US 8,569,294 B2Granted

2-(cyclic amino)-pyrimidone derivatives

AssigneesMitsubishi Tanabe Pharma Corporation, Sanofi

InventorsKenji Fukunaga, Toshiyuki Kohara, Kazutoshi Watanabe, Yoshihiro Usui, Fumiaki Uehara, Satoshi Yokoshima, Daiki Sakai, Shin-ichi Kusaka, Kazuki Nakayama

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Abstract

A compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutical acceptable salt thereof: wherein R2 represents a hydrogen or the like; R3 represents methyl group or the like; R20 represents a halogen atom or the like; q represents an integer of 0 to 3; Z represent nitrogen atom, CH, or the like; R4 represents hydrogen or the like; R5 represents hydrogen or the like; R6 represents a substituted alkyloxy and the like; p represents an integer of 0 to 3; X represents bond, CH2, oxygen atom, NH, or the like; any one or more of R5 and R6, R5 and R4, R6 and R4, X and R5, X and R4, X and R6, and R6 and R6 may combine to each other to form a ring, which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity such as a neurodegenerative diseases (e.g. Alzheimer disease).

Claims8

Dependent claims

A compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutically acceptable salt thereof:

wherein each symbol is defined as below:
R4 represents a group represented by the following formula (II):
A14-A13-A12- (II)
wherein
A14 represents hydrogen atom, a C1-C6 alkyl group which may be substituted, a C2-C6 alkenyl group which may be substituted, a C2-C6 alkynyl group which may be substituted, a C3-C7 cycloalkyl group which may be substituted, a C3-C7 cycloalkenyl group which may be substituted, or a heterocyclic group which may be substituted;
A13 represents bond, or oxygen atom;
A12 represents bond, or a C1-C3 methylene group, and A14 and A13 may combine to each other to form a 5 to 7 membered heterocyclic ring;
X represents oxygen atom;
R5 represents a hydrogen atom, a C1-C6 alkyl group which may be substituted, or a group represented by the following formula (IV):
wherein n represents 0 or integer of 1 to 3,
A represents a C6-C10 aryl group,
R7 may be the same or different and represents a halogen atom, or a group represented by the following formula (IV-a):
C4—C3—C2—C1— (IV-a)
wherein C4 represents hydrogen atom (except when all of C3, C2, and C1 represent bond), a C1-C6 alkyl group which may be substituted, a C6-C10 aryl group which may be substituted, a heterocyclic group which may be substituted,
C3 represents bond, or oxygen atom,
C2 represents bond, or C═O,
C1 represents bond;
s represents 0 or an integer of 1 to 5,
R6 may be the same or different and represents a halogen atom, nitro group, cyano group, or a group represented by the following formula (V):
B14—B13—B12—B11— (V)
wherein B14 represents hydrogen atom(except when all of B13, B12, and B11 represent bond), a C1-C6 alkyl group which may be substituted, a heterocyclic group which may be substituted,
B13 represents bond,
B12 represents bond,
B11 represents bond;
p represents an integer of 0 to 6;
Z represents nitrogen atom, C—H or C—R20;
R20 may be the same or different and represents a halogen atom, or a group represented by the following formula (VI):
D4-D3-D2-D1- (VI)
wherein D4 represents a C1-C6 alkyl group which may be substituted,
D3 represents bond, or oxygen atom,
D2 represents bond,
D1 represents bond,
q represents 0 or an integer of 1 to 3;
R2 represents hydrogen atom, a halogen atom or a C1-C6 alkyl group which may be ubstituted;
R3 represents a C1-C12 alkyl group;
any one or more of R5 and R6, R5 and R4, R6 and R4, and R6 and R6 may combine to each other to form a fused, carbocyclic or heterocyclic ring, together with the ring which contains X, and R5, R4 and R6 bind to;
and each symbol satisfies the following proviso (1):
(1) when R4 is a hydrogen atom, at least one of R5 and R6, and R6 and R6 combine to each other to form a fused carbocyclic or heterocyclic ring, together with the ring which contains X, and R5, R4 and R6 bind to.

35 more elements

A compound selected from the group consisting of:

2-((3S)-3-Benzyl-morpholin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;
2-((4aRS,10bRS)-trans-2,3,4a,5,6,10b-Hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
6-(3-Fluoro-pyridin-4-yl)-2-((4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho [1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one;
2-((4aRS,10bRS)-trans-3,4,4a,5,6,10b-Hexahydro-2H-naphtho[1,2-b][1,4]oxazin-4-yl) -3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one;
2-(8-Methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
6-(3-Fluoro-pyridin-4-yl)-2-(8-methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one;
2-(8-Methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;
2-(7-Methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
6-(3-Fluoro-pyridin-4-yl)-2-(7-methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one;
2-(7-Methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;
2-(9-Methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
6-(3-Fluoro-pyridin-4-yl)-2-(9-methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one,
2-(9-Methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;
2-((4aRS,10bSR)-cis-2,3,4a,5,6,10b-Hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
6-(3-Fluoro-pyridin-4-yl)-2-((4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one;
2-((4aRS,10bSR)-cis-2,3,4a,5,6,10b-Hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;
6-(3-Fluoro-pyridin-4-yl)-3-methyl-2-((4aRS,10bRS)-trans-2,3,10,10a-tetrahydro-4aH-4,9-dioxa-1-aza-phenanthren-1-yl)-3H-pyrimidin-4-one;
6-(3-Fluoro-pyridin-4-yl)-2-(8-methoxy-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one;
6-(3-Fluoro-pyridin-4-yl)-2-(6-methoxy-(4aRS,10aRS)-trans-2,3,10,10a-tetrahydro-4aH-4,9-dioxa-1-aza-phenanthren-1-yl)-3-methyl-3H-pyrimidin-4-one;
2-(9-Methoxy-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
6-(3-Fluoro-pyridin-4-yl)-2-(9-methoxy-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one;
2-(9-Methoxy-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;
2-(7-Methoxy-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
6-(3-Fluoro-pyridin-4-yl)-2-(7-methoxy-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one;
2-(7-Methoxy-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;
3-Methyl-6-pyridin-4-yl-2-((4aRS,10aRS)-cis-2,3,10,10a-tetrahydro-4aH-4,9-dioxa-1-aza-phenanthren-1-yl)-3H-pyrimidin-4-one;
6-(3-Fluoro-pyridin-4-yl)-3-methyl-2-((4aRS,10aRS)-cis-2,3,10,10a-tetrahydro-4aH-4,9-dioxa-1-aza-phenanthren-1-yl)-3H-pyrimidin-4-one;
1-Methyl-2-((4aRS,10aRS)-cis-2,3,10,10a-tetrahydro-4aH-4,9-dioxa-1-aza-phenanthren-1-yl)-1H-[4,4′]bipyrimidinyl-6-one;
6-(3-Fluoro-pyridin-4-yl)-2-(6-methoxy-(4aRS,10aRS)-cis-2,3,10,10a-tetrahydro-4aH-4,9-dioxa-1-aza-phenanthren-1-yl)-3-methyl-3H-pyrimidin-4-one;
2-(6-Methoxy-(4aRS,10aRS)-cis-2,3,10,10a-tetrahydro-4aH-4,9-dioxa-1-aza-phenanthren-1-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;
2-(9-Fluoro-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
2-(9-Fluoro-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-6-(3-fluoro-pyridin-4-yl)-3-methyl-3H-pyrimidin-4-one;
2-(9-Fluoro-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;
2-(9-Fluoro-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;
2-(9-Fluoro-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-6-(3-fluoro-pyridin-4-yl)-3-methyl-3H-pyrimidin-4-one;
2-(9-Fluoro-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;
3-Methyl-2-((3R)-3-methyl-morpholin-4-yl)-6-pyridin-4-yl-3H-pyrimidin-4-one;
6-(3-Fluoro-pyridin-4-yl)-3-methyl-2-((3R)-3-methyl-morpholin-4-yl)-3H-pyrimidin-4-one;
1-Methyl-2-((3R)-3-methyl-morpholin-4-yl)-1H-[4,4′]bipyrimidinyl-6-one;
6-(3-Fluoro-pyridin-4-yl)-3-methyl-2-((3S)-3-methyl-morpholin-4-yl)-3H-pyrimidin-4-one;
3-Methyl-2-((4aRS,8aRS)-trans-octahydro-benzo[1,4]oxazin-4-yl)-6-pyridin-4-yl-3H-pyrimidin-4-one;
6-(3-Fluoro-pyridin-4-yl)-3-methyl-2-((4aRS,8aRS)-trans-octahydro-benzo[1,4]oxazin-4-yl)-3H-pyrimidin-4-one;
1-Methyl-2-((4aRS,8aRS)-trans-octahydro-benzo[1,4]oxazin-4-yl)-1H-[4,4′]bipyrimidinyl-6-one;
2-((3R)-3-Ethyl-morpholin-4-yl)-6-(3-fluoro-pyridin-4-yl)-3-methyl-3H-pyrimidin-4-one;
2-((3R)-3-Ethyl-morpholin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;
6-(3-Fluoro-pyridin-4-yl)-2-((3R)-3-isopropyl-morpholin-4-yl)-3-methyl-3H-pyrimidin-4-one;
and
6-(3-Fluoro-pyridin-4-yl)-2-((3R)-3-isobutyl-morpholin-4-yl)-3-methyl-3H-pyrimidin-4-one;
and an optically active isomer thereof, or a pharmaceutically acceptable salt thereof.

46 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/282,396Filed 14 Mar 2007
Priority: JP 2006-11024215 Mar 2006
Published: US 2009/0233918 A117 Sep 2009
Granted: 29 Oct 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 413/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

US 2009/0233918 A1Pre-grant publication · published 17 Sep 2009
US 8,569,294 B2This patent

From the US filing history. Foreign family members aren’t listed.

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