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Bicyclic Pyridine Compound

Abstract: The present invention addresses the problem of providing a pharmaceutical composition particularly a compound suitable for the treatment of nocturia. Extensive and intensive studies have been made on compounds capable of inhibiting placental leucineaminopeptidase (P LAP) in the anticipation that an antidiuretic activity associated with the maintenance of or increase in an endogenous AVP concentration can be exerted by inhibiting P LAP which is a metabolic enzyme for AVP in the nighttime and the urination frequency in the nighttime can be decreased through the antidiuretic activity. As a result it is found that a (2R) 3 amino 2 (bicyclic pyridylmethyl) 2 hydroxypropanoic acid derivative has a good P LAP inhibition activity and it is also found that in an antidiuretic test using a drinking water fed rat the compound has a urine production inhibition activity associated with the increase in an endogenous AVP concentration which is resulted from the P LAP inhibition by the compound. Thus the present invention provides a compound which is expected to be used as a therapeutic agent for nocturia and of which the mechanism of action against nocturia is through the inhibition of P LAP.

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Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
03 October 2017
Publication Number
41/2017
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application
Patent Number
Legal Status
Grant Date
2022-12-20
Renewal Date

Applicants

ASTELLAS PHARMA INC.
5-1, Nihonbashi-Honcho 2-chome, Chuo-ku, Tokyo 103-8411, Japan
KOTOBUKI PHARMACEUTICAL CO., LTD.
6351, Oaza-Sakaki, Sakaki-machi, Hanishina-gun, Nagano 389-0697, Japan

Inventors

1. KAWAGUCHI, Kenichi
o Astellas Pharma Inc., 5-1, Nihonbashi-Honcho 2-chome, Chuo-ku, Tokyo 103-8411, Japan
2. ISHIHATA, Akihiro
c/o Astellas Pharma Inc., 5-1, Nihonbashi-Honcho 2-chome, Chuo-ku, Tokyo 103-8411, Japan
3. KANAI, Akira
c/o Astellas Pharma Inc., 5-1, Nihonbashi-Honcho 2-chome, Chuo-ku, Tokyo 103-8411, Japan
4. INAGAKI, Yusuke
c/o Astellas Pharma Inc., 5-1, Nihonbashi-Honcho 2-chome, Chuo-ku, Tokyo 103-8411, Japan
5. HIRAMOTO, Masashi
c/o Astellas Pharma Inc., 5-1, Nihonbashi-Honcho 2-chome, Chuo-ku, Tokyo 103-8411, Japan
6. ENJO, Kentaro
1-9, Matsushiro 3-chome, Tsukuba-shi, Ibaraki 305-0035, Japan
7. TAKAMATSU, Hajime
c/o Astellas Pharma Inc., 5-1, Nihonbashi-Honcho 2-chome, Chuo-ku, Tokyo 103-8411, Japan

Specification

More Than 100 Pages Hence Not Pasted

CLAIMS
[Claim 1]
A compound represented by Formula (I) or a salt thereof: [Chemical Formula 11]

wherein, X is O or S;
a dotted line is a single bond or a double bond;
R1 is lower alkyl which optionally has one to four substituents selected from the Group G1, cycloalkyl which optionally has one to five substituents selected from the Group G2, or -lower alkylene-(cycloalkyl which optionally has one to five substituents selected from the Group G2);
R2 and R5 are the same or different from each other, and are H, lower alkyl or cycloalkyl;
R3 is -lower alkylene-X3-lower alkyl, -lower alkylene-X3-lower alkylene-(cycloalkyl which optionally has one to five substituents selected from the Group G2), -lower alkylene-(cycloalkyl which optionally has one to five substituents selected from the Group G2), or -lower alkylene-X3-(cycloalkyl which optionally has one to five substituents selected from the Group G2);
X3 is O or S(O)n, wherein n is 0, 1, or 2;

R4 is OH, NH2, or -O-lower alkyl and R6 is H; or R4 and R6 are linked to each other to form, together with -C(=O)-C-O- to which they are attached, 2,2-di(lower alkyl)-4-oxo-1,3-dioxolane-5,5-diyl;
the Group G1 consists of halogen, OH, -O-lower alkyl, -S-lower alkyl, and -O-(lower halogenoalkyl); and
the Group G2 consists of lower alkyl, halogen, lower halogenoalkyl, OH, -O-lower alkyl, -S-lower alkyl, and -O-lower halogenoalkyl. [Claim 2]
The compound or a salt thereof according to claim 1, wherein R4 is OH, NH2, or -O-lower alkyl and R6 is H. [Claim 3]
The compound or a salt thereof according to claim 2, wherein X is O, and a dotted line is a single bond or a double bond; or X is S, and a dotted line is a double bond. [Claim 4]
The compound or a salt thereof according to claim 3, wherein:
R1 is lower alkyl which optionally has one to four substituents selected from the group consisting of halogen, OH, and -O-lower alkyl; cycloalkyl which is optionally substituted by one to two lower alkyls; or -lower alkylene-(cycloalkyl which is optionally substituted by one to two lower alkyls);
R3 is -lower alkylene-X3-lower alkyl, -lower alkylene-X3-lower alkylene-(cycloalkyl which is optionally substituted by one to two lower alkyls), -lower alkylene-(cycloalkyl which is optionally substituted by one to two lower alkyls), or -lower alkylene-X3-(cycloalkyl which is optionally substituted by one to two lower alkyls); and
R2 and R5 are the same or different from each other, and are H or lower alkyl. [Claim 5]

The compound or a salt thereof according to claim 4, wherein:
R1 is lower alkyl which optionally has one to four substituents selected from the group consisting of halogen and OH; cycloalkyl; or -lower alkylene-cycloalkyl; and
R3 is -lower alkylene-S(O)n-lower alkyl, -lower alkylene-O-lower alkylene-cycloalkyl, -lower alkylene-S-lower alkylene-cycloalkyl, -lower alkylene-cycloalkyl, or -lower alkylene-S-cycloalkyl. [Claim 6]
The compound or a salt thereof according to claim 5, wherein R1 is lower alkyl, cycloalkyl, or -lower alkylene-cycloalkyl; R3 is -lower alkylene-S-lower alkyl, -lower alkylene-O-lower alkylene-cycloalkyl, -lower alkylene-S-lower alkylene-cycloalkyl, -lower alkylene-cycloalkyl, or -lower alkylene-S-cycloalkyl; R2 is H or lower alkyl; R5 is H; and R4 is OH. [Claim 7]
The compound or a salt thereof according to claim 6, wherein X is O, and a dotted line is a double bond; R1 is lower alkyl, or -lower alkylene-cycloalkyl; and R3 is -lower alkylene-S-lower alkyl, or -lower alkylene-cycloalkyl. [Claim 8]
The compound or a salt thereof according to claim 2, wherein X is O, and a dotted line is a double bond. [Claim 9]
The compound or a salt thereof according to claim 1, which is a compound selected from the group consisting of the following compounds, or a salt thereof: (2R,3R)-3-amino-2-{[2-(2-cyclopropylethyl)furo[3,2-c]pyridin-4-yl]methyl}-4-(ethylsulfanyl)-2-hydroxybutanoic acid, (2R,3S)-3-amino-5-cyclopropyl-2-{[2-(2-cyclopropylethyl)furo[3,2-c]pyridin-4-yl]methyl}-2-hydroxypentanoic acid, (2R,3R)-3-amino-2-{[2-(2-cyclopropylethyl)furo[3,2-c]pyridin-4-yl]methyl}-2-

hydroxy-4-(methylsulfanyl)butanoic acid, and (2R,3R)-3-amino-2-[(2-butyl-7-methylfuro[3,2-c]pyridin-4-yl)methyl]-2-hydroxy-4-(methylsulfanyl)butanoic acid. [Claim 10]
A pharmaceutical composition comprising the compound or a salt thereof according to claim 1. [Claim 11]
The pharmaceutical composition according to claim 10, which is an agent for treating nocturia. [Claim 12]
A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 and an excipient. [Claim 13]
Use of the compound or a salt thereof according to claim 1 for production of a pharmaceutical composition for treating nocturia. [Claim 14]
Use of the compound or a salt thereof according to claim 1 for treating nocturia. [Claim 15]
The compound or a salt thereof according to claim 1 for treating nocturia. [Claim 16]
A method of treating nocturia comprising administering an effective amount of the compound or a salt thereof according to claim 1 to a subject.

Documents

Application Documents

# Name Date
1 201747034884-IntimationOfGrant20-12-2022.pdf 2022-12-20
1 201747034884-TRANSLATIOIN OF PRIOIRTY DOCUMENTS ETC. [03-10-2017(online)].pdf 2017-10-03
2 201747034884-PatentCertificate20-12-2022.pdf 2022-12-20
2 201747034884-STATEMENT OF UNDERTAKING (FORM 3) [03-10-2017(online)].pdf 2017-10-03
3 201747034884-Response to office action [19-12-2022(online)].pdf 2022-12-19
3 201747034884-PROOF OF RIGHT [03-10-2017(online)].pdf 2017-10-03
4 201747034884-PRIORITY DOCUMENTS [03-10-2017(online)].pdf 2017-10-03
4 201747034884-Correspondence_Assignment_POA_15-12-2022.pdf 2022-12-15
5 201747034884-POWER OF AUTHORITY [03-10-2017(online)].pdf 2017-10-03
5 201747034884-8(i)-Substitution-Change Of Applicant - Form 6 [12-12-2022(online)].pdf 2022-12-12
6 201747034884-FORM 1 [03-10-2017(online)].pdf 2017-10-03
6 201747034884-ASSIGNMENT DOCUMENTS [12-12-2022(online)].pdf 2022-12-12
7 201747034884-PA [12-12-2022(online)].pdf 2022-12-12
7 201747034884-DECLARATION OF INVENTORSHIP (FORM 5) [03-10-2017(online)].pdf 2017-10-03
8 201747034884-FORM 3 [25-10-2022(online)].pdf 2022-10-25
8 201747034884-COMPLETE SPECIFICATION [03-10-2017(online)].pdf 2017-10-03
9 201747034884-CLAIMS UNDER RULE 1 (PROVISIO) OF RULE 20 [03-10-2017(online)].pdf 2017-10-03
9 201747034884-Information under section 8(2) [25-10-2022(online)].pdf 2022-10-25
10 201747034884-FORM 3 [19-05-2022(online)].pdf 2022-05-19
10 201747034884.pdf 2017-10-06
11 201747034884-Information under section 8(2) [19-05-2022(online)].pdf 2022-05-19
11 Correspondence by Agent_Form-1, Power of Attorney_16-10-2017.pdf 2017-10-16
12 201747034884-FORM 3 [09-09-2021(online)].pdf 2021-09-09
12 201747034884-RELEVANT DOCUMENTS [25-10-2017(online)].pdf 2017-10-25
13 201747034884-Information under section 8(2) [09-09-2021(online)].pdf 2021-09-09
13 201747034884-MARKED COPIES OF AMENDEMENTS [25-10-2017(online)].pdf 2017-10-25
14 201747034884-ABSTRACT [04-12-2020(online)].pdf 2020-12-04
14 201747034884-FORM 13 [25-10-2017(online)].pdf 2017-10-25
15 201747034884-Annexure [25-10-2017(online)].pdf 2017-10-25
15 201747034884-CLAIMS [04-12-2020(online)].pdf 2020-12-04
16 201747034884-AMMENDED DOCUMENTS [25-10-2017(online)].pdf 2017-10-25
16 201747034884-FER_SER_REPLY [04-12-2020(online)].pdf 2020-12-04
17 201747034884-FORM 3 [15-03-2018(online)].pdf 2018-03-15
17 201747034884-FORM 13 [04-12-2020(online)].pdf 2020-12-04
18 201747034884-FORM 3 [02-11-2018(online)].pdf 2018-11-02
18 201747034884-OTHERS [04-12-2020(online)].pdf 2020-12-04
19 201747034884-FORM 18 [11-12-2018(online)].pdf 2018-12-11
19 201747034884-FORM 3 [03-09-2020(online)].pdf 2020-09-03
20 201747034884-FER.pdf 2020-03-11
20 201747034884-FORM 4(ii) [03-09-2020(online)].pdf 2020-09-03
21 201747034884-Information under section 8(2) [03-09-2020(online)].pdf 2020-09-03
22 201747034884-FER.pdf 2020-03-11
22 201747034884-FORM 4(ii) [03-09-2020(online)].pdf 2020-09-03
23 201747034884-FORM 18 [11-12-2018(online)].pdf 2018-12-11
23 201747034884-FORM 3 [03-09-2020(online)].pdf 2020-09-03
24 201747034884-OTHERS [04-12-2020(online)].pdf 2020-12-04
24 201747034884-FORM 3 [02-11-2018(online)].pdf 2018-11-02
25 201747034884-FORM 3 [15-03-2018(online)].pdf 2018-03-15
25 201747034884-FORM 13 [04-12-2020(online)].pdf 2020-12-04
26 201747034884-AMMENDED DOCUMENTS [25-10-2017(online)].pdf 2017-10-25
26 201747034884-FER_SER_REPLY [04-12-2020(online)].pdf 2020-12-04
27 201747034884-Annexure [25-10-2017(online)].pdf 2017-10-25
27 201747034884-CLAIMS [04-12-2020(online)].pdf 2020-12-04
28 201747034884-ABSTRACT [04-12-2020(online)].pdf 2020-12-04
28 201747034884-FORM 13 [25-10-2017(online)].pdf 2017-10-25
29 201747034884-Information under section 8(2) [09-09-2021(online)].pdf 2021-09-09
29 201747034884-MARKED COPIES OF AMENDEMENTS [25-10-2017(online)].pdf 2017-10-25
30 201747034884-FORM 3 [09-09-2021(online)].pdf 2021-09-09
30 201747034884-RELEVANT DOCUMENTS [25-10-2017(online)].pdf 2017-10-25
31 201747034884-Information under section 8(2) [19-05-2022(online)].pdf 2022-05-19
31 Correspondence by Agent_Form-1, Power of Attorney_16-10-2017.pdf 2017-10-16
32 201747034884-FORM 3 [19-05-2022(online)].pdf 2022-05-19
32 201747034884.pdf 2017-10-06
33 201747034884-CLAIMS UNDER RULE 1 (PROVISIO) OF RULE 20 [03-10-2017(online)].pdf 2017-10-03
33 201747034884-Information under section 8(2) [25-10-2022(online)].pdf 2022-10-25
34 201747034884-COMPLETE SPECIFICATION [03-10-2017(online)].pdf 2017-10-03
34 201747034884-FORM 3 [25-10-2022(online)].pdf 2022-10-25
35 201747034884-DECLARATION OF INVENTORSHIP (FORM 5) [03-10-2017(online)].pdf 2017-10-03
35 201747034884-PA [12-12-2022(online)].pdf 2022-12-12
36 201747034884-FORM 1 [03-10-2017(online)].pdf 2017-10-03
36 201747034884-ASSIGNMENT DOCUMENTS [12-12-2022(online)].pdf 2022-12-12
37 201747034884-POWER OF AUTHORITY [03-10-2017(online)].pdf 2017-10-03
37 201747034884-8(i)-Substitution-Change Of Applicant - Form 6 [12-12-2022(online)].pdf 2022-12-12
38 201747034884-PRIORITY DOCUMENTS [03-10-2017(online)].pdf 2017-10-03
38 201747034884-Correspondence_Assignment_POA_15-12-2022.pdf 2022-12-15
39 201747034884-Response to office action [19-12-2022(online)].pdf 2022-12-19
39 201747034884-PROOF OF RIGHT [03-10-2017(online)].pdf 2017-10-03
40 201747034884-STATEMENT OF UNDERTAKING (FORM 3) [03-10-2017(online)].pdf 2017-10-03
40 201747034884-PatentCertificate20-12-2022.pdf 2022-12-20
41 201747034884-TRANSLATIOIN OF PRIOIRTY DOCUMENTS ETC. [03-10-2017(online)].pdf 2017-10-03
41 201747034884-IntimationOfGrant20-12-2022.pdf 2022-12-20

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