US 7,045,619 B2Granted

2-(pyrazol-3-yl)carbapenem derivatives

AssigneeSmithKline Beecham Corporation

InventorsEric Hunt, Steven Coulton, Jeremy David Hinks, Stephen Frederick Moss, Stephen Christopher Martin Fell, Alfred John Eglington, George Burton

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Abstract

A compound of formula (I): wherein Rα is hydrogen, optionally substituted (C1-6)alkyl or optionally substituted aryl; Rβ is hydrogen, optionally substituted (C1-6)alkyl or optionally substituted aryl; or Rα and Rβ together form an optionally substituted 5 or 6 membered heterocyclic ring with or without additional heteroatoms; R1 is (C1-6)alkyl which is unsubstituted or substituted by fluoro, a hydroxy group which is optionally protected by a removable hydroxy protecting group, or by an amino group which is optionally protected by a removable amino protecting group; R2 is hydrogen or methyl; and —CO2R3 is carboxy or a carboxylate anion or the group R3 is a removable carboxy protecting group. This invention also relates to processes for its preparation, intermediates and pharmaceutical compositions comprising compounds of formula (I). Compounds of formula (I) which include pharmaceutically acceptable salts or pharmaceutically acceptable in vivo hydrolysable esters thereof have a broad spectrum of anti-bacterial activity and show good stability towards DHP-1.

Claims5

Dependent claims

A compound of formula (Ia):

wherein:
Rα is hydrogen, optionally substituted (C1-6)alkyl or optionally substituted aryl;
Rβ is hydrogen, optionally substituted (C1-6)alkyl or optionally substituted aryl;
or Rα and Rβ together with the atoms to which they are attached form an optionally substituted 5 or 6 membered non-aromatic heterocyclic ring optionally containing up to four additional heteroatoms selected from oxygen, nitrogen and sulphur, which ring may be unsubstituted or substituted by up to three substituents selected from halogen, (C1-6)alkyl, aryl(C1-4)alkyl(C1-6)alkoxy, (C1-6)alkoxy(C1-6)alkyl, halo(C1-6)alkyl, hydroxy, amino, mono- and di-N-(C1-6)alkylamino, (C2-6)acylamino, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(C1-6)alkylcarbonyl, (C1-6) alkoxycarboxylate, aryloxycarbonyl, (C1-6)alkoxycarbonyl(C1-6alkyl, aryl, oxo, ureido, guanidino, sulphonylamino, aminosulphonyl, (C1-6)alkylthio, (C1-6)alkylsulphinyl, (C1-6)alkylsulphonyl, heterocyclyl and heterocyclyl(C1-4)alkyl;
when Rα and Rβ are either or both (C1-6)alkyl, the optional substituents are selected from halogen, hydroxy, (C1-6)alkoxy, carboxy and salts thereof, (C1-6)alkoxycarbonyl, carbamoyl, mono- or di(C1-6)alkylcarbamoyl, sulphamoyl, mono- and di(C1-6)alkylsulphamoyl, amino, mono- and di(C1-6)alkylamino, (C2-6)acylamino, ureido, (C1-6)alkoxycarbonylamino, aminocarbonyloxy and mono- and di(C1-6)alkylaminocarbonyloxy, 2,2,2-trichloroethoxycarbonylamino, aryl, heterocyclyl, oxo, (C2-6)acyl, heteroaryl, (C1-6)alkylthio, arylthio, heterocyclythio, (C1-6)alkane-sulphinyl, arylsulphinyl, (C1-6)alkanesulphonyl, arylsulphonyl, (C1-6)alkoxyimino, hydroxyimino, and hydrazono;
when Rα and Rβ are either or both aryl, the optional substituents are selected from halogen, (C1-6)alkyl, aryl(C1-4)alkyl, (C1-6)alkoxy, (C1-6)alkoxy(C1-6)alkyl, halo(C1-6)alkyl, hydroxy, amino, mono- and di-N-(C1-6)alkylamino, (C2-6)acylamino, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(C1-6)alkylcarbamoyl, (C1-6)alkoxycarbonyl, (C1-6)alkoxycarboxylate, aryloxycarbonyl, (C1-6)alkoxycarbonyl(C1-6)alkylaryl, ureido, guanidino, sulphonylamino, aminosulphonyl, (C1-6)alkylthio, (C1-6)alkylsulphinyl (C1-6)alkylsulphonyl, heterocyclyl and heterocyclyl (C1-4)alkyl, or two adjacent ring carbon atoms may be linked by a (C3-5)alkylene chain, to form a carbocyclic ring;
R1 is (C1-6)alkyl which is unsubstituted or substituted by fluoro, a hydroxy group, or an amino group;
R2 is hydrogen or methyl;
and
heterocyclyl is an aromatic or non-aromatic ring, optionally fused to a second ring, in which the, or each, ring contains up to four heteroatoms, each of which is selected from oxygen, nitrogen and sulphur, each ring having 5 or 6 ring atoms, and a fused heterocyclic ring system may include a carbocyclic ring;
or a pharmaceutically acceptable salt or a pharmaceutically acceptable in vivo hydrolysable ester thereof.

8 more elements

A compound selected from:

sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1,5-dimethylpyrazol-3-yl)carbapen-2-em-3-carboxylate,
sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1-phenylpyrazol-3-yl)carbapen-2-em-3-carboxylate,
sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate,
sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(5-methyl-1-phenethylpyrazol-3-yl)carbapen-2-em-3-carboxylate,
sodium (5R,6S)-6-[(R)-1-hydroxyethyl)]-2-[1-(2-phenethyl)pyrazol-3-yl]carbapen-2-em-3-carboxylate,
sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[4,5,6,7-tetrahydropyridino-(1,2-b)-pyrazol-2-yl]carbapen-2-em-3-carboxylate,
sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(5-methyl-1-phenylpyrazol-3-yl)carbapen-2-em-3-carboxylate,
sodium (5R,6S)-2-[5,6-dihydro-4H-pyrrolo(1,2-b)-pyrazol-2-yl]-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,
sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1,5-diethylpyrazol-3-yl)carbapen-2-em-3-carboxylate,
sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1-ethyl-5-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate,
sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[1-(2-hydroxyethyl)-5-methylpyrazol-3-yl]carbapen-2-em-3-carboxylate,
sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[1-(2-methoxyethyl)-5-methylpyrazol-3-yl]carbapen-2-em-3-carboxylate,
sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(5-benzyl-1-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate,
sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-{5-methyl-1-[2-(1-methyl-tetrazol-5-ylthio)ethyl]pyrazol-3-yl}carbapen-2-em-3-carboxylate,
sodium (5R,6S)-2-[1-(2-acetamidoethyl)-5-methylpyrazol-3-yl]-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,
sodium (5R,6S)-2-[1-(2-methylthioethyl)-5-methylpyrazol-3-yl]-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,
sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1-methyl-5-ethylpyrazol-3-yl)carbapen-2-em-3-carboxylate,
t-butyloxycarbonyloxymethyl (5R,6S)-2-(1,5-dimethylpyrazol-3-yl)-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,
cyclohexyloxycarbonyloxymethyl (5R,6S)-2-(1,5-dimethylpyrazol-3-yl)-6[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,
cyclohexyloxycarbonyloxymethyl (5R,6S)-2-(1-ethyl-5-methylpyrazol-3yl)-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,
sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[5-methyl-1-(2-methylsulphonylethyl)pyrazol-3-yl]carbapen-2-em-3-carboxylate,
sodium (5R,6S)-2-[1-[2-N,N-dimethylaminocarbonyloxy)ethyl]-5-methylpyrazol-3-yl]-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,
2-ethoxycarbonyl-E-but-2-enyl (5R,6S)-2-(1-ethyl-5-methylpyrazol-5-yl)-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,
1-methylcyclohexyloxycarbonyloxymethyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1-ethyl-5-methyl-pyrazol-3-yl)carbapen-2-em-3-carboxylate,
2-methoxyprop-2-ylcarbonyloxymethyl (5R,6S)-2-(1-ethyl-5-methylpyrazol-3-yl)-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,
isobutyryloxymethyl (5R,6S)-2-[1-ethyl-5-methylpyrazol-3yl]-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl (5R,6S)-2-[1-ethyl-5-methylpyrazol-3-yl]-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate, and
benzoyloxymethyl (5R,6S)-2-[1-ethyl-5-methylpyrazol-3-yl]-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate.

25 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/324,593Filed 19 Dec 2002 · continuation
Priority: GB 932228429 Oct 1993
Published: US 2003/0166923 A14 Sep 2003
Granted: 16 May 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 477/14
With hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6: with hydrogen atoms, hydrocarbon or substituted…
C07D 477/08
From compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or…:…
Y02P 20/55
Improvements relating to the production of bulk chemicals: design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
C07D
Heterocyclic compounds

Family

PCT/GB94/02347Parent of this continuation-in-part · filed 25 Oct 1994
PCT/EP96/01882Parent of this continuation-in-part · filed 2 May 1996
PCT/EP96/01880Parent of this continuation-in-part · filed 2 May 1996
Application09/205,254Parent of this continuation · filed 4 Dec 1998
Application10/055,489Parent of this continuation · filed 23 Jan 2002
US 2003/0166923 A1Pre-grant publication · published 4 Sep 2003
Application08/624,624Parent of this continuation-in-part
Application09/205,254Parent of this continuation-in-part
Application08/945,521Parent of this continuation-in-part
Application08/945,524Parent of this continuation-in-part
US 2002/0147333 A1Published application
US 7,045,619 B2This patent

From the US filing history. Foreign family members aren’t listed.