WO1995014007B1 - Phenyl-alkyl imidazoles as h3-receptor antagonists - Google Patents

Abstract

The invention provides novel phenyl-alkyl-imidazoles of formula (I) wherein A, R1, R2, m and n are as defined in the specification, and the group —(CH¿2?)n—A—R?1¿ is at the 3- or 4-position, together with their pharmaceutically acceptable salts. These phenyl-alkyl-imidazoles and salts have valuable pharmacological properties, especially CNS activities and activity against inflammatory disease.

Claims

AMENDED CLAIMS

[received by the International Bureau on 17 May 1995 (17.05.95);

original claims 1-23 amended; new claim 24 added (7 pages)]

A compound of the formula

wherein: A Is selected from -O-CO-NR¹-, -O-CO-, -NR¹-CO-NR¹-, -NR¹-CO-, -CO-NR¹-, -CH₂-NR¹- and -C( NR¹)-NR¹-; the groups R¹, which may be the same or different when there are two or three such groups in the molecule of formula I, are selected from hydrogen, and lower alkyl, aryl, cyctoalkyl, heterocydic and heterocyclyl-alkyl groups, and groups of the formula -(CH₂)_y-G. where G is selected from CO₂R³, COR³, CONR³R⁴, OR³, SR³, NR³R⁴, heteroaryl and phenyl, which phenyl is optionally substituted by halogen, lower alkoxy or polyhalotoweralkyl, and y is an integer from 1 to 3;

R² is selected from hydrogen and halogen atoms, and alkyl, alkenyl, alkynyl and trifluoromethyl groups, and groups of the formula OR³, SR³ and NR³R⁴; R³ and R⁴ are independently selected from hydrogen, and lower alkyl and cycloalkyl groups, or R³ and R⁴ together with the intervening nitrogen atom can form a saturated ring containing 4 to 6 carbon atoms that can be substituted with one or two lower alkyl groups;

with the proviso that, when y is 1 and G is OR³, SR³ or NR³R⁴, then neither R³ nor R⁴ is hydrogen; the group -(CH₂)_n-A-R¹ is at the 4-position, and the group R² is at any free position; m is an integer from 1 to 3;

and n is 0 or an integer from 1 to 3; or a pharmaceutically acceptable acid addition salt thereof;

or a pharmaceutically acceptable salt thereof with a base when G is CO₂H; including a tautomeric form thereof.

2. A compound of the formula

wherein:

X is H₂ or NH; the groups R¹, which may be the same or different when there are two or three such groups in the molecuie of formula I, are selected from hydrogen, and lower alkyl, aryl, cycioalkyi, and heterocyclic groups, and groups of the formula

-(CH₂)_y-G, where G is selected from CO2R³, COR³, CONR³R⁴, OR³, SR³, NR³R⁴, heteroaryl and phenyl, which phenyl is optionally substituted by halogen, lower alkoxy or polyhaloioweralkyl, and y is an integer from 1 to 3; m, n, R³ and R⁴ are as defined in claim 1 ; the group -(CH₂) _n-CX-NR¹R² is at the 3- or 4-position; or a pharmaceutically acceptable acid addition salt thereof;

or a pharmaceutically acceptable salt thereof with a base when G is CO₂H; including a tautomeric form thereof.

3. A compound as claimed in claim 2 wherein m is 1 or 2 and n is 0, 1 or 2.

4. A compound as claimed in claim 3 having the formula

wherein m, n, and R¹ are as defined in claim 1.

5. A compound of the formula IB defined in claim 4 wherein the side chain -(CH₂) _n-C( =NH)NR¹ ₂ is at the 4-position.

6. A compound as ciaimed in claim 5 wherein m is 1 or 2 and n is 0, 1 or 2.

7. A compound as claimed in claim 6 wherein the groups R¹ , which may be the same or different, are selected from hydrogen, and aryl groups, and groups of the formula -(CH₂)_y-G, where G is selected from pyridyl and phenyl, which phenyl is optionally substituted by halogen, lower alkoxy or polyhaloioweralkyl, and y is 1 or 2.

8. A compound as claimed in claim 7 wherein one of the groups R¹ is selected from hydrogen, 4-chlorophenylrnethyl, 4-methoxyphenylmethyl, 2-phenylethyl, 4-trifluoromβthylphenylmβthyl and 4-pyridylmethyl, and the other is a hydrogen atom.

9. A compound as claimed In claim 3 wherein A is -O-CO-NR¹-,

10. A compound as claimed in claim 9 wherein the side chain

-(CH₂)_n-A-R¹ is at the 4-position, m is 1 or 2 and n is 0, 1 or 2.

11. A compound as ciaimed in claim 10 wherein the groups R¹ , which may be the same or different, are selected from hydrogen, and aryl groups, and groups of the formula -(CH₂)_y-G, where G is selected from pyridyl and phenyl, which phenyl is optionally substituted by halogen, lower alkoxy or polyhaloioweralkyi, and y is 1 or 2.

12. A compound as ciaimed in claim 11 wherein one of the groups R¹ is selected from hydrogen, 4-chlorophenylmethyl, 4-mβthoxyphenylmethyl,

2-phenylethyl, 4-trifluoromethylphenylmethyl and 4-pyridylmethyl, and the other is a hydrogen atom.

13. A compound as claimed in claim 1 having the formula

14. A compound of claim 1 , having the name N-[(4-chlorophenyl)methyl}-4-[(1H-imidazol-4-yl)methyl)benzene methanimidamide and the structure:

or a pharmaceutically acceptable acid addition salt thereof. 15. A compound of claim 1 , having the name N-[(4-chtorophenyl)methyl]-4-{(1H-imidazol-4-yl)methyl]benzene ethanimidamide and the structure:

or a pharmaceutically acceptable acid addition salt thereof. 16. The dihydrochloride of the compound of claim 14. 17. The dihydrochloride of the compound of claim 15.

16. A pharmaceutical composition containing as active ingredient a

compound of the formula I defined in claim 1 or of the formula IC defined in claim 2 or a pharmaceutically acceptable acid addition salt thereof or a pharmaceutically acceptable salt thereof with a base when G is CO₂H, together with a pharmaceutical carrier or excipient.

19. A method for treating inflammation, which comprises administering to a patient suffering from inflammation an effective amount of a compound or salt as claimed in claim 1 or claim 2.

20. A method for treating allergy, which comprises administering to a patient suffering from allergy an effective amount of a compound or salt as claimed in claim 1 or claim 2.

21. A method for treating diseases of the Gl-tract, which comprises

administering to a patient suffering from a disease of the Gl-tract an effective amount of a compound or salt as claimed in claim 1 or claim 2. 22. A method for treading cardiovascular disease, which comprises

administering to a patient suffering from cardiovascular disease an effective amount of a compound or salt as ciaimed in claim 1 or claim 2.

23. A method for treating disturbances of the central nervous system, which comprises administering to a patient suffering from disturbances of the central nervous system an effective amount of a compound or salt of the formula

wherein:

A is selected from -O-CO-NR¹-, -O-CO-, -NR¹-CO-NR¹-, -NR¹-CO-.

-CO-NR¹-, -COO-, -CH₂-NR¹- and -C(:NR¹)-NR¹-; the groups R¹ , which may be the same or different when there are two or three such groups in the molecule of formula I, are selected from hydrogen, and lower alkyl, aryl, cycloalkyt, heterocyclic and hθterocyclyl-alky! groups, and groups of the formula -(CH₂)_y-G, where G is selected from CO₂R³, COR³, CONR³R⁴, OR³, SR³, NR³R⁴, heteroaryl and phenyl, which phenyl is optionally substituted by halogen, lower alkoxy or polyhaloioweralkyl, and y is an integer from 1 to 3;

R² is selected from hydrogen and halogen atoms, and alkyl, alkenyl, alkynyl and trifluoromethyl groups, and groups of the formula OR³, SR³ and NR³R⁴; R³ and R⁴ are independently selected from hydrogen, and lower alkyl and cydoalkyl groups, or R³ and R⁴ together with the intervening nitrogen atom can form a saturated ring containing 4 to 6 carbon atoms that can be substituted with one or two lower alkyl groups;

with the proviso that, when y is 1 and G is OR³, SR³ or NRSR⁴, then neither R³ nor R⁴ is hydrogen; the group -(CH₂)_n- A-R¹ is at the 4-position, and the group R² is at any free position; m is an integer from 1 to 3;

and n is 0 or an integer from 1 to 3; or a pharmaceutically acceptable acid addition salt thereof;

or a pharmaceutically acceptable salt thereof with a base when G is CO₂H; including a tautomeric form thereof.

24. A method for treating disturbances of the central nervous system, which comprises administering to a patient suffering from cardiovascular disease an effective amount of a compound or salt as claimed in claim 2.