 6743-6749, 2004). Excessive glucocorticoid levels also affects psychopathology, as shown in animal models, it leads to increased anxiety and aggression. Chronic elevation of cortisol has been also associated with depression in Cushing's disease (McEwen, Metab. Clin. & Exp. Vol. 54, pages 20-23 (2005)). A number of animal and clinical studies have provided evidence for the correlation between increases in glucocorticoid levels and neuropsychiatric disorders such as major depressive disorder, psychotic depression, anxiety, panic disorder, post traumatic stress disorder, and depression in Cushing's syndrome (Budziszcwska, Polish J. of Pharmacol. Vol. 54 pages 343-349, 2002; Ströhle and Holboer, Pharmacopsychiatry Vol. 36 pages S207-S214, 2003; DeBattista and Belanoff, TRENDS in Endocr. Metab., Vol. 17 pages 117-120, 2006; Norman and Burrows, Expert Rev. Neurotherapeutics Vol. 7, pages 203-213, 2007).
Brief description of the drawings7 figures
#FIG. 1 shows the results of memory consolidation in treated and untreated mice measured as Mean Transfer Latency.
#FIG. 2 depicts amount of phosphorylation of CREB in treated and untreated mice.
#FIG. 3 shows the results of memory consolidation in treated and untreated mice measured as Mean Transfer Latency.
Detailed description10,769 words
#Cognitive symptoms of Alzheimer's are currently treated with acetylcholine esterase inhibitors such as donepezil or NMDA antagonists such as memantine. The efficacy is minimal and short-lived. There is currently no treatment available that will halt or slow the degenerative progression of the disease.
#Cognitive deficits associated with schizophrenia are minimally treated with atypical antipsychotics such as olanzapine. There is no adequate treatment for these deficits.
#11β-HSD1 ligands regulate central glucocorticoid functioning, which in turn has a significant role in cognitive disorders, stress and mood disorders, schizophrenia and related psychoses, etc. Significant evidence indicates that selective HSD-1 inhibitors will protect against age- or glucocorticoid-related declines in cognitive function such as those seen in Alzheimer's and associated dementias. In addition, evidence implicates excessive glucocorticoids as a risk factor in the development and progression of schizophrenia and indicates that cognitive deficits seen in the disorder are linked to abnormalities in glucocorticoid regulation. Thus, ligands that regulate glucocorticoid levels such as 11β-HSD1 inhibitors can provide useful treatment for these disorders by enhancing cognitive function and delaying disease progression in patients with Alzheimer's, schizophrenia or related disorders. For example, it has been shown that a non-selective 11βHSD1 inhibitors like carbenoxolone improves cognitive function in humans, however the liability of adverse cardiovascular effects liability in particular hypertension, diminishes the value of non-selective 11β-HSD1 inhibitors as useful therapeutic agents. The compounds described in U.S. patent application publication Nos. 2005/0277747, 2006/0281773, and 2006/0149070, and in U.S. patent application Ser. No. 11/697,044, are selective 11β-HSD1 inhibitors. As demonstrated below, these compounds significantly enhance cognitive functioning and induce biochemical events necessary for synaptic plasticity in preclinical species.