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US 2001/0011085 A1Published application
4-substituted cephem derivatives as elastase inhibitors
OwnerMarco Alpegiani, Pierluigi Bissolino +2inventors
InventorsMARCO ALPEGIANI, PIERLUIGI BISSOLINO, MASSIMILIANO PALLADINO, ETTORE PERRONE
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Abstract
The present invention relates to cephem-derivatives and to a process for their preparation, having proper substituents at C-2 position, i.e. heterocyclylthio or acyloxy group. They are potent protease inhibitors, in particular human leucocyte elastase (HLE) inhibitors. These inhibitors can be synthesised by way of a substitution reaction starting from known cephem compounds having a 2-position a suitable leaving group.
Claims7
A compound of the formula I and the pharmaceutically and veterinarily acceptable salts thereof:
- 34
- wherein n is one or two;
- X is
- (1) a heterocyclyl-thio group, wherein the heterocyclyl group is an optionally substituted 3-6 membered, saturated or unsaturated heterocyclic ring, containing at least one heteroatom selected from O, S and N, which is optionally fused to a second 5-6 membered, saturated or unsaturated heterocyclyl group, or to a C3-C8 cycloalkyl group, or to a cyclopentenyl group, or to a C6-C10 aryl group;
- (2) an acyloxy group —O—C(O)A wherein A is an organic radical selected from C1-C12 straight or branched alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-C14 aryl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, or C7-C18 aralkyl, C1-C18 aralkenyl, C1-C18 aralkynyl, (cycloalkyl) alkyl, (cycloalkyl)alkenyl, heterocyclyl, (heterocyclyl)alkyl, (heterocyclyl)alkenyl;
- Q represents a group —OA, —SA or —NAA′ wherein A is as defined above and A′ is hydrogen or, being the same or different, is as defined above for A;
- or A and A′ taken together with the nitrogen atom to which they are attached represent a 5-7 membered ring optionally containing an additional heteroatom selected from N, O and S;
- R1 and R2 independently represent
- (1) hydrogen, chloro, fluoro, bromo or iodo;
- (2) A as defined above;
- (3) hydroxy —OH or an ether —OA wherein A is as defined above;
- (4) a thioether, sulfoxide or sulfone —S(O)mA wherein m is either zero, one or two and A is as defined above;
- (5) acyloxy —OC(O)A wherein A is as defined above;
- (6) acyl —C(O)A or —C(O)OA wherein A is as defined above;
- (7) sulfonyloxy —OS(O)2A wherein A is as defined above;
- (8) acetylamino or trifluoroacetamido, or an acylamino group ZNH—CHR—CONH—, wherein R is methyl, ethyl, isopropyl Me2CH—, EtMeCH—, Me2CHCH2—, EtMeCHCH2, and Z is either hydrogen or:
- phenylcarbonyl or phenoxymethylcarbonyl or phenoxy-methylcarbonyl, wherein the phenyl ring is either unsubstituted or substituted by one or two chloro, fluoro or methyl groups, or by a group selected among the following ones:
- a) carboxy
- b) OCH2CO2H
- c) OCH2CH2-4-morpholinyl
- d) OCH2CH2-1-pyrrolidinyl
- e) SO2-1-morpholinyl
- f) SO2-(4-methyl)-1-piperazinyl
- g) SO2N(Me)CH2CH2NMe2
- h) CONH—CO-1-morpholinyl
- i) CO-1-morpholinyl
- j) CO-(4-methyl)-1-piperazinyl
- k) CONH—CH2CH2-1-morpholinyl
- l) COO—CH2CH2-1-morpholinyl
- m) SO2NH—Ar, or CONHSO2—Ar wherein Ar is a phenyl ring either unsubstituted or substituted by Cl, F or carboxy, said carboxy being optionally as the ethyl ester COOC2H5 or amides CONH2, CONHCH3, CONHCH2 CO2H,
- an amino-blocking group, selected from the group consisting of e), f), g), i), k), l) above or from the following ones:
- methyl, dimethyl, benzyl, CO2CH3, COSCH3;
- SO2CH3;
- (9) azido, nitro or cyano;
- or R1 and R2 taken together constitute an oxo group (═O) or a group of formula ═CHA′, ═CHC(O)A′, ═CHC(O)OA′ or ═CHS(O)2A wherein A and A′ are as defined above;
- R3 represents:
- (1) A′ as defined above;
- (2) chloro or fluoro;
- (3) a sulfenyl, sulfinyl or sulfonyl group —S(O)mA wherein m and A are as defined above;
- (4) an ether group —O—A wherein A is as defined above;
- (5) an acyl group —C(O)A, —C(O)OA or —CO2H wherein A is as defined above;
- (6) an oxymethyl group —CH2—OA′ wherein A′ is as defined above;
- (7) a thiomethyl group or a derivative thereof of formula CH2S(O)mA wherein m and A are as defined above;
- (8) an acyloxymethyl group —CH2OC(O)A′ wherein A′ is as defined above;
- (9) an acylthiomethyl group —CH2SC(O)A wherein A is as defined above;
- (10) carbamoyloxymethyl —CH2OCONH2 or carbamoylthiomethyl (i.e., —CH2SCONH2), and the N-methyl and N,N-dimethyl derivatives thereof;
- (11) an aminomethyl group —CH2—N(A)A′ wherein A and A′ are as defined above;
- (12) ammoniomethyl —CH2N+(A)(A′)A″ wherein A and A′ are as defined above and A″, being the same or different, is as defined for A;
- or A is alkyl and A′ and A″ together with the nitrogen atom to which they are attached represent a 5-7 membered ring containing one nitrogen and optionally one oxygen or sulfur atom;
- (13) an acylaminomethyl group —CH2NH—C(O)A wherein A is as defined above.
47 more elements
Dependencies are inferred from the claim text.