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.
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.
| # | 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 |
| 1 | SEARCHSTRATEGY_27-02-2020.pdf |