Claims
- 1. A pharmaceutical composition for treating or managing elastase mediated conditions in a mammalian species comprising a non-toxic pharmaceutical carrier and an effective amount of a compound of structural formula: ##STR34## wherein T is ##STR35## wherein n is an integer of 0 to 2;
- M is
- (1) trifluoromethyl;
- (2) chloro of fluoro;
- (3) --COOH;
- (4) --CH.sub.2 A wherein A represents:
- (a) R.sub.a CO--O-- wherein R.sub.a represents
- (1) H;
- (2) straight or branched chain alkyl having from 1 to 6 carbon atoms;
- (3) phenyl;
- (4) cycloalkyl having from 3 to 8 carbon atoms;
- (5) alkenyl having from 2 to 6 carbon atoms;
- (6) phenyl C.sub.1-6 alkyl;
- (7) halo C.sub.1-6 alkyl;
- the above groups (1) to (7) can be unsubstituted or substituted with one or more radicals selected from the group consisting of hydroxy, nitro, C.sub.1-6 alkanoyloxy, halo, cyano, carboxy, ##STR36## carbamoyl, ##STR37## carbamoyloxy, carboxamido, amino, monoalkyl amino or dialkylamino; (b) R.sub.a R.sub.b NCO--O-- wherein R.sub.b is defined as R.sub.a and can be the same as or different from R.sub.a ;
- (c) R.sub.a COCH.sub.2 NR.sub.b --CO--O--;
- (d) ##STR38## or (e) phenoxy;
- R.sup.1 is
- (1) C.sub.1-6 alkyl;
- (2) --OR.sub.a ;
- (3) ##STR39## (5) hydrogen; or (6) phenyl;
- R.sup.2 is
- (1) H;
- (2) C.sub.1-6 alkyl; or
- (3) benzyl as defined below;
- Q.sup.1 and Q.sup.2 independently are:
- (1) hydrogen;
- (2) C.sub.1-6 alkyl;
- (3) benzyl as defined below;
- R is:
- (a) H;
- (b) phenyl of formula ##STR40## wherein X.sub.1 and X.sub.2 are as defined below; (c) benzyl of formula: ##STR41## wherein X.sub.1 X.sub.2 independently are H, OC.sub.1-6 alkyl, --COOH, C.sub.1-6 alkyl, --CH.sub.2 COOC.sub.1-6 alkyl;
- (d) C.sub.1-6 alkyl;
- (e) --CH.sub.2 COOH; or
- (f) --CH.sub.2 COOt Bu.
- 2. The composition of claim 1 wherein:
- M is
- (1) trifluoromethyl;
- (2) chloro or fluoro; or
- (3) --CH.sub.2 A wherein A represents:
- (a) R.sub.a --CO--O-- wherein R.sub.a is as defined below;
- (b) R.sub.a NH--CO--O--;
- (c) R.sub.a O--CO--CH.sub.2 NH--CO--O--; or
- (d) R.sub.a --S--;
- R.sup.1 is
- (1) C.sub.1-6 alkyl;
- (2) hydroxy;
- (3) OR.sub.a where R.sub.a is
- (a) C.sub.1-6 alkyl;
- (b) --C.sub.6 H.sub.5 ;
- (c) --CH.sub.2 C.sub.6 H.sub.5 ;
- (d) --CH.sub.2 CH.sub.2 C.sub.6 H.sub.5 ;
- (e) ##STR42## 10 where R.sub.h represents hydrogen, C.sub.1-6 alkyl, phenyl, benzyl, or C.sub.1-6 alkylamino; or
- (6) --SO.sub.2 R.sub.h ;
- (7) phenyl; or
- (8) haloC.sub.1-6 alkyl--CO--NH--;
- R.sup.2 is H;
- Q.sup.1 and Q.sup.2 independently are:
- (1) hydrogen;
- (2) methyl, ethyl or i-or n-propyl;
- (3) methylene;
- (4) phenylthiomethyl or phenyl sulfonylmethyl;
- (5) benzyl of formula ##STR43## wherein X.sub.1 and X.sub.2 independently are H, OCH.sub.3, --COOH, C.sub.1-6 alkyl, --COOC.sub.1-6 alkyl, --CH.sub.2 COOH, or CH.sub.2 COOC.sub.1-6 alkyl; or
- (6) --CH.sub.2 --CO--OR.sub.h ; and
- R is
- (1) H;
- (2) CH.sub.3 ;
- (3) CH.sub.2 COOH;
- (4) benzyl of formula ##STR44## where X.sub.1 represents OCH.sub.3, --COOH, or --COOt--Bu; or (5) --CH.sub.2 COOt-Bu.
- 3. A compound of formula: ##STR45## wherein T is ##STR46## wherein n is an integer of 0 to 2; M is
- (1) trifluoromethyl;
- (2) chloro of fluoro;
- (3) --COOH;
- (4) --CH.sub.2 A wherein A represents:
- (a) R.sub.a CO--O--wherein R.sub.a represents
- (1) H;
- (2) straight or branched chain alkyl having from 1 to 6 carbon atoms;
- (3) phenyl;
- (4) cycloalkyl having from 3 to 8 carbon atoms;
- (5) alkenyl having from 2 to 6 carbon atoms;
- (6) phenyl C.sub.1-6 alkyl;
- (7) halo C.sub.1-6 alkyl;
- the above groups (1) to (7) can be unsubstituted or substituted with one or more radicals selected from the group consisting of hydroxy, nitro, C.sub.1-6 alkanoyloxy, halo, cyano, carboxy, ##STR47## carbamoyl, ##STR48## carbamoyloxy, carboxyamido, amino, monoalkylamino or dialkylamino; (b) R.sub.a R.sub.b NCO--O-- wherein R.sub.b is defined as R.sub.a and can be the same as or different from R.sub.a ;
- (c) R.sub.a COCH.sub.2 NR.sub.b --CO--O--;
- (d) ##STR49## or (e) phenoxy;
- R.sup.1 is
- (1) C.sub.1-6 alkyl;
- (2) --OR.sub.a ;
- (3) ##STR50## (5) hydrogen; or (6) phenyl;
- R.sup.2 is
- (1) H;
- (2) C.sub.1-6 alkyl; or
- (3) benzyl as defined below;
- Q.sup.1 and Q.sup.2 independently are:
- (1) hydrogen;
- (2) C.sub.1-6 alkyl;
- (5) benzyl as defined below; or
- (6)
- R is:
- (a) H;
- (b) phenyl of formula ##STR51## wherein X.sub.1 and X.sub.2 are as defined below; (c) benzyl of formula: ##STR52## wherein X.sub.1, X.sub.2 independently are H, OC.sub.1-6 alkyl, --COOH, C.sub.1-6 alkyl, --COOC.sub.1-6 alkyl, --CH.sub.2 COOH, or --CH.sub.2 COOC.sub.1-6 alkyl;
- (d) C.sub.1-6 alkyl;
- (e) --CH.sub.2 COOH; or
- (f) --CH.sub.2 COOt--Bu.
- 4. The compound of claim 3 wherein:
- M is
- (1) trifluoromethyl;
- (2) chloro or fluoro; or
- (3) --CH.sub.2 A wherein A represents:
- (a) R.sub.a --CO--O--; wherein R.sub.a is as defined below
- (b) R.sub.a HN--CO--O--;
- (c) R.sub.a O--CO--CH.sub.2 NH--CO--O--; or
- (d) R.sub.a --S--;
- R.sup.1 is
- (1) C.sub.1-6 alkyl;
- (2) hydroxy;
- (3) OR.sub.a where R.sub.a is
- (a) C.sub.1-6 alkyl;
- (b) --C.sub.6 H.sub.5 ;
- (c) --CH.sub.2 C.sub.6 H.sub.5 ;
- (d) --CH.sub.2 CH.sub.2 C.sub.6 H.sub.5 ;
- (e) ##STR53## where R.sub.h represents hydrogen, C.sub.1-6 alkyl, phenyl, benzyl, or C.sub.1-6 alkylamino; or
- (5) H;
- (6) --SO.sub.2 R.sub.h ; or
- (7) phenyl;
- (8) haloC.sub.1-6 alkyl--CO--H--;
- R.sup.2 is H;
- Q.sup.1 and Q.sup.2 independently are:
- (1) hydrogen;
- (2) methyl, ethyl or i-or n-propyl;
- (3) methylene;
- (4) phenylthiomethyl or phenyl sulfonylmethyl;
- (5) benzyl as previously defined;
- (6) --CH.sub.2 --CO--OR.sub.h ; and
- R is
- (1) H;
- (2) CH.sub.3 ;
- (3) CH.sub.2 COOH;
- (4) benzyl of formula ##STR54## wherein X.sub.1 represents CH.sub.3, --COOH, or --COOt--Bu; or (5) --CH.sub.2 COOt--Bu.
- 5. The composition of claim 1 wherein the compound is
- (a) 3-Acetoxymethyl-7.alpha.-methoxy-4-(tetrazol-5-yl)-3-cephem-1,1-dioxide;
- (b) 3-Acetoxymethyl-7.alpha.-methoxy-4-[2-(p-t-butoxycarbonyl-benzyl)tetrazol-5-yl]-3-cephem-1,1-dioxide;
- (c) 3-Acetoxymethyl-7.alpha.-methoxy-4-[2-(p-hydroxycarbonyl-benzyl)tetrazol-5-yl]-3-cephem-1,1-dioxide;
- (d) 3-Acetoxymethyl-7.alpha.-methoxy-2-methyl-4-(tetrazol-5-yl)-3-cephem;
- (e) 3-Acetoxymethyl-2-benzyl-7.alpha.-methoxy-4-(1-p-methoxy-benzyltetrazol-1-yl)-3-cephem-1,1-dioxide;
- (f) 3-Hydroxymethyl-7.alpha.-methoxy-4-(1-p-methoxybenzyl-tetrazol-5-yl)-2-cephem;
- (g) 3-(N-benzylcarbamoyloxymethyl)-7.alpha.-methoxy-4(1-p-methoxybenzyl-tetrazol-5-yl)-2-cephem;
- (h) 3-(N-benzyl-carbamoyloxy-methyl-7.alpha.-methoxy-4-(1-p-methoxybenzyl-tetrazol-5-yl)-3-cephem-1,1-dioxide;
- (i) 3-(N-Benzyl-carbamoyloxy-methyl)-7.alpha.-methoxy-4-(1H-tetrazol-5-yl)-3-cephem-1,1-dioxide;
- (j) 3-Chloromethyl)-7.alpha.-methoxy-4-(1-p-methoxybenzyl-tetrazol-yl)-3-cephem-1,1-dioxide;
- (k) 7.alpha.-Methoxy-3-[(1,2,5,6-tetrahydro-5,6-dioxo-2-methyl-as-triazin-3-yl)thio]methyl-4-p-methoxy-benzyl-tetrazol-5-yl)-3-cephem-1,1-dioxide;
- (l) 7.alpha.-Methoxy-3-[[(1,2,5,6-tetrahydro-5,6-dioxo-2-methyl-as-triazin-3-yl)thio]methyl]4(1-H-tetrazol-5-yl)-3-cephem-1,1-dioxide;
- (m) 3-(N-Benzyl-carbamoyloxy-methyl)-7.alpha.-methoxy-4-(1H-tetrazol-5-yl)-3-cephem-1,1-dioxide.
- 6. The composition of claim 1 wherein the compound is 3-acetoxy-2-benzyl-7.alpha.-methoxy-4-(1-p-methyoxybenzyl-tetrazol-5-yl)-3-cephem-1,1-dioxide.
- 7. The compound of claim 3 which is
- (a) 3-Acetoxymethyl-7.alpha.-methoxy-4-(tetrazol-5-yl) -3-cephem-1,1-dioxide;
- (b) 3-Acetoxymethyl-7.alpha.-methoxy-4-[2-(p-t-butoxycarbonyl-benzyl)tetrazol-5-yl]-3-cephem-1,1-dioxide;
- (c) 3-Acetoxymethyl-7.alpha.-methoxy-4-[2-(p-hydroxycarbonyl-benzyl)tetrazol-5-yl]-3-cephem-1,1-dioxide;
- (d) 3-Acetoxymethyl-7.alpha.-methoxy-2-methyl-4-(tetrazol-5-yl)-3-cephem;
- (e) 3-Acetoxymethyl-2-benzyl-7.alpha.-methoxy-4-(1-p-methoxy-benzyltetrazol-1-yl)-3-cephem-1,1-dioxide;
- (f) 3-Hydroxymethyl-7.alpha.-methoxy-4-(1-p-methoxybenzyl-tetrazol-5-yl)-2-cephem;
- (g) 3-(N-benzylcarbamoyloxymethyl)-7.alpha.-methoxy-4-p-methoxybenzyl-tetrazol-5-yl)-2-cephem;
- (h) 3-(N-benzyl-carbamoyloxy-methyl-7.alpha.-methoxy-4-p-methoxybenzyl-tetrazol-5-yl)-3-cephem-1,1-dioxide;
- (i) 3-(N-Benzyl-carbamoyloxy-methyl)-7.alpha.-methoxy-4-(1H-tetrazol-5-yl)-3-cephem-1,1-dioxide;
- (j) 3-Chloromethyl)-7.alpha.-methoxy-4-(1-p-methoxybenzyl-tetrazol-5-yl)-3-cephem-1,1-dioxide;
- (k) 7.alpha.-Methoxy-3-[(1,2,5,6-tetrahydro-5,6-dioxo-2-methyl-as-triazin-3-yl)thio]methyl-4-(1-p-methoxy-benzyl-tetrazol-5-yl)-3-cephem-1,1-dioxide;
- (l) 7.alpha.-Methoxy-3-[[(1,2,5,6-tetrahydro-5,6-dioxo-2-methyl-as-triazin-3-yl)thio]methyl]4-(1H-tetrazol-5-yl)-3-cephem-1,1-dioxide;
- (m) 3-(N-Benzyl-carbamoyloxy-methyl)-7.alpha.-methoxy-4-(1H-tetrazol-5-yl)-3-cephem-1,1-dioxide.
- 8. The compound of claim 3 which is 3-acetoxy-2-benzyl-7.alpha.-methoxy-4-(1-p-methoxybenzyl-tetrazol-5-yl)-3-cephem1,1-dioxide.
Parent Case Info
This is a division of application Ser. No. 750,432 filed July 1, 1985, now U.S. Pat. No. 4,699,904.
US Referenced Citations (2)
Number |
Name |
Date |
Kind |
4045436 |
Barth |
Aug 1977 |
|
4699904 |
Doherty et al. |
Oct 1987 |
|
Foreign Referenced Citations (2)
Number |
Date |
Country |
1520479 |
Oct 1975 |
GBX |
1520480 |
Oct 1975 |
GBX |
Divisions (1)
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Number |
Date |
Country |
Parent |
750432 |
Jul 1985 |
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