IP Library › Granted Patent US 8,653,100

Granted Patent B2

US 8,653,100 · App. 12/933,326 · Granted Feb 18, 2014

Tetrahydroisoquinolines, pharmaceutical compositions containing them, and their use in therapy

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Quick Facts

Patent No.: US 8,653,100
App. No.: 12/933,326
Granted: Feb 18, 2014
Kind: B2

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Abstract

The present invention relates to tetrahydroisoquinoline of the formula (I) or a physiologically tolerated salt thereof. The invention relates to pharmaceutical compositions comprising such tetrahydroisoquinolines, and the use of such tetrahydroisoquinolines for therapeutic purposes. The tetrahydroisoquinolines are GlyT1 inhibitors.

Claims (111)

1. A tetrahydroisoquinoline compound of the formula (I)

wherein

R is R 1 —W-A 1 -Q-Y-A 2 -X—;

R 1 is hydrogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkyloxycarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkyl, (C 6 -C 12 -aryl-C 1 -C 6 -alkyl)amino-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl, optionally substituted C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, C 1 -C 6 -alkylcarbonyl, halogenated C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, halogenated C 1 -C 6 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, (halogenated C 1 -C 4 -alkyl)aminocarbonyl, C 6 -C 12 -arylaminocarbonyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 1 -C 6 -alkylcarbonyloxy, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy, amino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylcarbonylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkoxycarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkoxy, (halogenated C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylsulfonylamino-C 1 -C 4 -alkoxy, (C 6 -C 12 -aryl-C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclylsulfonylamino-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 3 -C 12 -heterocyclyloxy, C 1 -C 6 -alkylthio, halogenated C 1 -C 6 -alkylthio, C 1 -C 6 -alkylamino, (halogenated C 1 -C 6 -alkyl)amino, di-C 1 -C 6 -alkylamino, di-(halogenated C 1 -C 6 -alkyl)amino, C 1 -C 6 -alkylcarbonylamino, (halogenated C 1 -C 6 -alkyl)carbonylamino, C 6 -C 12 -arylcarbonylamino, C 1 -C 6 -alkylsulfonylamino, (halogenated C 1 -C 6 -alkyl)sulfonylamino, C 6 -C 12 -arylsulfonylamino or optionally substituted C 3 -C 12 -heterocyclyl;

W is —NR 8 — or a bond;

A 1 is optionally substituted C 1 -C 4 -alkylene or a bond;

Q is —S(O) 2 — or —C(O)—;

Y is —NR 9 — or a bond;

A 2 is optionally substituted C 1 -C 4 -alkylene, C 1 -C 4 -alkylene-O—C 1 -C 4 -alkylene, C 1 -C 4 -alkylene-NR 10 —C 1 -C 4 -alkylene, optionally substituted C 6 -C 12 -arylene, optionally substituted C 6 -C 12 -heteroarylene or a bond;

X is —O—, —NR 11 —, —S— or optionally substituted C 1 -C 4 -alkylene;

provided that X is optionally substituted C 1 -C 4 -alkylene if A 2 is a bond;

R 2 is hydrogen, halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, —CN, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyloxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonyloxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, aminosulfonyl, amino, C 1 -C 6 -alkylamino, C 2 -C 6 -alkenylamino or optionally substituted C 3 -C 12 -heterocyclyl;

R 3 is hydrogen, halogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, or two radicals R 3 together with the carbon atom to which they are attached form a carbonyl group;

R 4 is hydrogen, C 1 -C 6 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, CH 2 CN, —CHO, C 1 -C 4 -alkylcarbonyl, (halogenated C 1 -C 4 -alkyl)carbonyl, C 6 -C 12 -arylcarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 2 -C 6 -alkenyl, —C(═NH)NH 2 , —C(═NH)NHCN, C 1 -C 6 -alkylsulfonyl, C 6 -C 12 -arylsulfonyl, amino, —NO or C 3 -C 12 -heterocyclyl;

R 5 is optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino -C 1 -C 4 -alkyl, C 3 -C 12 -heterocyclyl-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl or hydroxy;

R 6 is hydrogen, optionally substituted C 1 -C 6 -alkyl or hydroxy, or

R 5 , R 6 together are carbonyl or optionally substituted C 1 -C 4 -alkylene, wherein one —CH 2 — of C 1 -C 4 -alkylene may be replaced by an oxygen atom or —NR 12 —;

R 7 is optionally substituted C 6 -C 12 -aryl, optionally substituted C 3 -C 12 -cycloalkyl or optionally substituted C 3 -C 12 -heterocyclyl;

R 8 is hydrogen or C 1 -C 6 -alkyl;

R 9 is hydrogen, C 1 -C 6 -alkyl or amino-C 1 -C 6 -alkyl;

R 10 is hydrogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkylsulfonyl;

R 11 is hydrogen or C 1 -C 6 -alkyl; or

R 9 , R 11 together are C 1 -C 4 -alkylene; and

R 12 is hydrogen or C 1 -C 6 -alkyl;

or a physiologically tolerated salt thereof.

2. The compound as claimed in claim 1 , wherein R 1 is C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkyloxycarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, C 6 -C 12 -aryl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkylamino, (halogenated C 1 -C 6 -alkyl)amino, di-C 1 -C 6 -alkylamino or optionally substituted C 3 -C 12 -heterocyclyl.

3. The compound as claimed in claim 1 wherein A 2 is optionally substituted C 1 -C 4 -alkylene or C 1 -C 4 -alkylene-NR 10 —C 1 -C 4 -alkylene.

4. The compound as claimed in claim 1 , wherein X is —O— or —NR 11 .

5. The compound as claimed in claim 1 , wherein A 2 is a bond and X is optionally substituted C 1 -C 4 -alkylene.

6. The compound as claimed in claim 1 , wherein —Y-A 2 -X— is —NR 9 —C 1 -C 4 -alkylene-O—, —C 1 -C 4 -alkylene-O—, —NR 9 —C 1 -C 4 -alkylene-NH—, —NR 9 —CH 2 CO—NH—, —NR 9 —C 1 -C 4 -alkylene-, —NR 9 -1,4-phenylene-O—, —NR 9 -1,2-phenylene-O—, —NR 9 -2,5-pyridylene-O— or —NR 9 -2,3-pyridylene-O—.

7. The compound as claimed in claim 1 , wherein —Y-A 2 -X— has 2 to 6 atoms in the main chain.

8. The compound as claimed in claim 1 , wherein R 1 —W-A 1 -Q-Y-A 2 -X— is R 1 —S(O) 2 —NH-A 2 -X—, R 1 —NH—S(O) 2 -A 2 -X—, R 1 —C(O)—NH-A 2 -X— or R 1 —NH—C(O)-A 2 -X—.

9. The compound as claimed in claim 1 , having one of the formulae

wherein R 1 , W, A 1 , Q, Y, A 2 , X, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are as defined in claim 1 .

10. The compound as claimed in claim 1 , wherein R 2 is hydrogen, halogen or C 1 -C 6 -alkoxy.

11. The compound as claimed in claim 1 , wherein R 3 is hydrogen or C 1 -C 6 -alkyl.

12. The compound as claimed in claim 1 , wherein R 4 is hydrogen, C 1 -C 6 -alkyl, halogenated C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, CH 2 CN, C 1 -C 4 -alkylcarbonyl, (halogenated C 1 -C 4 -alkyl)carbonyl, —C(═NH)NH 2 , —C(═NH)NHCN, C 1 -C 6 -alkylsulfonyl, amino, —NO or C 3 -C 12 -heterocyclyl.

13. The compound as claimed in claim 1 , wherein R 5 is C 1 -C 6 -alkyl and R 6 is hydrogen or C 1 -C 6 -alkyl, or R 5 , R 6 together are optionally substituted C 1 -C 4 -alkylene.

14. The compound as claimed in claim 1 , having the formula

wherein R 1 , W, A 1 , Q, Y, A 2 , X, R 2 , R 3 , R 4 , R 5 , R 6 are as defined in claim 1 , and

R 13a , R 13b , R 13c , R 13d , R 13e

independently are hydrogen, halogen, optionally substituted C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, CN, hydroxy, C 1 -C 6 -alkoxy, amino, C 1 -C 6 -alkylamino, di-C 1 -C 6 -alkylamino or C 3 -C 12 -heterocyclyl.

15. The compound as claimed in claim 1 , having the formula

wherein R 1 , W, A 1 , Q, Y, A 2 , X, R 2 , R 3 , R 4 , R 5 , R 6 are as defined in claim 1 , and

R 13b , R 13c , R 13d , R 13e

16. The compound as claimed in claim 1 , wherein

R 1 is C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 1 -C 6 - alkyloxycarbonylamino -C 1 -C 4 -alkyl, C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, C 6 -C 12 -aryl-C 1 -C 4 -alkyl, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 2 -C 6 -alkenyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkylamino, di-C 1 -C 6 -alkylamino or optionally substituted C 3 -C 12 -heterocyclyl;

W is —NR 8 — or a bond;

A 1 is C 1 -C 4 -alkylene or a bond;

Q is —S(O) 2 — or —C(O)—;

Y is —NR 9 —, C 1 -C 4 -alkylene or a bond;

A 2 is C 1 -C 4 -alkylene, C 6 -C 12 -arylene or C 6 -C 12 -heteroarylene;

X is —O—, —NR 11 — or C 1 -C 4 -alkylene;

R 2 is hydrogen, halogen or C 1 -C 6 -alkoxy;

R 3 is hydrogen or C 1 -C 6 -alkyl;

R 4 is hydrogen, C 1 -C 6 -alkyl, halogenated C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, CH 2 CN, C 1 -C 4 -alkylcarbonyl, (halogenated C 1 -C 4 -alkyl)carbonyl, —C(═NH)NH 2 , —C(═NH)NHCN, C 1 -C 6 -alkylsulfonyl, amino, —NO or C 3 -C 12 -heterocyclyl;

R 5 is C 1 -C 6 -alkyl or optionally substituted C 3 -C 12 -aryl;

R 6 is hydrogen, hydroxy or C 1 -C 6 -alkyl, or

R 5 , R 6 together are optionally substituted C 1 -C 4 -alkylene;

R 7 is optionally substituted C 6 -C 12 -aryl or optionally substituted C 3 -C 12 -heteroaryl;

R 8 is hydrogen;

R 9 is hydrogen or amino-C 1 -C 6 -alkyl;

R 10 is hydrogen; and

R 11 is hydrogen, or

R 9 , R 11 together are C 1 -C 4 -alkylene.

17. The compound as claimed in claim 1 , wherein

R 1 is C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkyloxycarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, C 6 -C 12 -aryl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkylamino, (halogenated C 1 -C 6 -alkyl)amino, di-C 1 -C 6 -alkylamino or Optionally substituted C 3 -C 12 -heterocyclyl;

W is —NR 8 — or a bond;

A 1 is a bond;

Q is —S(O) 2 — or —C(O)—;

Y is —NR 9 — or a bond;

A 2 is C 1 -C 4 -alkylene;

X is —O— or —NR 11 —;

R 2 is hydrogen, halogen or C 1 -C 6 -alkoxy;

R 3 is hydrogen or C 1 -C 6 -alkyl;

R 5 is C 1 -C 6 -alkyl;

R 6 is hydrogen or C 1 -C 6 -alkyl, or

R 5 , R 6 together are optionally substituted C 1 -C 4 -alkylene;

R 7 is optionally substituted C 6 -C 12 -aryl or optionally substituted C 3 -C 12 -heteroaryl; and

R 8 is hydrogen;

R 9 is hydrogen;

R 10 is hydrogen;

R 11 is hydrogen, or

R 9 , R 11 together are C 1 -C 4 -alkylene.

18. A pharmaceutical composition which comprises a carrier and a compound of claim 1 .

19. A method for treating a neurologic or psychiatric disorder in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound as claimed in claim 1 , wherein the neurologic disorder is selected from the group consisting of dementia, cognitive impairment, and attention deficit disorder, and wherein the psychiatric disorder is selected from the group consisting of anxiety disorder, depression, bipolar disorder, schizophrenia, and psychosis.

20. A dihydroisoquinoline compound of the formula (II)

wherein

R is R 1 -W-A 1 -Q-Y-A 2 -X-;

R 1 is hydrogen, C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 alkyl, amino C 1 C 4 alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 C 6 - alkylamino C 1 -C 4 -alkyl, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkyloxycarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, di-C 1 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkyl, (C 6 -C 12 -aryl-C 1 -C 6 -alkyl)amino-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl, optionally substituted C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, C 1 -C 6 -alkylcarbonyl, halogenated C 1 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, halogenated C 1 -C 6 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, (halogenated C 1 -C 4 -alkyl)aminocarbonyl, C 6 -C 12 arylaminocarbonyl, C 2 -C 6 -alkenyl, C 2 -C 6 alkynyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 1 -C 6 -alkylcarbonyloxy, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy, amino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylcarbonylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkoxycarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 aryl-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkoxy, (halogenated C 1 -C 6 -alkyl)sulfonylamino-C 1 - 4 -alkoxy, C 6 -C 12 -arylsulfonylamino-C 1 -C 4 -alkoxy, (C 6 -C 12 -aryl-C 3 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclylsulfonylamino-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 alkoxy, C 6 -C 12 -aryloxy, C 3 -C 12 heterocyclyloxy, C 1 -C 6 -alkylthio, halogenated C 1 -C 6 -alkylthio, C 1 -C 6 -alkylamino, (halogenated C 1 -C 6 -alkyl)amino, di-C 1 -C 6 -alkylamino, di-(halogenated C 1 -C 6 -alkyl)amino, C 1 -C 6 -alkylcarbonylamino, (halogenated C 1 -C 6 -alkyl)carbonylamino, C 6 -C 12 -arylcarbonylamino,C 1 -C 6 -alkylsulfonylamino, (halogenated C 1 -C 6 -alkyl)sulfonylamino, C 6 -C 12 -arylsulfonylamino or optionally substituted C 3 -C 12 -heterocyclyl;

W is —NR 8 — or a bond;

A 1 is optionally substituted C 1 -C 4 -alkylene or a bond;

Q is —S(O) 2 — or —C(O)—;

Y is —NR 9 — or a bond;

X is —O—, —NR 11 —, —S— or optionally substituted C 1 -C 4 -alkylene;

provided that X is optionally substituted C 1 -C 4 -alkylene if A 2 is a bond;

R 3 is hydrogen, halogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, or two radicals R 3 together with the carbon atom to which they are attached form a carbonyl group;

R 5 is optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 3 -C 12 -heterocyclyl-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl or hydroxy;

R 6 is hydrogen, optionally substituted C 1 -alkyl or hydroxy, or

R 5 , R 6 together are carbonyl or optionally substituted C 1 -C 4 -alkylene, wherein one —CH 2 — of C 1 -C 4 -alkylene may be replaced by an oxygen atom or —NR 12 —:

R 7 is optionally substituted C 6 -C 12 -aryl, optionally substituted C 3 -C 12 -cycloalkyl or optionally substituted C 3 -C 12 -heterocyclyl:

R 8 is hydrogen or C 1 -C 6 -alkyl;

R 9 is hydrogen, C 1 -C 6 -alkyl or amino-C 1 -C 6 -alkyl;

R 10 is hydrogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkylsulfonyl;

R 11 is hydrogen or C 1 -C 6 -alkyl: or

R 9 , R 11 together are C 1 -C 4 -alkylene: and

R 12 is hydrogen or C 1 -C 6 -alkyl.

Assignments (4)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 16, 2013

From: ABBOTT GMBH & CO KG

To: ABBVIE DEUTSCHLAND GMBH & CO KG

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