Diphenylazetidinone derivatives, process for their...

Details Diphenylazetidinone derivatives, process for their... Diphenylazetidinone derivatives, process for their...

2001-12-19

2004-03-09

Berch, Mark L (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S200000

Reexamination Certificate

active

06703386

ABSTRACT:

This application claims the benefit of priority under 35 U.S.C. §119(a) to German patent application no. 10064402.3, filed on Dec. 21, 2000, and German patent application no. 10154518.5, filed on Nov. 7, 2001. The contents of both priority documents are incorporated by reference herein.
The invention relates to substituted diphenylazetidinones, to their physiologically acceptable salts and to derivatives having physiological function.
Diphenylazetidinones (such as, for example, ezetimibe) and their use for treating hyperlipidemia and arteriosclerosis and hypercholesterolemia have already been described [cf. Drugs of the Future 2000, 25(7):679-685].
It was an object of the invention to provide further compounds having a therapeutically utilizable hypolipidemic action. In particular, it was an object to find novel compounds which, compared to the compounds described in the prior art, are absorbed to a very low extent. Very low absorption is to be understood as meaning an intestinal absorption of less than 10%, preferably less than or equal to 5%. In particular, absorption of the novel compounds should be less than that of ezetimibe. Pharmaceutically active compounds which are absorbed to a very low extent generally have considerably fewer side-effects.
Accordingly, an embodiment of the invention relates to compounds of the formula I,
in which
R1, R2, R3, R4, R5, R6 independently of one another are (C
0
-C
30
)-alkylene-L, where one or more carbon atoms of the alkylene radical may be replaced by —O—, —(C═O)—, —CH═CH—, —C≡C—, —N((C
1
-C
6
)-alkyl)- or —NH—; or
H, F, Cl, Br, I, CF
3
, NO
2
, CN, COOH, COO(C
1
-C
6
)-alkyl, CONH
2
, CONH(C
1
-C
6
)-alkyl, CON[(C
1
-C
6
)-alkyl]
2
, (C
1
-C
6
)-alkyl, (C
2
-C
6
)-alkenyl, (C
2
-C
6
)-alkynyl or O—(C
1
-C
6
)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine; or
SO
2
—NH
2
, SO
2
NH(C
1
-C
6
)-alkyl, SO
2
N[(C
1
-C
6
)-alkyl]
2
, S—(C
1
-C
6
)-alkyl, S—(CH
2
)
n
-phenyl, SO—(C
1
-C
6
)-alkyl, SO—(CH
2
)
n
-phenyl, SO
2
—(C
1
-C
6
)-alkyl or SO
2
—(CH
2
)
n
-phenyl, where n=0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF
3
, NO
2
, CN, OCF
3
, O—(C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkyl or NH
2
; or
NH
2
, NH—(C
1
-C
6
)-alkyl, N((C
1
-C
6
)-alkyl)
2
, NH(C
1
-C
7
)-acyl, phenyl or O—(CH
2
)
n
-phenyl, where n=0-6, where the phenyl ring may be mono- to trisubstituted by F, Cl, Br, I, OH, CF
3
, NO
2
, CN, OCF
3
, O—(C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkyl, NH
2
, NH(C
1
-C
6
)-alkyl, N((C
1
-C
6
)-alkyl)
2
, SO
2
—CH
3
, COOH, COO—(C
1
-C
6
)-alkyl or CONH
2
;
L is shown connected to (C
0
-C
30
)-alkylene as follows:
Rx, Ry, Rz independently of one another are H, F, Cl, Br, I, CF
3
, NO
2
, CN, COOH, COO—(C
1
-C
6
)-alkyl, CONH
2
, CONH—(C
1
-C
6
)-alkyl, CON—[(C
1
-C
6
)-alkyl]
2
, (C
1
-C
6
)-alkyl, (C
2
-C
6
)-alkenyl, (C
2
-C
6
)-alkynyl or O—(C
1
-C
6
)-alkyl, where one, more or all hydrogens in the alkyl radicals may be replaced by fluorine; or
SO
2
—NH
2
, SO
2
NH—(C
1
-C
6
)-alkyl, SO
2
N—[(C
1
-C
6
)-alkyl]
2
, S—(C
1
-C
6
)-alkyl, S—(CH
2
)
n
-phenyl, SO—(C
1
-C
6
)-alkyl, SO—(CH
2
)
n
-phenyl, SO
2
—(C
1
-C
6
)-alkyl or SO
2
—(CH
2
)
n
-phenyl, where n=0-6 and the phenyl radical may be substituted up to two times by F, Cl, Br, OH, CF
3
, NO
2
, CN, OCF
3
, O—(C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkyl or NH
2
; or
NH
2
, NH—(C
1
-C
6
)-alkyl, N—((C
1
-C
6
)-alkyl)
2
, NH—(C
1
-C
7
)-acyl, phenyl or O—(CH
2
)n-phenyl, where n=0-6, where the phenyl ring may be mono- to trisubstituted by F, Cl, Br, I, OH, CF
3
, NO
2
, CN, OCF
3
, O—(C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkyl, NH
2
, NH—(C
1
-C
6
)-alkyl, N—((C
1
-C
6
)-alkyl)
2
, SO
2
—CH
3
, COOH, COO—(C
1
-C
6
)-alkyl or CONH
2
;
wherein at least one of the radicals R1 or R6 has the meaning (C
0
-C
30
)-alkylene-L, where one or more carbon atoms of the alkylene radical may be replaced by —O—, —(C═O)—, —CH═CH—, —C≡C—, —N((C
1
-C
6
)-alkyl)- or —NH—, and its pharmaceutically acceptable salts.
Another embodiment of the invention relates to compounds of the formula I, in which at least one of the radicals R1 to R6 has the meaning (C
0
-C
30
)-alkylene-L, where one or more carbon atoms of the alkylene radical may be replaced by —O—, —(C═O)—, or —NH—.
Another embodiment of the invention relates to compounds of the formula I, in which one of the radicals R1 or R3 has the meaning (C
0
-C
30
)-alkylene-L, where one or more carbon atoms of the alkylene radicals may be replaced by —O—, —(C═O)— or —NH—.
Another embodiment of the invention relates to compounds of the formula I, in which one of the radicals R1 or R3 has the meaning —(CH
2
)
0-1
—NH—(C═O)
0-1
—(C
3
-C
25
)-alkylene-(C═O)
0-1
—NH—L; where one or more carbon atoms of the alkylene radical may be replaced by oxygen atoms.
One of the radicals R1 to R6 may be linked, for example, to the L radical in the meta position of ring C of the L groups.
Owing to their increased solubility in water, compared to the parent compounds, pharmaceutically acceptable salts are particularly suitable for medical applications. These salts should have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, and of organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid, for example. For medical purposes, very particular preference is given to using the chloride salt. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
The scope of the invention also includes salts having a pharmaceutically unacceptable anion, which salts may be useful intermediates for preparing or purifying pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
Here, the term “derivative having physiological function” refers to any physiologically acceptable derivative of a compound according to the invention, for example an ester, capable of forming, upon administration to a mammal, for example man, to form such a compound or an active metabolite (directly or indirectly).
A further aspect of this invention are prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to give a compound according to the invention. These prodrugs may or may not be active in their own right.
The compounds according to the invention can also be present in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. The scope of the invention includes all polymorphous forms of the compounds according to the invention, which form a further aspect of the invention. The compounds of the invention may also exist in the form of solvates.
The compounds of the formula I and their pharmaceutically acceptable salts, esters, prodrugs and derivatives having physiological function are ideal medicaments for treating an impaired lipid metabolism, in particular hyperlipidemia. The compounds of the formula I are also suitable for modulating the serum cholesterol concentration and for treating arteriosclerotic manifestations. The compounds of the invention are also suitable for the treatment of insulin resistance.
As used here, “treatment” or “therapy” of a condition and “treating” a condition can mean successfully eliminating the condition, reducing the effects associated with it, and/or reducing its severity. It also includes administering the relevant compounds to a patient to

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