Compounds, preparation and therapeutic use thereof
The invention relates to benzodiazepine derivatives having PDE2 inhibitory activities, as well as therapeutic methods of administering said compounds, in particular for treating various diseases of the central or peripheral nervous system. The invention further includes methods of preparing the subject compounds and pharmaceutical compositions containing them.
1 - 15 . (canceled)
16 . A compound represented by the formula (I):
wherein:
R 1 , represents hydrogen, an alkyl, aryl, alkylaryl, or arylalkyl group, wherein said group is unsubstituted or substituted with at least one group selected from an alkyl group, a halogen and a haloalkyl group,
R 2 represents hydrogen, a halogen, an alkyl, alkoxy, alkoxyalkyl, alkoxyalkynyl, aminoalkyl, trifluoromethyl, alkenyl, alkynyl, aminoalkynyl, hydroxy group, —CN, —CHO, —CONH 2 group, or a group represented by the following formula: —(R 5 ) n NHCOR 6 , where R 5 is an alkyl, alkenyl or alkynyl group, n is an integer from 0 to 3, and R 6 is an alkyl, aryl, aryloxy or alkoxy group,
R 3 , represents hydrogen, an alkyl, or haloalkyl group,
R 4 represents an aryl or heteroaryl group, said aryl or heteroaryl group being unsubstituted or substituted by one or more groups selected from a halogen, an alkyl, an alkoxy and a haloalkyl group, or a pharmaceutically acceptable salt or solvate thereof.
17 . A compound of formula (I) in accordance with claim 16 , wherein R 1 , represents hydrogen or an alkyl group, selected from methyl, ethyl, propyl and cyclopropylmethyl groups.
18 . A compound of formula (I) in accordance with claim 16 , wherein R 1 represents an arylalkyl group selected from benzyl, phenethyl and 3-phenyl-propyl, wherein the aryl group may be unsubstituted or substituted with a haloalkyl group.
19 . A compound of formula (I) in accordance with claim 16 , wherein R 2 is other than hydrogen and is substituted on position 3 of the phenyl group.
20 . A compound of formula (I) in accordance with claim 16 , wherein R 2 is selected from hydrogen, halogen, —CN, and —CONH 2 .
21 . A compound of formula (I) in accordance with claim 16 , wherein R 2 , is selected from 3-alkoxypropynyl, 3-aminopropynyl, 3-alkoxypropyl and 3-aminopropyl.
22 . A compound of formula (I) in accordance with claim 16 , wherein R 2 is a group represented by the following formula: —(R 5 ) n NHCOR 6 wherein R 5 is an alkyl or alkynyl group, n is an integer from 1 to 3, and R 6 is an alkoxy group.
23 . A compound of formula (I) in accordance with claim 16 , wherein R 3 represents an alkyl group.
24 . A compound of formula (I) in accordance with claim 16 , wherein R 4 is a phenyl group that may be unsubstituted or substituted by one or more groups selected from halogen, an alkyl, alkoxy and a haloalkyl groups.
25 . A compound of formula (I) in accordance with claim 16 , wherein R 4 is a pyridine group that may be unsubstituted or substituted by one or more groups selected from halogen, an alkyl, alkoxy and a haloalkyl groups.
26 . A compound of formula (I) in accordance with claim 16 , wherein said compound is selected from the group of compounds consisting of:
3-(6,8-Dimethoxy-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile;
3-[7-(4-Chloro-phenyl)-6,8-dimethoxy-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-benzonitrile;
6,8-Dimethoxy-5,7-diphenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one;
3-(6,8-Dimethoxy-2-oxo-7-pyridin-3-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile;
5-(3-Bromo-phenyl)-6,8-dimethoxy-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 3-(6,8-Dimethoxy-1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile;
3-[7-(4-Chloro-[rho]henyl)-6,8-dimethoxy-1-methyl-2-oXo-2,3-diliydro-1H-benzo[e][1,4]diazepin-5-yl]-benzonitrile;
3-(6,8-Dimethoxy-1-methyl-2-oxo-7-pyridin-3-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile;
6,8-Dimethoxy-1-methyl-5,7-diphenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one;
5-(3-Bromo-phenyl)-6,8-dimethoxy-1-[pi]iethyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one;
3-(6,8-Dimethoxy-2-oxo-7-phenyl-1-ethyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile;
3-(6,8-Dimethoxy-2-oxo-7-phenyl-1-propyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile;
3-(1-Cyclopropylmethyl-6,8-dimethoxy-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile 3-(1-Benzyl-6,8-dimethoxy-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile;
3-[6,8-Dimethoxy-2-oxo-7-phenyl-1-(4-trifluoromethyl-benzyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-Y]-benzonitrile;
3-[6,8-Dimethoxy-2-oxo-7-phenyl-1-(3-phenyl-propyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-benzonitrile;
3-(6,8-Dimethoxy-1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzamide;
3-[7-(4-Chloro-phenyl)-6,8-dimethoxy-1-methyl-2-oXo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-benzamide 3-(6,8-Dimethoxy-2-oxo-7-pyridin-3-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzamide;
3-(6,8-Dimethoxy-2-oxo-7-pyridin-3-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzamide;
3-(6,8-Dimethoxy-2-oxo-7-phenyl-1-ethyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzamide;
3-(6,8-Dimethoxy-2-oxo-7-phenyl-1-propyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzamide 3-(1-Cyclopropylmethyl-6,8-dimethoxy-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzamide;
3-(1-Benzyl-6,8-dimethoxy-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzamide;
3-[6,8-Dimethoxy-2-oxo-7-phenyl-1-(4-trifluoromethyl-benzyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-benzamide;
3-[6,8-Dimethoxy-2-oxo-7-phenyl-1-(3-phenyl-propyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-benzamide;
6,8-Dimethoxy-5-[3-(3-methoxy-prop-1-ynyl)-phenyl]-1methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one {3-[3-(6,8-Dimethoxy-1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-phenyl]-prop-2-ynyl}-carbamic acid tert-butyl ester;
6,8-Dimethoxy-5-[3-(3-methoxy-propyl)-phenyl]-1-methyl-7-phenyl-1,3-dihydro-benzo [e][1,4]diazepin-2-one;
{3-[3-(6,8-Dimethoxy-1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-phenyl]-prop-2-ynyl}-carbamic acid tert-butyl ester;
5-[3-(3-Amino-prop-1-ynyl)-phenyl]-6,8-dimethoxy-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one; and
5-[3-(3-Amino-propyl)-phenyl]-6,8-dimethoxy-1-methyl-7-phenyl-1,3-dihydro-benzo [e][1,4]diazepin-2-one.
27 . A pharmaceutical composition comprising at least one compound of formula (I) in accordance with claim 16 , and a pharmaceutically acceptable vehicle or support therefor.
28 . A method for the treatment of diseases of the central nervous system associated with an abnormal regulation of neurotransmitter effect or a release deficiency of a neurotransmitter which comprises administration to a patient in need of such treatment an effective amount of a compound of formula (I) in accordance with claim 16 .
29 . A method of treatment in accordance with claim 28 wherein said disease is selected in the group consisting of depression, schizophrenia, autism, anxiety, bipolar disorder, attention deficit hyperactivity disorder (ADHD), convulsion, sleeping disorders, obsessive compulsive disorders (OCD), Post Traumatic Stress Disorder (PTSD), fibromyalgia, Tourette's syndrome, drug or alcohol dependence, epilepsia, movement disorders, including dystonia and tardive dyskinesia, Alzheimer's disease, Huntington's chorea, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, obesity, Restless Legs Syndrome (RLS), psychosis, cerebrovascular diseases, migraine, convulsion, amnesia, premenstrual dysphoric disorder (PMDD), post-traumatic stress disorder (PTSD), panic disorders, memory deficiency, cognitive disorders, social disorders, bulimia nervosa, dementia including Lewy body dementia and senile dementia of the Alzheimer type, rheumatism, sepsis, diabetes-induced pathologies, cancer, autoinflammatory diseases, dysfunction of liver due to ageing, and disorders due to Trypanosoma and Candida albicans.