Substituted acylguanidines, process for their preparation,...

Details Substituted acylguanidines, process for their preparation,... Substituted acylguanidines, process for their preparation,...

2000-09-05

2002-09-17

Qazi, Sabiha (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S171000, C514S182000, C552S553000, C552S554000

Reexamination Certificate

active

06451781

ABSTRACT:

This application claims the benefit of foreign priority under 35 U.S.C. §119 to German patent application no. 19941764.4-43, filed on Sep. 2, 1999, the contents of which are incorporated by reference herein.
The invention relates to substituted acylguanidines and their pharmaceutically tolerable salts and physiologically functional derivatives.
In addition to a number of factors, the formation of gallstones is essentially determined by the composition of the bile, in particular by the concentration and the ratio of cholesterol, phospholipids and bile salts. A prerequisite for the formation of cholesterol gallstones is the presence of bile which is supersaturated in cholesterol (ref. Carey, M. C. and Small, D. M. (1978) The physical chemistry of cholesterol solubility in bile. Relationship to gallstone formation and dissolution in man, J. Clin. Invest. 61: 998-1026).
Up to now, gallstones have mainly been removed surgically, so that there is a great therapeutic need for the medicinal dissolution of gallstones and for the prevention of gallstone formation.
The invention was based on the object of making available compounds which are able to prevent the formation of gallstones by preventing the supersaturation of the bile with cholesterol, or by delaying the formation of cholesterol crystals from supersaturated biles.
The invention therefore relates to compounds of the formula I
in which:
T1 and T2 independently of one another are
or hydrogen, where
T1 and T2 cannot simultaneously be hydrogen;
Z is
A is a bond, (C
1
-C
4
)-alkyl, (C
0
-C
4
)-alkyl-X;
X is —O—, —CO—, —CH[OH]—, —CH[OCH
3
]—, —SO
(0-2)
— or —NH—,—N(CH
3
)—;
D is phenylene which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, —CF
3
, (C
1
-C
4
)-alkyl, hydroxyl, methoxy, —NH
2
, NHCH
3
, N(CH
3
)
2
, CH
3
SO
2
— and H
2
NO
2
S—;
R(A), R(B), R(C), R(D), R(E), R(F) independently of one another are hydrogen, F, Cl, Br, I, CN, OH, OR(6), NR(7)R(8), (C
1
-C
8
)-alkyl, O—(C
1
-C
12
)-alkyl, (C
3
-C
8
)-cycloalkyl, it being possible in the alkyl radicals for one, a number or all hydrogens to be replaced by fluorine;
R(6) is (C
3
-C
6
)-alkenyl, (C
3
-C
8
)-cycloalkyl, phenyl or benzyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF
3
, methyl, methoxy, NR(9)R(10);
R(9), R(10) independently of one another are H, (C
1
-C
4
)-alkyl or (C
1
-C
4
)-perfluoroalkyl;
R(7) and R(8) independently of one another are (C
1
-C
4
)-alkyl, (C
3
-C
6
)-alkenyl, (C
3
-C
8
)-cycloalkyl, phenyl or benzyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF
3
, methyl, methoxy, NR(9)R(10); or
R(7) and R(8) together form a chain of 4 or 5 methylene groups, of which one CH
2
group can be replaced by oxygen, sulfur, NH, N—CH
3
or N-benzyl;
s is zero or 1,
x is zero, 1 or 2;
y is zero, 1 or 2;
R(1), R(2), R(3) independently of one another are hydrogen, F, Cl, Br, I, CN, —(C═O)—N═C(NH
2
)
2
, —SO
(0-1)
—(C
1
-C
8
)-alkyl, O—(C
0
-C
4
)—alkylphenyl, —(C
0
-C
4
)-alkylphenyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF
3
, methyl, methoxy, —(C
0
-C
4
)-alkyl-NR(21)R(22);
(C
1
-C
8
)-alkyl, O—(C
1
-C
12
)-alkyl, (C
3
-C
8
)-cycloalkyl, it being possible in the alkyl radicals for one, a number or all hydrogens to be replaced by fluorine;
R(21), R(22) independently of one another are H, (C
1
-C
4
)-alkyl;
L is (C
1
-C
15
)-alkyl, it being possible for one or more (CH
2
) groups to be replaced by —CH═CH—, —C≡C—, —O—, —NR(47)—, —NR(48)—, —CO—, —SO
2
—;
R(47) is hydrogen, (C
1
-C
8
)-alkyl, R(48)—CO—, phenyl, benzyl;
R(48) is hydrogen, (C
1
-C
8
)-alkyl, phenyl, (CH
2
)-phenyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF
3
, methyl, methoxy;
R(40) to R(45) independently of one another are H, —O R(50), —S R(50), NH R(50), —N R(50)
2
, —O—(CO)— R(50), —S—(CO)— R(50), —NH—(CO)— R(50), —O—PO—(O R(50))—O R(50), —O—(SO
2
)—O R(50), —R(50), a bond to L; or
R(40) and R(41), R(42) and R(43), R(44) and R(45) in each case together are the oxygen of a carbonyl group;
just one of the radicals always having the meaning of a bond to L;
R(50) is hydrogen, (C
1
-C
4
)-alkyl, phenyl, (CH
2
)-phenyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF
3
, methyl, methoxy;
K is —OR(51), —NH(R51), —N(R51)
2
, —HN—CH
2
—CH
2
—CO
2
H, —HN—CH
2
—CH
2
—SO
3
H, —N(CH
3
)CH
2
CO
2
H, —HN—CH(R46)CO
2
H, —OKa, Ka being a cation, such as, for example, an alkali metal or alkaline earth metal ion or a quaternary ammonium ion;
R(46) is hydrogen, C
1
-C
4
-alkyl, benzyl, —CH
2
—OH, H
3
CSCH
2
CH
2
—, HO
2
CCH
2
—, HO
2
CCH
2
CH
2
—;
R(51) is H, (C
1
-C
4
)-alkyl, phenyl, (CH
2
)-phenyl, it being possible for the phenyl radical to be up to trisubstituted by F, Cl, CF
3
, methyl, methoxy;
and their pharmaceutically tolerable salts and physiologically functional derivatives.
Preferred compounds are those of the formula I
in which one or more radical(s) has or have the following meaning:
T1 and T2 independently of one another are equal to
or hydrogen, where
T1 and T2 cannot simultaneously be hydrogen,
L—Z is
A is a bond, —CH
2
—, CH
2
—X—;
X is —O—, —CO—, —CH[OH]—, —CH[OCH
3
]—, —SO
(0-2)
— or —NH—, N(CH
3
)—;
s is zero or 1;
D is phenylene which can be up to disubstituted by F, Cl, —CF
3
, (C
1
-C
4
)-alkyl, hydroxyl, methoxy, —NH
2
, NHCH
3
, N(CH
3
)
2
, CH
3
SO
2
—, H
2
NO
2
S—;
R(E) is F, Cl, CN, OR(12), (C
1
-C
4
)-alkyl, O—(C
1
-C
4
)-alkyl, (C
3
-C
6
)-cycloalkyl, it being possible in the alkyl radicals for one, a number or all hydrogens to be replaced by fluorine;
R(6) is (C
3
-C
6
)-alkenyl, (C
3
-C
8
)-cycloalkyl, phenyl or benzyl, it being possible for the phenyl nucleus to be up to trisubstituted by F, Cl, CF
3
, methyl, methoxy, NR(9)R(10);
R(9), R(10) independently of one another are H, (C
1
-C
4
)-alkyl or (C
1
-C
4
)-perfluoroalkyl;
R(F) is hydrogen;
R(1), R(2), R(3) independently of one another are hydrogen, F, Cl, Br, I, CN, —(C═O)—N═C(NH
2
)
2
, —SO(
0-1
)—(C
1
-C
8
)-alkyl, O—(C
0
-C
4
)-alkylphenyl, —(C
0
-C
4
)-alkylphenyl, it being possible for the phenyl nucleus to be up to trisubstitued by F, Cl, CF
3
, methyl, methoxy;
L is (C
1
-C
8
)-alkyl, where one or more (CH
2
) groups can be replaced by —CH═CH—, —C≡C—, —O—, —NR(47)—, —NR(48)—, —CO—, —SO2—;
R(47) is hydrogen, (C
1
-C
4
)-alkyl, R(48)—CO—, phenyl, (CH
2
)-phenyl;
R(47) is hydrogen, (C
1
-C
4
)-alkyl, R(48)-CO—, phenyl, (CH
2
)-phenyl;
R(48) is hydrogen, (C
1
-C
4
)-alkyl, phenyl, (CH
2
)-phenyl, it being possible methyl, methoxy;
R(41), R(42), R(45) independently of one another are H, —O R(50), —S R(50), NH R(50), —N R(50)
2
, —O—(CO)— R(50), —S—(CO)— R(50), —NH—(CO)— R(50), —O—PO—(O R(50))—O R(50), —O—(SO
2
)—O R(50), —R(50);
R(50) is hydrogen, (C
1
-C
4
)-alkyl, phenyl, (CH
2
)-phenyl, it being possible for the phenyl nucleus to be up to trisubstitued by; F, Cl, CF
3
, methyl, methoxy;
K is —OR(51), —NH(R51), —N(R51)
2
, —HN—CH
2
—CH
2
—CO
2
H, —HN—CH
2
—CH
2
—SO
3
H, —N(CH
3
)CH
2
CO
2
H, —HN—CH(R46)CO
2
H, —OKa, Ka being a cation, such as, for example, an alkali metal or an alkaline earth metal ion or a quaternary ammonium ion,
R(46) is H, C
1
-C
4
-alkyl, benzyl, —CH
2
—OH, H
3
CSCH
2
CH
2
—, HO
2
CCH
2
—, HO
2
CCH
2
CH
2
—;
R(51) is H, (C
1
-C
4
)-alkyl, phenyl, (CH
2
)-phenyl, it being possible for the phenyl radical to be up to trisubstituted by F, Cl, CF
3
, methyl, methoxy;
and their pharmaceutically tolerable salts.
Particularly preferred compounds are those of the formula I
in which one or more radical(s) has or have the following meaning:
T1 and T2 independently of one another are equal to
or hydrogen, where
T1 and T2 cannot simultaneously be hydrogen,
L—Z is
A is a bond, —CH
2
—, CH
2
—X—, —X—;
X is —O—, —CO—, —SO
(0-2)
—;
s is zero or 1;
D is phenylene which can be up to disubstituted by F, Cl, —CF
3
,(C
1
-C
4
)-alkyl, hydroxyl, methoxy, —NH
2
, NHCH
3
, N(CH
3
)
2
, CH
3
SO
2
—, H
2
NO
2

Affiliated with

Also associated with

Rating

Substituted acylguanidines, process for their preparation,... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Substituted acylguanidines, process for their preparation,..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted acylguanidines, process for their preparation,... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2878018