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2-Substituted Methyl Penam Derivatives 2-Substituierte Methyl-Penam-Derivate Dérivés 2-Substitués Du Méthyl Pénam

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2-Substituted Methyl Penam Derivatives 2-Substituierte Methyl-Penam-Derivate Dérivés 2-Substitués Du Méthyl Pénam (19) TZZ ZZ _T (11) EP 2 046 802 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: C07D 499/87 (2006.01) C07D 499/21 (2006.01) of the grant of the patent: C07D 499/28 (2006.01) C07D 499/32 (2006.01) 21.08.2013 Bulletin 2013/34 A61K 31/431 (2006.01) A61P 31/00 (2006.01) (21) Application number: 07804590.3 (86) International application number: PCT/IB2007/001941 (22) Date of filing: 11.07.2007 (87) International publication number: WO 2008/010048 (24.01.2008 Gazette 2008/04) (54) 2-SUBSTITUTED METHYL PENAM DERIVATIVES 2-SUBSTITUIERTE METHYL-PENAM-DERIVATE DÉRIVÉS 2-SUBSTITUÉS DU MÉTHYL PÉNAM (84) Designated Contracting States: • SRIRAM, Rajagopal AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Chennai, Tamil Nadu 600 119 (IN) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE • PAUL-SATYASEELA, Maneesh SI SK TR Chennai, Tamil Nadu 600 119 (IN) • SOLANKI, Shakti, Singh (30) Priority: 12.07.2006 IN CH12172006 Chennai, Tamil Nadu 600 119 (IN) • DEVARAJAN, Sathishkumar (43) Date of publication of application: Chennai, Tamil Nadu 600 119 (IN) 15.04.2009 Bulletin 2009/16 (74) Representative: Murphy, Colm Damien et al (73) Proprietor: Allecra Therapeutics GmbH Ipulse 79539 Lörrach (DE) Carrington House 126-130 Regent Street (72) Inventors: London W1B 5SE (GB) • UDAYAMPALAYAM, Palanisamy, Senthilkumar Chennai, Tamil Nadu 600 119 (IN) (56) References cited: • GNANAPRAKASAM, Andrew EP-A1- 0 097 446 EP-A1- 0 367 124 Chennai, Tamil Nadu 600 119 (IN) JP-A- 60 215 688 US-A1- 2005 070 705 • GANAPATHY, Panchapakesan US-A1- 2005 228 176 Chennai, Tamil Nadu 600 119 (IN) • MUKUT, Gohain Remarks: Chennai, Tamil Nadu 600 119 (IN) Thefile contains technical information submitted after • VENKATASUBRAMANIAN, Hariharan the application was filed and not included in this Chennai, Tamil Nadu 600 119 (IN) specification Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 046 802 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 046 802 B1 Description Field of the Invention 5 [0001] Described are 2-substituted methyl penam derivatives of the formula (I), their tautomeric forms, their stereoi- somers, their polymorphs, their solvates, and their pharmaceutically acceptable salts thereof, 10 15 wherein A = C or N; Het is a three- to seven- membered heterocyclic ring; R1 represents carboxylate anion, or -COOR4 wherein R4 represents hydrogen, methoxybenzyl, nitrobenzyl, silyl, alkyl, diphenylmethyl, proxetil, axetil, pivoxil, hexetil, daloxate or a pharmaceutically acceptable salt; R2 and R3 may be same or different and independently represent hydrogen, halogen, amino, optionally substituted alkyl, alkenyl, or alkynyl; R represents substituted or unsubstituted 20 alkyl. The present invention further provides a process for preparing the compound of formula (I). [0002] The novel compounds herein are useful as β-lactamase inhibitors, which enhance the antibiotic spectrum of a suitable antibiotic agent. Background of the Invention 25 [0003] The β-lactam type antibiotics, namely penicillins and cephalosporins are frequently used antibiotics. It is known that β-lactamase produced by microorganisms hydrolyze theβ -lactam ring thereby deactivating antibiotic activity. In order to reduce the effect of β-lactamase, the antibiotics are administered in combination withβ -lactamase inhibitor. These inhibitors function by binding to the beta- lactamase enzymes more efficiently than the actual beta- lactam antibiotic 30 itself. This combination allows the antibiotic to "do its job" without being degraded by the beta-lactamase enzymes. Several antibiotic/β-lactamase inhibitor combinations exist in the market for example, Ampicillin/ Sulbactam, Amoxicillin/ Clavulanate and Ticarcillin/Clavulanate. These β-lactam/β-lactamase inhibitor combination antibiotic are being used for the treatment of infections in the community and in the hospital setting. [0004] Among many β-lactamase inhibitors that are known in the literature, compound of following formula is disclosed 35 in US 4,562,073, 40 1 2 wherein R is hydrogen or trialkylsilyl; R is hydrogen, trialkylsilyl or COOR2’ wherein R2’ is hydrogen, C1-18 alkyl, C2-7 45 alkoxymethyl, C3-8 alkylcarbonyloxymethyl, C4-9 alkylcarbonyloxyethyl, (C5-7 cycloalkyl)carbonyloxymethyl, C9-14 ben- zylcarbonyloxyalkyl, C3-8 alkoxycarbonylmethyl, C4-9 alkoxycarbonylethyl, phthalidyl, crotonolacton- 4-yl, gamma.-buty- rolacton-4-yl, halogenated C 1-6 alkyl substituted with 1 to 3 halogen atoms, C1-6 alkoxy- or nitro-substituted or unsub- stituted benzyl, benzhydryl, tetrahydropyranyl, dimethylaminoethyl, dimethylchlorosilyl, trichlorosilyl, (5- substituted C1-6 alkyl or phenyl or unsubstituted-2-oxo-1,3-dioxoden-4-yl)methyl, C8-13 benzoyloxyalkyl or group for forming a pharma- 50 3 ceutically acceptable salt; and R has the same meaning as above R 2’. This patent describes a β-lactam inhibitor wherein R1 = R2 = R3 = H, which hereinafter referred as Tazo. [0005] We have focused our research to identify novel β-lactamase inhibitors and succeeded with novel 2- substituted methyl penam derivatives of the formula (I). The novel 2-substituted methyl penam derivatives of the formula (I) are β- lactamase inhibitors used in combination with β-lactam antibiotics. The novel compounds herein in combination with 55 suitable β-lactam antibiotic are effective against a number of human or animal pathogens and clinical isolates. 2 EP 2 046 802 B1 Objective of the Invention [0006] One objective herein is to provide novel 2-substituted methyl penam derivatives of the formula (f). [0007] Another objective herein is to provide a pharmaceutical composition with the novel 2- substituted methyl penam 5 derivatives in combination with antibiotics. [0008] Another objective herein is to provide a method of preventing or treating a bacterial infection in a host, typically an animal, and most typically a human, including administering to the host a therapeutic amount of compound of formula (I) of the novel compounds, or a pharmaceutically acceptable salt thereof along with β-lactam antibiotic. [0009] Yet another objective herein is to provide a cost effective process for the preparation of 2-substituted methyl 10 penam derivatives of the formula (I). Summary of the Invention [0010] The present invention relates to novel 2-substituted methyl penam derivatives of the formula (I), 15 20 their tautomeric forms, their stereoisomers, their polymorphs, their solvates, their pharmaceutically acceptable salts 25 thereof, wherein A = C or N; Het is a three- to seven- membered heterocyclic ring; R1 represents carboxylate anion, or -COOR4 wherein R 4 represents hydrogen, methoxy benzyl, nitrobenzyl, silyl, alkyl, diphenylmethyl, proxetil, axetil, pivoxil, hexetil, daloxate or a pharmaceutically acceptable salt; R 2 and R 3 may be same or different and independently represent hydrogen, halogen, amino, optionally substituted alkyl, alkenyl, or alkynyl; R represents substituted or unsubstituted alkyl. 30 Brief Description of the Drawing [0011] The Figure 1 illustrates a comparison of IC50 values of the novel compounds of Examples 1 to 7 compared with Tazo against Penicillanase enzyme. 35 Detailed Description [0012] Novel 2-substituted methyl penam derivatives of formula (I) are as defined above. [0013] R is represented by substituted or unsubstituted alkyl and selected from linear or branched alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl, trifluoroethyl, diethoxyethyl, 40 hydroxyethyl, hydroxypropyl, and dihydroxypropyl. Suitable substituent is selected from halo, alkyl, alkenyl, alkynyl, alkyloxy, allyl, cyano, nitro, carboxy, alkoxycarbonyl, amino, amide, sulfonyl, carbamoyl, aryl, aryloxy, heterocyclyl car- bonyl, carboxylic acid and its derivatives such as esters, amides hydroxamic acids, and the like which in turn further substituted with alkoxycarbonylakyl, hydroxyethyl, alkyl, aryl, heterocycyl, esters and the like. [0014] Preferable R groups are selected from but not limited to2 )n-(CH-CH3,-(CH2)nC6H5, -(CH2)n-CH=CH2, 45 t -CH2-CONH2, -CH2COOBu , -(CH2)nCO-heterocyclyl, -CH2-CONH-(CH2)n-COOEt, 50 and the like, and the corresponding acids of the esters, where n is an integer up to 5. Described herein involves any 55 substitution on heterocyclyl nitrogen(s) that is hitherto unreported hence novel. [0015] Het represents a "heterocyclic group containging three- to seven-membered ring which may have suitable substituent(s)" and, especially preferable heterocyclic group may be heterocyclic group such as pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl,pyrimidinyl, pyrazinyl, piperadinyl, oxazolidinyl,thiazolyl, benzothiazolyl, purinyl, pyridazi nyl, 3 EP 2 046 802 B1 triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl), tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl), pyrro- lidinyl, imidazolidinyl, indolyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl. The defined heterocyclic groups may optionally be substituted with the same or different one or more substituents, suitable
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