IP Library Granted Patent US 7,064,135
Granted Patent B2
US 7,064,135 · App. 10/267,620 · Granted Jun 20, 2006

Substituted piperidines

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Quick Facts
Patent No.
US 7,064,135
App. No.
10/267,620
Granted
Jun 20, 2006
Kind
B2
Abstract

A novel class of substituted piperidines, pharmaceutical compositions comprising them and use thereof in the treatment of diseases and disorders related to the histamine H3 receptor. More particularly, the compounds are useful for the treatment of diseases and disorders in which an interaction with the histamine H3 receptor is beneficial.

Claims (50)

1. A compound of the general formula (I):

wherein

m is 1,

q is 1,

X is —CH 2 —(CH 2 ) n —, —(CH 2 ) n —CH═CH—(CH 2 ) p —, —CH 2 —(CH 2 ) n —O—(CH 2 ) p —, —CH 2 —(CH 2 ) n —C(═O)—(CH 2 ) p —, —CH 2 —(CH 2 ) n —S—(CH 2 ) p —, —CH 2 —(CH 2 ) n —S(═O)—(CH 2 ) p — or —CH 2 —(CH 2 ) n —S(═O) 2 —(CH 2 ) p —,

n and p are independently 0, 1, 2, 3 or 4,

R 1 and R 2 are independently hydrogen, methyl or trifluoromethyl,

Y is

(a) aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from

nitro, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 3 R 4 and —O(C═O)NR 3 R 4 , wherein R 3 and R 4 independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl,

or wherein two substituents in adjacent positions form a radical —O—(CH 2 ) 1-3 —O—,

aryl, aryl-C 1-6 -alkyl and aryl-C 1-6 -alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from

halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 5 R 6 and —O(C═O)NR 5 R 6 ,

 wherein R 5 and R 6 independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

or wherein two substituents in adjacent positions form a radical —O—(CH 2 ) 1-3 —O

(b) C 3-8 -cycloalkyl or C 5-8 -cycloalkenyl, which may optionally be substituted with one or more substituents selected from

C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halogen,

aryl and aryloxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from

halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 7 R 8 and —O(C=O)NR 7 R 8 ,

 wherein R 7 and R 8 independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

or wherein two substituents in adjacent positions form a radical —O—(CH 2 ) 1-3 —O—

(c) C 1-6 -alkyl, C 2-6 -alkenyl and C 2-6 -alkynyl, which may optionally be substituted with one or more substituents selected from halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, and trifluoromethoxy,

aryl, aryl-C 1-6 -alkyl and aryl-C 1-6 -alkoxy, wherein the ring moieties optionally may be substituted with one or more substituents selected from

halogen, nitro, cyano, hydroxy, C 1-7 -alkanoyl, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-8 -cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR 11 R 12 and —O(C═O)NR 11 R 12 ,

 wherein R 11 and R 12 independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl, or R 11 and R 12 together with the nitrogen atom to which they are attached form a 4 to 7 membered, saturated or unsaturated ring,

or wherein two substituents in adjacent positions form a radical —O—(CH 2 ) 1-3 —O—,

with the proviso that the compound must not be

as well as any diastereomer or enantiomer or tautomeric form thereof, mixtures of these or a pharmaceutically acceptable salt thereof.

2. A compound according to any one of the preceding claim 1 , wherein R 1 and R 2 are both hydrogen.

3. A compound according to any one of the preceding claim 1 , wherein X is —CH 2 —(CH 2 ) n —, —(CH 2 ) n —CH═CH—(CH 2 ) p —, —CH 2 —(CH 2 ) n —O—(CH 2 ) p —, —CH 2 —(CH 2 ) n —C(═O)—(CH 2 ) p —, or —CH 2 —(CH 2 ) n —S—(CH 2 ) p —, wherein n and p are as defined in claim 1 .

4. A compound according to claim 3 , wherein X is —CH 2 —(CH 2 ) n —, —CH═CH—, —CH 2 —(CH 2 ) n —O—, —CH 2 —(CH 2 ) n —C(═O)—, —CH 2 —S—(CH 2 ) p —, wherein n is 0, 1, 2 or 3, and p is 0 or 1.

5. A compound according to claim 4 , wherein X is —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —CH═CH—, —CH 2 —O—, —(CH 2 ) 3 —O—, —(CH 2 ) 2 C(═O)—, —CH 2 —S—CH 2 — or —CH 2 —S—.

6. A compound according to any one of the preceding claim 1 , wherein Y is C 1-6 -alkyl, C 3-8 -cycloalkyl, aryl or heteroaryl, which may optionally be substituted as defined in claim 1 .

7. A compound according to claim 6 , wherein Y is C 1-6 -alkyl, cyclohexyl, phenyl, naphthyl, pyridyl, benzoxazolyl, imidazolyl or benzothiophenyl, which may optionally be substituted as defined in claim 1 .

8. A compound according to claim 7 , wherein Y is phenyl or naphthyl, which may optionally be substituted with one or more substituents selected from

trifluoromethyl, trifluoromethoxy, nitro, C 1-6 -alkyl, —NR 3 R 4 , —O(C═O)NR 3 R 4 and C 1-7 -alkanoyl, wherein R 3 and R 4 independently are hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl, C 1-7 -alkanoyl or aryl,

aryl-C 1-6 -alkoxy, aryl-C 1-6 -alkyl and aryl, which may optionally be substituted with halogen or C 1-6 -alkyl,

or wherein two substituents in adjacent positions form a radical —O—(CH 2 ) 1-3 —O—.

9. A compound according to claim 8 , wherein Y is phenyl or naphthyl, which may optionally be substituted with one or more substituents selected from

trifluoromethyl, trifluoromethoxy, nitro, C 1-6 -alkyl, —NR 3 R 4 , —O(C═O)NR 3 R 4 and C 1-7 -alkanoyl, wherein R 3 and R 4 independently are hydrogen or C 1-6 -alkyl,

phenyl-C 1-6 -alkoxy, phenyl-C 1-6 -alkyl and phenyl, which may optionally be substituted with halogen or C 1-6 -alkyl,

or wherein two substituents in adjacent positions form a radical —O—(CH 2 ) 1-3 —O—.

10. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to claim 1 together with one or more pharmaceutically acceptable carriers or excipients.

11. A pharmaceutical composition according to claim 10 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to claim 1 .

12. A method for the treatment of disorders or diseases selected from the following: obesity, overweight, impaired glucose tolerance (IGT), type 1 diabetes, type 2 diabetes, progression of IGT to type II diabetes, and progression of non-insulin-requiring type II diabetes to insulin-requiring type II diabetes the method comprising administering to a subject in need thereof an effective amount of a compound as defined in claim 1 or a pharmaceutical composition comprising the same.

13. The method according to claim 12 , wherein the effective amount of the compound is in the range of from about 0.05 mg to about 2000 mg, from about 0.1 mg to about 1000 mg, or from about 0.5 mg to about 500 mg per day.

14. A method according to claim 12 , wherein the disorder or disease is selected from impaired glucose tolerance and type II diabetes.

15. A method according to claim 12 , wherein the disorder or disease is selected from: progression of IGT to type II diabetes, and progression of non-insulin-requiring type II diabetes to insulin-requiring type II diabetes.

16. A method according to claim 12 , wherein the disorder or disease is selected from obesity or overweight.

17. A method according to claim 12 , wherein the disorder or disease is type I diabetes.

Assignments (7)
NOTICE OF RELEASE OF SECURITY INTEREST IN PATENTS FOR REEL/FRAME 030982/0793 Recorded Apr 7, 2014
From: M&F TTP HOLDINGS LLC
To: HIGH POINT PHARMACEUTICALS, LLC
Reel/Frame 032621/0867 →
SECURITY AGREEMENT Recorded Aug 9, 2013
From: HIGH POINT PHARMACEUTICALS, LLC
To: M&F TTP HOLDINGS LLC C/O MACANDREWS & FORBES HOLDINGS INC.
Reel/Frame 030982/0793 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 27, 2009
From: TRANSTECH PHARMA, INC.
To: HIGH POINT PHARMACEUTICALS, LLC
Reel/Frame 022584/0958 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 20, 2009
From: NOVO NORDISK A/S
To: TRANSTECH PHARMA, INC.
Reel/Frame 022562/0365 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 30, 2008
From: TRANSTECH PHARMA, INC.
To: HIGH POINT PHARMACEUTICALS, LLC
Reel/Frame 021754/0978 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 30, 2008
From: NOVO NORDISK A/S
To: TRANSTECH PHARMA, INC.
Reel/Frame 021018/0022 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 26, 2002
From: DORWALD, FLORENCIO ZARAGOZA
To: NOVO NORDISK A/S
Reel/Frame 013526/0133 →