N,N-bis (quinolin-4-yl)-diamine derivatives, their preparation and their use as antimalarials

• US 5,736,557 A
• Filed: 12/16/1996
• Issued: 04/07/1998
• Est. Priority Date: 06/17/1994
• Status: Expired due to Fees

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Leupin, Werner, Hofheinz, Werner
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): HUANG, EVELYN MEI
• Application Number:
  US08/765,751
• Time in Patent Office: 477 Days
• Field of Search: 546/163, 514/313
• US Class Current: 514/313
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: C07D 215/44 with aryl radicals attached to said nitrogen atoms
• CPC Class Codes: C07D 215/46 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed are N,N'"'"'-bis(quinolin-4-yl)diamine derivatives of general formula I wherein R¹ signifies halogen or trifluoromethyl, R² signifies hydrogen or halogen, A signifies cyclohexane-1,3-diyl, 2-methyl-cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, dicyclohexylmethane-4,4'"'"'-diyl, cyclopentane-1,3-diyl, phenylene-1,4, phenylene-1,3 and phenylene-1,2; n is 1 or 2; m is 1 or 2, as well as their pharmaceutically acceptable salts. These products are useful as agents for preventing malaria and for treating it, especially where the pathogens are resistant to chloroquine. ##STR1##

Claims

1. Compounds of the formula, ##STR4## wherein R¹ is halogen or trifluoromethyl;

R² is hydrogen or halogen;

A is selected from the group consisting of cyclohexane-1,3-diyl, 2-methyl-cyclohexane-1,3,-diyl, cyclohexane-1,4-diyl, dicyclohexylmethane-4,4'"'"'-diyl, cyclopentane-1,3-diyl, phenylene-1,4, phenylene-1,3 and phenylene-1,2;

n is 1 or 2;

m is 1 or 2; and

pharmaceutically acceptable acid addition salts.

2. The compound of claim 1, wherein R¹ is chlorine;

A is selected from the group consisting of cyclohexane-1,3-diyl, 2 methyl-cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, dicyclohexylmethane-4,4'"'"'-diyl, cyclopentane-1,3-diyl, phenylene-1,4, phenylene-1,3 and phenylene-1,2; and

n and m are 1.

3. The compound of claim 1, wherein R¹ is chlorine and n and m are 1.

4. A pharmaceutical composition comprising a compound of the formula ##STR5## wherein R¹ is halogen or trifluoromethyl;

R² is hydrogen or halogen;

A is selected from the group consisting of cyclohexane-1,3-diyl, 2-methyl-cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, dicyclohexylmethane-4,4'"'"'-diyl, cyclopentane-1,3-diyl, phenylene-1,4, phenylene-1,3 and phenylene-1,2;

n is 1 or 2;

m is 1 or 2; and

pharmaceutically acceptable acid addition salts.

5. The pharmaceutical composition of claim 4, further comprising pharmaceutically inert, inorganic or organic carriers, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts, buffers, coating agents and antioxidants.

6. A method for the treatment of malaria comprising administering to a patient an effective amount of a compound of the formula ##STR6## wherein R¹ is halogen or trifluoromethyl;

R² is hydrogen or halogen;

A is selected from the group consisting of cyclohexane-1,3-diyl, 2-methyl-cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, dicyclohexylmethane-4,4'"'"'-diyl, cyclopentane-1,3-diyl, phenylene-1,4, phenylene-1,3 and phenylene-1,2;

n is 1 or 2;

m is 1 or 2; and

pharmaceutically acceptable acid addition salts.

7. The method of claim 6 wherein the effective amount is from about 10 mg to about 2.5 g per day.

8. The method of claim 6 wherein the malaria is chloroquine-resistant.

9. The method of claim 6 wherein the malaria is chloroquine-sensitive.

10. A compound selected from the group consisting of

(7-chloroquinolin-4-yl)-amine,

(7-chloroquinolin-4-yl)-amine,

(7-chloroquinolin-4-yl)-amine,

(7-chloroquinolin-4-yl)-amine.