# US 8,541,408 B2 · Aminodihydrothiazine derivatives substituted with a cyclic group

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- Number: US 8,541,408 B2
- Document ID: US8541408B2
- Status: Granted
- Kind: B2
- Application number: 13/417,786
- Filed: 2012-03-12
- Published: 2012-07-05
- Granted: 2013-09-24
- Earliest claimed: 2007-04-24
- Assignees: Shionogi & Co., Ltd.
- Applicants: Yuusuki Tamura; Shinji Suzuki; Yukio Tada; Chiaki Fujikoshi; Sae Matsumoto; Yuuji Kooriyama
- Inventors: Yuusuki Tamura; Shinji Suzuki; Yukio Tada; Chiaki Fujikoshi; Sae Matsumoto; Yuuji Kooriyama
- Web page: https://patentgrep.com/patent/US8541408B2

## CPC

- C07C 215/20: the carbon skeleton being saturated and containing rings
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 279/06: not condensed with other rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 493/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

This invention provides a compound of the formula (I): wherein the ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; R1 is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl; R2a and R2b are each independently hydrogen, optionally substituted lower alkyl or optionally substituted acyl; R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxy or optionally substituted lower alkyl etc.; a pharmaceutically acceptable salt or solvate thereof, which is useful for treating diseases induced by production, secretion and/or deposition of amyloid β protein.

## Claims

### Claim 1

A compound of the formula (I):
wherein the ring A is an optionally substituted benzofuran, wherein a substituent of the optionally substituted benzofuran is at least one selected from the group consisting of
(A) the substituent group α, the substituent group α being at least one selected from the group consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, imino, hydroxyimino, lower alkoxyimino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfonyl, cyano, nitro, a carbocyclic group and a heterocyclic group;
(B) lower alkyl optionally substituted with one or more substituent(s) selected from the substituent group α, hydroxyimino and lower alkoxyimino;
(C) amino lower alkyl substituted with one or more substituent(s) selected from the substituent group α;
(D) hydroxyimino lower alkyl;
(E) lower alkoxyimino lower alkyl;
(F) lower alkenyl optionally substituted with one or more substituent(s) selected from the substituent group α;
(G) lower alkynyl optionally substituted with one or more substituent(s) selected from the substituent group α;
(H) lower alkoxy optionally substituted with one or more substituent(s) selected from the substituent group α;
(I) lower alkoxy lower alkoxy optionally substituted with one or more substituent(s) selected from the substituent group α;
(J) lower alkenyloxy optionally substituted with one or more substituent(s) selected from the substituent group α;
(K) lower alkoxy lower alkenyloxy optionally substituted with one or more substituent(s) selected from the substituent group α;
(L) lower alkynyloxy optionally substituted with one or more substituent(s) selected from the substituent group α;
(M) lower alkoxy lower alkynyloxy optionally substituted with one or more substituent(s) selected from the substituent group α;
(N) lower alkylthio optionally substituted with one or more substituent(s) selected from the substituent group α;
(O) lower alkenylthio optionally substituted with one or more substituent(s) selected from the substituent group α;
(P) lower alkynylthio optionally substituted with one or more substituent(s) selected from the substituent group α;
(Q) lower alkylamino substituted with one or more substituent(s) selected from the substituent group α;
(R) lower alkenylamino substituted with one or more substituent(s) selected from the substituent group α;
(S) lower alkynylamino substituted with one or more substituent(s) selected from the substituent group α;
(T) aminooxy optionally substituted with one or more substituent(s) selected from lower alkylidene and the substituent group α;
(U) acyl substituted with one or more substituent(s) selected from the substituent group α;
(V) lower alkylsulfonyl optionally substituted with one or more substituent(s) selected from the substituent group α;
(W) lower alkylsulfinyl optionally substituted with one or more substituent(s) selected from the substituent group α;
(X) sulfamoyl;
(Y) lower alkylsulfamoyl optionally substituted with one or more substituent(s) selected from the substituent group α;
(Z) a carbocyclic group optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AA) a heterocyclic group optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AB) carbocyclyl lower alkyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AC) heterocyclyl lower alkyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AD) carbocyclyloxy optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AE) heterocyclyloxy optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AF) carbocyclyl lower alkoxy optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AG) heterocyclyl lower alkoxy optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AH) carbocyclyl lower alkoxycarbonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AI) heterocyclyl lower alkoxycarbonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AJ) carbocyclylthio optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AK) heterocyclylthio optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AL) carbocyclyl amino optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AM) heterocyclyl amino optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AN) carbocyclyl lower alkylamino optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AO) heterocyclyl lower alkylamino optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AP) lower alkylsulfamoyl optionally substituted with one or more substituent(s) selected from the substituent group α;
(AQ) carbocyclylsulfamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AR) heterocyclylsulfamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AS) carbocyclylsulfonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AT) heterocyclylsulfonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AU) carbocyclylcarbamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AV) heterocyclyl carbamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AW) carbocyclyl lower alkylcarbamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AX) heterocyclyl lower alkylcarbamoyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AY) carbocyclyloxycarbonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(AZ) heterocyclyloxycarbonyl optionally substituted with one or more substituent(s) selected from the substituent group α, azide, lower alkyl and halogeno lower alkyl;
(BA) lower alkylenedioxy optionally substituted with halogen;
(BB) oxo;
(BC) azide; and
(BD) one of the following formulae:
wherein Ak1, Ak2 and Ak3 are each independently a single bond, optionally substituted lower alkylene wherein the substituent(s) is selected from the substituent group α, optionally substituted lower alkenylene wherein the substituent(s) is selected from the substituent group α, or optionally substituted lower alkynylenewherein the substituent(s) is selected from the substituent group α;
Ak4 is optionally substituted lower alkylene wherein the substituent(s) is selected from the substituent group α, optionally substituted lower alkenylene wherein the substituent(s) is selected from the substituent group α, or optionally substituted lower alkynylene wherein the substituent(s) is selected from the substituent group α;
W1 and W3 are each independently O or S,
W2 is O, S or NR5,
R5 and R6 are each independently hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclyl lower alkyl, lower alkenyl, hydroxyl lower alkenyl, lower alkoxy lower alkenyl, lower alkoxycarbonyl lower alkenyl, carbocyclyl lower alkenyl, lower alkynyl, hydroxyl lower alkynyl, lower alkoxy lower alkynyl, lower alkoxycarbonyl lower alkynyl, carbocyclyl lower alkynyl or acyl;
R7 is hydrogen or lower alkyl;
the ring B is a carbocyclic group or a heterocyclic group, the carbocyclic group and the heterocyclic group being substituted optionally with at least one selected from the above (A) to (BC) and
p is 1 or 2; W1, W3 or W5 may be independent when it is pluralized,
R1 is optionally substituted lower alkyl wherein the substituent(s) is selected from the substituent group α, optionally substituted lower alkenyl wherein the substituent(s) is selected from the substituent group α, optionally substituted lower alkynyl wherein the substituent is selected from the substituent group α, an optionally substituted carbocyclic group wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, or an optionally substituted heterocyclic group wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α,
R2a and R2b are each independently hydrogen, optionally substituted lower alkyl wherein the substituent(s) is selected from the substituent group a or optionally substituted acyl wherein acyl includes aliphatic acyl, carbocyclyl carbonyl and heterocyclyl carbonyl, and the substituent(s) is selected from the substituent group α, and the substituent(s) for a moiety of the ring in carbocyclyl carbonyl and heterocyclylcarbonyl is selected from a group of lower alkyl, the substituent group α and lower alkyl substituted with one or more substituent(s) selected from the substituent group α, and
R3a, R3b, R3c and R3d are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl wherein the substituent(s) is selected from the substituent group α, optionally substituted lower alkenyl wherein the substituent(s) is selected from the substituent group α, optionally substituted acyl wherein acyl includes aliphatic acyl, carbocyclyl carbonyl and heterocyclic carbonyl, and the substituent(s) is selected from the substituent group α, and the substituent(s) for a moiety of the ring in carbocyclyl carbonyl and heterocyclylcarbonyl is selected from a group of lower alkyl, the substituent group α and lower alkyl substituted with one or more substituent(s) selected from the substituent group α, optionally substituted lower alkoxy wherein the substituent(s) is selected from the substituent group α, optionally substituted carbocyclyl lower alkyl wherein the substituent(s) is selected from the substituent group α, optionally substituted heterocyclyl lower alkyl wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, optionally substituted carbocyclyl lower alkoxy wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, optionally substituted heterocyclyl lower alkoxy wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, optionally substituted aralkyl wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, optionally substituted heteroaralkyl wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, optionally substituted aralkyloxy wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, optionally substituted heteroaralkyloxy wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, optionally substituted lower alkylthio wherein the substituent(s) is selected from the substituent group α, carboxy, optionally substituted lower alkoxycarbonyl wherein the substituent(s) is selected from the substituent group α, optionally substituted amino wherein the substituent(s) is selected from a group of lower alkyl, acyl, hydroxyl, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group, optionally substituted carbamoyl wherein the substituent(s) is selected from a group of lower alkyl, acyl, hydroxyl, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group, an optionally substituted carbocyclic group wherein the substituent(s) is selected from a group of lower alkyl and the substituent group a or an optionally substituted heterocyclic group wherein the substituent(s) is selected from a group of lower alkyl and the substituent group α, or
R3a and R3b or R3c and R3d may form a carbocyclic ring together with a linked carbon atom or may form oxo,
or a pharmaceutically acceptable salt.

### Claim 2 (depends on 1)

The compound of claim 1,
wherein the ring A is
wherein the ring A′ is benzofuran and,
G is
wherein R5 is hydrogen, lower alkyl or acyl,
R6 is optionally substituted lower alkyl which is substituted with one of more of substituent(s) selected from the substituent group α, optionally substituted lower alkenyl which is substituted with one of more of substituent(s) selected from the substituent group α or optionally substituted lower alkynyl which is substituted with one of more of substituent(s) selected from the substituent group α,
W1 is O or S,
W2 is O, S or NR5,
Ak is optionally substituted lower alkylene wherein the substituent(s) is selected from the substituent group α, optionally substituted lower alkenylene wherein the substituent(s) is selected from the substituent group α or optionally substituted lower alkynylene wherein the substituent(s) is selected from the substituent group α,
the ring B is a carbocyclic group or a heterocyclic group, the carbocyclic group and the heterocyclic group being substituted optionally with at least one selected from the above (A) to (BC) and each R5 may be independent:
R4 is halogen, hydroxyl, mercapto, halogeno lower alkyl, lower alkoxy, amino, lower alkylamino, acylamino or lower alkylthio, n is an integer of 0 to 2, and each R4 may be independent;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R1 is C1-C3 alkyl; or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1, wherein both of R2a and R2b are hydrogen; or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein all of R3a, R3b, R3c and R3d are hydrogen; or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R3a and R3b are the same substituent selected from halogen and optionally substituted lower alkyl wherein the substituent(s) is selected from the substituent group a; or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R3c and R3d are the same substituent selected from halogen and optionally substituted lower alkyl wherein the substituent(s) is selected from the substituent group α; or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R3a and R3b, or R3c and R3d form a carbocyclic ring together with a linked carbon atom; or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 1)

A method for treating a condition selected from the group consisting of Alzheimer's dementia, Down's disease, prion disease, mild cognitive impairment (MCI), Dutch-type hereditary cerebral hemorrhage with amyloidosis, cerebral amyloid angiopathy, vascular degenerated mixed dementia, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear paralysis, dementia associated with corticobasal degeneration, diffuse Lewy Bodies Alzheimer's disease, age-related macular degeneration, Parkinson's disease, or amyloid angiopathy in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.