Substituted 4-benzylaminoquinolines and their hetero...

Details Substituted 4-benzylaminoquinolines and their hetero... Substituted 4-benzylaminoquinolines and their hetero...

2000-09-22

2002-01-15

Badio, Barbara P. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C540S107000, C540S113000

Reexamination Certificate

active

06339077

ABSTRACT:

The invention relates to substituted 4-benzylaminoquinolines and their hetero analogs, and to pharmaceutically acceptable salts and physiologically functional derivatives thereof.
The formation of gallstones is, in addition to a number of factors, essentially determined by the composition of bile, in particular by the concentration and the ratio of cholesterol, phospholipids and bile salts. A precondition for the formation of cholesterol gallstones is the presence of cholesterol-supersaturated bile (Carey, M. C. and Small, D. M.; “The physical chemistry of cholesterol solubility in bile. Relationship to gallstone formation and dissolution in man,”
J. Clin. Invest
. 61:998-1026 (1978)).
A great therapeutic demand exists for both the medical dissolution of gallstones and for the prevention of gallstones forming as an alternative to surgical removal of gallstones.
The invention provides compounds which are able to prevent the formation of gallstones by preventing the supersaturation of bile with cholesterol, or by delaying the formation of cholesterol crystals from supersaturated bile.
The invention comprises compounds of formula I:
wherein:
G is
K is —OR(7), —NR(7)R(8), —HN—CH
2
—CH
2
—CO
2
H, —HN—CH
2
—CH
2
—SO
3
H, —NH—CH
2
—CO
2
H, —N(CH
3
)CH
2
CO
2
H, —HN—CHR(9)CO
2
H, or —Ocat, where cat is a cation such as, for example, an alkali metal or alkaline earth metal ion or a quaternary ammonium ion;
R(7), R(8) are independently of one another selected from hydrogen, (C
1
-C
4
)-alkyl, phenyl, and benzyl, wherein an aromatic group is optionally substituted from 1 to 3 times by radicals independently of one another selected from F, Cl, CF
3
, methyl, and methoxy;
R(9) is (C
1-C
4
)-alkyl, benzyl, —CH
2
—OH, H
3
CSCH
2
CH
2
—, HO
2
CCH
2
—, or HO
2
CCH
2
CH
2
—;
R(1) to R(6) are independently of one another selected from hydrogen, —OR(10), —SR(10), —NR(10)R(13), —OCOR(10), —SCOR(10), —NHCOR(10), —OPO(OR(10))
2
, —OSO
2
OR(10), —R(10), and one or more pairs of R(1) and R(2), R(3) and R(4), R(5) and R(6), wherein these pairs optionally form a carbonyl group, wherein only one of the radicals R(1) to R(6) is a bond to L;
R(10), R(13) are independently of one another selected from hydrogen, (C
1
-C
4
)-alkyl, phenyl, and benzyl, wherein an aromatic group is optionally substituted from 1 to 3 times by radicals independently of one another selected from F, Cl, CF
3
, methyl, and methoxy;
L is (C
1
-C
15
)-alkyl, wherein one or more CH
2
units is optionally replaced by —CH═CH—, —C≡C—, —NR(11)—, —CO—, —O—, —SO
2
—, or —S—;
R(11) is hydrogen, (C
1
-C
8
)-alkyl, R(12)—CO—, phenyl, or benzyl;
 R(12) is hydrogen, (C
1
-C
8
)-alkyl, phenyl, or benzyl, wherein an aromatic group is optionally substituted from 1 to 3 times by radicals independently of one another selected from F, Cl, CF
3
, methyl, and methoxy;
P is
 wherein:
R(16) to R(24) are independently of one another selected from hydrogen, F, Cl, Br, I, (C
1
-C
4
)-alkyl, CN, NO
2
, NR(25)R(26), OR(25), OCOR(25), COR(25), COOR(25), CONR(25)R(26), SO
2
R(25), SO
2
OR(25), and SO
2
NR(25)R(26), wherein an alkyl radical is optionally substituted one or more times by fluorine, and wherein only one of the radicals R(16) to R(24) is a bond to L; and
R(25), R(26) are independently of one another selected from hydrogen, (C
1
-C
4
)-alkyl, phenyl, and benzyl, wherein an alkyl radical is optionally substituted one or more times by fluorine;
or any pharmaceutically acceptable salts or physiologically functional derivatives thereof.
In another embodiment, the compounds of formula I have one or more radical(s) with the following meaning(s):
G is
K is OR(7), —NR(7)R(8), —HN—CH
2
—CH
2
—CO
2
H, —HN—CH
2
—CH
2
—SO
3
H, —NH—CH
2
—CO
2
H, —N(CH
3
)CH
2
CO
2
H, —HN—CHR(9)CO
2
H, or —Ocat, where cat is a cation such as, for example, an alkali metal or alkaline earth metal ion or a quaternary ammonium ion;
R(7), R(8) are independently of one another selected from hydrogen, (C
1
-C
4
)-alkyl, phenyl, and benzyl, wherein an aromatic group is optionally substituted from 1 to 3 times by radicals independently of one another selected from F, Cl, CF
3
, methyl, and methoxy;
R(9) is (C
1
-C
4
)-alkyl, benzyl, —CH
2
—OH, H
3
CSCH
2
CH
2
—, HO
2
CCH
2
—, or HO
2
CCH
2
CH
2
—;
R(1), R(3), R(5) are independently of one another selected from hydrogen, —OR(10), NR(10)R(13), —OCOR(10), and —NHCOR(10);
R(10), R(13) are independently of one another selected from hydrogen, (C
1
-C
4
)-alkyl, phenyl, and benzyl, wherein an aromatic group is optionally substituted from 1 to 3 times by radicals independently of one another selected from F, Cl, CF
3
, methyl, and methoxy;
L is (C
1
-C
8
)-alkyl, wherein one or more CH
2
units is optionally replaced by —CH═CH—, —C≡C—, —NR(11)—, —CO—, —O—, or —SO
2
—;
R(11) is hydrogen, (C
1
-C
4
)-alkyl, R(12)—CO—, phenyl, or benzyl;
R(12) is hydrogen, (C
1
-C
4
)-alkyl, phenyl, or benzyl, wherein an aromatic group is optionally substituted from 1 to 3 times by radicals independently of one another selected from F, Cl, CF
3
, methyl, and methoxy;
P is
R(16) to R(24) are independently of one another selected from hydrogen, F, Cl, Br, (C
1
-C
4
)-alkyl, NR(25)R(26), OR(25), OCOR(25), COR(25), COOR(25), and CONR(25)R(26), wherein an alkyl radical is optionally substituted one or more times by fluorine, and wherein only one of the radicals R(16) to R(24) is a bond to L; and
R(25), R(26) are independently of one another selected from hydrogen, (C
1
-C
4
)-alkyl, phenyl, and benzyl, wherein an alkyl radical is optionally substituted one or more times by fluorine;
or any pharmaceutically acceptable salts or physiologically functional derivatives thereof.
Compounds of formula I are found in yet another embodiment in which one or more radical(s) has or have the following meaning(s):
G is
K is —OR(7), —NR(7)R(8), —HN—CH
2
—CH
2
—CO
2
H, —HN—CH
2
—CH
2
—SO
3
H, —NH—CH
2
—CO
2
H, —N(CH
3
)CH
2
CO
2
H, or —Ocat, where cat is a cation such as, for example, an alkali metal or alkaline earth metal ion or a quaternary ammonium ion;
R(7), R(8) are independently of one another selected from hydrogen, (C
1
-C
4
)-alkyl, phenyl, and benzyl, wherein an aromatic group is optionally substituted from 1 to 3 times by radicals independently of one another selected from F, Cl, CF
3
, methyl, and methoxy;
R(1) is hydrogen, or —OH;
L is (C
1
-C
5
)-alkyl, wherein one or more CH
2
units is optionally replaced by —CH═CH—, —C≡C—, —NR(11)—, —CO—, —O—, or —SO
2
—;
R(11) is hydrogen, (C
1
-C
4
)-alkyl, R(12)—CO—, phenyl, or benzyl;
R(12) is hydrogen, (C
1
-C
4
)-alkyl, phenyl, or benzyl, wherein an aromatic group is optionally substituted from 1 to 3 times by radicals independently of one another selected from F, Cl, CF
3
, methyl, and methoxy;
P is
R(16) to R(24) are independently of one another selected from hydrogen, F, Cl, (C
1
-C
4
)-alkyl, NR(25)R(26), OR(25), OCOR(25), COR(25), COOR(25), and CONR(25)R(26), wherein an alkyl radical is optionally substituted one or more times by fluorine, and wherein only one of the radicals R(16) to R(24) is a bond to L; and
R(25), R(26) are independently of one another selected from hydrogen, (C
1
-C
4
)-alkyl, phenyl, and benzyl, wherein an alkyl radical is optionally substituted one or more times by fluorine;
or any pharmaceutically accept able salt thereof.
Of further interest are compounds of formula I in which one or more radicals have the following meaning(s):
G is
R(1) is hydrogen or —OH; p
2
L is (C
1
-C
5
)-alkyl, wherein one or more CH
2
units is optionally replaced by —CH═CH—, —C≡C—, —NR(11)—, —CO—, —O—, or —SO
2
—;
P is
 wherein:
R(16) to R(24) are independently of one another selected from hydrogen, F, Cl, (C
1
-C
4
)-alkyl, NR(25)R(26), OR(25), OCOR(25), COR(25), COOR(25), and CONR(25)R(26), wherein an alkyl radical is optionally substituted one or more times by fluorine, and wherein only one of the radicals R(16) to R(24) is a bond to L; and
R(25), R(26) are independently of one another selected from hydrogen, (C
1
-C
4
)-alkyl, phenyl, and benzyl, wherein

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