US 7,579,339 B2
Ring-substituted diphenylazetidinones, process for their preparation, medicaments comprising these compounds, and their use
Gerhard Jaehne, Frankfurt (Germany); Wendelin Frick, Hünstetten-Beuerbach (Germany); Stefanie Flohr, Basel (Switzerland); Andreas Lindenschmidt, Bad Soden (Germany); Heiner Glombik, Hofheim (Germany); Werner Kramer, Mainz-Laubenheim (Germany); Hubert Heuer, Schwabenheim (Germany); and Hans-Ludwig Schaefer, Hochheim (Germany)
Assigned to Sanofi-Aventis Deutschland GmbH, Frankfurt am Main (Germany)
Filed on Aug. 10, 2006, as Appl. No. 11/501,758.
Application 11/501758 is a continuation of application No. 10/463807, filed on Jun. 18, 2003, granted, now 7,176,194.
Claims priority of provisional application 60/411984, filed on Sep. 19, 2002.
Claims priority of application No. 102 27 506 (DE), filed on Jun. 19, 2002.
Prior Publication US 2006/0270613 A1, Nov. 30, 2006
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 205/08 (2006.01); C07D 227/00 (2006.01); A61K 31/397 (2006.01); A61P 3/06 (2006.01); A61P 9/10 (2006.01)
U.S. Cl. 514—210.02  [540/200] 16 Claims
 
1. A compound of the formula I,

OG Complex Work Unit Drawing
wherein:
R1, R2, R3, R4, R5, and R6, independently of one another, are chosen from:
(C1-C30)-alkyl, wherein the (C1-C30)-alkyl is substituted by q LAG units,
wherein at least one carbon atom of the alkyl radical is replaced by:
aryl or heteroaryl radicals, which are unsubstituted or substituted one, two, or three times by R7, or by (C3-C10)-cycloalkyl or heterocycloalkyl radicals, which are unsubstituted or substituted one, two, three, or four times by R7, and
wherein at least one carbon atom of the alkyl radical is optionally replaced by a radical chosen from: —S(O)m— (where m=0-2), —O—, —(C═O)—, —(C═S)—, —CH═CH—, —C≡C—, —N((C1-C6)-alkyl)-, —N(phenyl), —N((C1-C6)-alkyl-phenyl)-, —N(CO—(CH2)1-10—COOH)— and —NH—; or
H, F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, or O—(C1-C6)-alkyl, wherein the alkyl radical is unsubstituted or at least one hydrogen in the alkyl radical is replaced by fluorine; or
SO2—NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S—(C1-C6)-alkyl, S—(CH2)n-phenyl, SO—(C1-C6)-alkyl, SO—(CH2)n-phenyl, SO2—(C1-C6)-alkyl, or SO2—(CH2)n-phenyl; wherein n=0-6, and wherein the phenyl radical is unsubstituted or substituted one or two times, each substituent chosen independently from: F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, (C1-C6)-alkyl, and NH2; or
NH2, NH—(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NHCO(C1-C6)-alkyl, phenyl, or O—(CH2)n-phenyl, wherein n=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substituent chosen independently from: F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2—CH3, COOH, COO—(C1-C6)-alkyl, and CONH2;
R7 represents F, Cl, Br, I, CF3, NO2, N3, CN, COOH, COO(C1-C6)-alkyl, CONH2, CONH(C1-C6)-alkyl, CON[(C1-C6)-alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, or O—(C1-C6)-alkyl, wherein the alkyl radical is unsubstituted or at least one hydrogen in the alkyl radical may be replaced by fluorine; or
PO3H2, SO3H, SO2—NH2, SO2NH(C1-C6)-alkyl, SO2N[(C1-C6)-alkyl]2, S—(C1-C6)-alkyl, S—(CH2)n-phenyl, SO—(C1-C6)-alkyl, SO—(CH2)n-phenyl, SO2—(C1-C6)-alkyl, or SO2—(CH2)n-phenyl, wherein n=0-6, and wherein the phenyl radical is unsubstituted or substituted one or two times, each substituent chosen independently from: F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, (C1-C6)-alkyl, and NH2; or
C(NH)(NH2), NH2, NH—(C1-C6)-alkyl, N((C1-C6)-alkyl)2, NHCO(C1-C6)-alkyl, phenyl, or O—(CH2)n-phenyl, wherein n=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substituent chosen independently from: F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2—CH3, COOH, COO—(C1-C6)-alkyl, and CONH2;
(LAG) is an acyclic trialkylammonium radical, a mono-, di- or tricyclic trialkylammonium radical, an acyclic trialkylammoniumalkyl radical, a mono-, di- or tricyclic trialkylammoniumalkyl radical, —O—(SO2)—OH; —(CH2)0-10—SO3H, —(CH2)0-10—P(O)(OH)2, —(CH2)0-10 —O—P(O)(OH)2, —(CH2)0-10—COOH, —(CH2)0-10—C(═NH)(NH2)′—(CH2)0-10—C(═NH)(NHOH), or —NR8—C(═NR9)(NR10R11);
wherein, when LAG is an acyclic trialkylammonium radical, a mono-, di- or tricyclic trialkylammonium radical, an acyclic trialkylammoniumalkyl radical, or a mono-, di- or tricyclic trialkylammoniumalkyl radical, a counterion to the positive charge of the acyclic trialkylammonium radical, mono-, di- or tricyclic trialkylammonium radical, acyclic trialkylammoniumalkyl radical, or mono-, di- or tricyclic trialkylammoniumalkyl radical is present in the compound of formula I;
wherein q=1-5 and wherein R8, R9, R10 and R11, independently of one another, are chosen from: H, (C1-C6)-alkyl, phenyl, (C1-C6)-alkyl-phenyl, and (C3-C8)-cycloalkyl,
and wherein at least one of the radicals R1 to R6 must have the meaning:
(C1-C30)-alkyl, wherein the C1-C30)-alkyl is substituted by q LAG units,
wherein at least one carbon atom of the alkyl radical is replaced by:
aryl or heteroaryl radicals, which are unsubstituted or substituted one, two, or three times by R7, or
(C3-C10)-cycloalkyl or heterocycloalkyl radicals, which are unsubstituted or substituted one, two, three, or four times by R7, or
—S(O)m— (where m=0-2), —O—, —(C═O)—, —(C═S)—, —CH═CH—, —C≡C—, —N((C1-C6)-alkyl)-, —N(phenyl)-, —N((C1-C6)-alkyl-phenyl)-, —N(CO—(CH2)1-10—COOH)— or —NH—;
wherein the mono-, di- or tricyclic trialkylammonium radical is chosen from:
a radical of formula II:

OG Complex Work Unit Drawing
wherein n=0 to 10 and Alk1 and Alk2, independently of one another, each denote a straight-chain or branched alkyl radical having 1 to 20 carbon atoms; and
wherein:
the end carbon atom of Alk1 is bound to the —(CH2)n— chain; or
the end carbon atom of Alk2 is bound to the —(CH2)n— chain; or
the end carbon atom of Alk1 is bound to the end carbon atom of Alk2; or
a combination thereof; and
a radical chosen from:

OG Complex Work Unit Drawing
wherein each of n, m and p, independently of one another, represent a number between 0-10; and
wherein one or more CH2 groups in said mono-, di- or tricyclic trialkylammonium radical, independently of one another, can be optionally replaced by a radical chosen from: O, S(O)t (wherein t is 0, 1, or 2), NH, N—(C1-C10)-alkyl, N-phenyl, and N—CH2-phenyl;
wherein the mono-, di- or tricyclic trialkylammoniumalkyl radical is chosen from:
a radical of formula III:

OG Complex Work Unit Drawing
wherein n=0 to 10 and Alk1, Alk2, and Alk3, independently of one another, each denote a straight-chain or branched alkyl radical having 1 to 20 carbon atoms; and
wherein:
the end carbon atom of Alk1 is bound to the —(CH2)n— chain; or
the end carbon atom of Alk2 is bound to the —(CH2)n— chain; or
the end carbon atom of Alk3 is bound to the —(CH2)n— chain; or
the end carbon atom of Alk1 is bound to the end carbon atom of Alk2; or
the end carbon atom of Alk1 is bound to the end carbon atom of Alk3; or
the end carbon atom of Alk2 is bound to the end carbon atom of Alk3; or
a combination thereof; and
a radical chosen from:

OG Complex Work Unit Drawing
wherein each of n, m and p, independently of one another, represent a number between 0-10; and
wherein one or more CH2 groups in said mono-, di- or tricyclic trialkylammoniumalkyl radical, independently of one another, can be optionally replaced by a radical chosen from: O, S(O)t (wherein t is 0, 1, or 2), NH, N—(C1-C10)-alkyl, N-phenyl, and N—CH2-phenyl; and wherein Alk1 is a straight-chain or branched alkyl radical having 1 to 20 carbon atoms
or a pharmaceutically acceptable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.