2-Substituted-6-substituted-1-carbadethiapen-2-em-3-carboxylic acids, processes for preparing them, antibiotic pharmaceutical compositions containing same and process for preparing intermediates

Claim 2

A compound having the structural formula: and pharmaceutically acceptable salt, ester and amide derivatives thereof; wherein R 6 , R 7 and R 8 are independently selected from the group consisting of: hydrogen; substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl, aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: chloro, bromo, fluoro, R 1 , -OH -OR 1 wherein, relative to the above listed substituents on R 6 , R 7 and R 8 , the groups R 1 and R 2 are independently selected from: hydrogen, alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon'atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4. oxygen, nitrogen or sulphur atoms and wherein the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; R 8 is selected from: wherein: R 8 , R 1 and R 2 are as defined; when R 6 /R 7 is hydrogen R 7 /R 6 is not: hydrogen; 8 when R is -SCH 2 CH 2 NH 2 , or when R 6 /R 7 is hydrogen R 7 /R 6 is not CH 3 CH(OH), or 0-derivative thereof, when R 8 is -SCH 2 CH 2 NH 2 or N-derivative thereof.

Claim 3

A compound according to Claim 1, wherein R is selected from H, OCH 3 and CH 3 .

Claim 4

A compound according to Claim 2 wherein R 6 is selected from the group consisting of: substituted and unsubstituted: alkyl, alkenyl and cycloalkylalkyl wherein the substituent or substituents are selected from hydroxyl, alkoxyl having from 1-6 carbon atoms, phenoxy, amino, and carboxy.

Claim 5

A compound according to Claims 2 or 3 wherein R 6 is selected from the group consisting of alkyl, cycloalkylalkyl, alkyl substituted by one or more hydroxyl.groups, or'cycloalkylalkyl substituted by one or more hydroxyl groups.

Claim 6

A compound according to Claims 2, 3 or 4 wherein R 7 is hydrogen.

Claim 7

A compound according to Claims 1, 2., 3, 4, or 5 wherein R 6 is selected from:

Claim 8

A compound. according to Claims 1, 2, 3, 4, 5, or 6 wherein R 6 is:

Claim 9

A compound according to Claims 1, 2,. 3, 4, 5, 6 or 7 wherein R 8 is selected from: 1.) aliphatic (including carbocyclic) groups having 1-10 carbon atoms selected from: alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl; 2.) substituted aliphatic groups having 1-10 carbon atoms selected from: alkyl, cycloalkyl, alkenyl, cycloalkenyl and alkynyl; wherein the substituents are selected from: 1 chloro, bromo, fluoro, R 1 , 3.) aryl and substituted aryl; wherein the aryl is phenyl and wherein the substituents are defined above under 2.); 4.) heteroaryl and substituted heteroaryl having 1-4 0, N or S atoms; and wherein the substituents are defined above under 2.); 5.) arylaliphatic, wherein aryl is phenyl, which are selected from the aliphatic groups defined under 1.) which are substituted.by phenyl or substituted phenyl; wherein such substituents on phenyl are defined under 2.), above; 6.) heteroarylaliphatic and heterocyclylaliphatic; wherein the aliphatic moiety is defined under 1.), above; the substituted and unsubstituted heteroaryl and heterocyclic moieties have 1-4 O, N or S atoms; wherein such substituents are defined under 2.),above; 7.) substituted and unsubstituted alkyl-heteroatom-alkyl having 4-12 carbon atoms; wherein the heteroatom is selected from: 0, S, NR° (R° is H, substituted or unsubstituted alkyl); wherein such substituents are defined under 2.),above.

Claim 10

A compound according to Claim 8, subparagraph 2.); wherein: are selected from:

Claim 11

A compound according to Claim 8, subparagraph 3.): wherein: are selected from:

Claim 12

A compound according to Claim 8, subparagraph 4.); wherein: are selected from:

Claim 13

A compound according to Claim 8, subparagraph 5.); wherein: are selected from:

Claim 14

A compound according to Claim 8, subparagraph 6.); wherein: are selected from:

Claim 15

A compound according to Claim 8, subparagraph 7.); wherein: are selected from:

Claim 16

A compound according to Claim 8, subparagraph 1.); wherein R 8 is selected from:

Claim 17

A compound according to Claim 8, subparagraph 2.); wherein R 8 is selected from: -(CH 2 ) n NH 2 ; n=2-6 -(CH 2 ) n NHR 1 ; n=2-6; R 1 =CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , n=3-5 R 1 and R 2 are independently chosen from H and CH 3 R 1 =H, CH 3 n=1, R 2 /R 1 =H,H; CH 3 ,H

Claim 18

A compound according to Claim 8, subparagraph 2.); wherein R 8 is selected from: n=0, 1, 2; m=0, 1, 2 n=0, 1, 2; m=0, 1, 2 R 1 and R 2 = H,H; H,CH 3 n=0, 1, 2; m= 0 , 1, 2 R 1 and R 2 =H,H; H,CH 3 ; R 2'=CH 3 n=0, 1, 2; m=0, 1, 2 R 1 =CH 3 wherein A is selected from:

Claim 19

A compound according to Claim 8, subparagraph 3.); wherein R 8 is selected from:

Claim 20

A compound according to Claim 8, subparagraph 3.); wherein R 8 is selected from: wherein A is selected from:

Claim 21

A compound according to Claim 8, subparagraph 4.), wherein R 8 is: wherein A is selected from:

Claim 22

A compound according to Claim 8, subparagraph 5.); wherein R 8 is: wherein A is selected from:

Claim 23

A compound according to Claim 8, subparagraph 6.); wherein R 8 is: wherein: n = 1,2,3; and A is selected from:

Claim 24

A compound according to Claim 8, subparagraph 7.); wherein R 8 is:

Claim 25

A compound according to Claim 8, subparagraph 7.); wherein R 8 is: wherein A is selected from:

Claim 26

A compound according to Claims 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 wherein R 7 is hydrogen and R 6 is selected from the group consisting of CH 3 CH 2 ,

Claim 27

A compound according to Claim 1 selected from the group:

Claim 28

27 . A compound according to Claim 1 having the structure: and the pharmaceutically acceptable salt and ester derivatives thereof; wherein R 6 and R 7 are independently selected from the group consisting of mercapto, hydroxyl, chloro, bromo, fluoro, hydrogen; substituted and unsubstituted: alkyl, alkoxyl, alkylthio, alkenyl, and alkynyl having from 1-6 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety; aryl, aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the alkyl moiety has 1-6 carbon atoms and wherein the heterocyclic structure comprises 4-6 atoms, the hetero atom or atoms being selected from the group consisting of 1-4 oxygen, nitrogen, or sulfur atoms; wherein the substituent or substituents on R 6 and R 7 are selected from the group consisting of: amino, mono- di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, chloro, bromo, fluoro, carboxy, oximino, ureido, alkoximino, and N-substituted ureido wherein the N-substituent or N-substituents are selected from alkyl, phenyl and phenylalkyl, and wherein the alkyl moieties of the aforementioned substituents have 1-6 carbon atoms; R 8 is selected from the group consisting of: hydrogen; substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moiety; aryl, aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic moiety has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl having 4-6 ring atoms; wherein the substituent or substituents relative to R are selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulphur atoms; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms.

Claim 29

28 . A compound according to Claim 27 wherein R 8 is selected from the group consisting of:

Claim 30

A compound according to Claim 28 wherein: R7is hydrogen, hydroxyl, alkoxyl, alkylthio, mercapto, chloro, fluoro, bromo, alkyl and substituted alkyl wherein the substituent or substituents are: alkoxyl or hydroxyl.

Claim 31

A compound according to Claim 29 wherein R 7 is hydrogen, hydroxyl, OCH 3 . CH 3 , hydroxyl- and polyhydroxyl-substituted alkyl.

Claim 32

A compound according to Claim 30 wherein R 7 is nydro g en, CH 3 or OCH 3 .

Claim 33

A compound according to Claim31 wherein R 6 is: hydrogen; substituted and unsubstituted: alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl; wherein the substituent or substituents are selected from: hydroxyl, chloro, fluoro, bromo, carboxyl, oximino, alkoximino, ureido, amino, alkoxyl, or alkylthio.

Claim 34

33 . A compound according to Claim32 wherein the substituent or substituents on R 6 are hydroxyl.

Claim 35

A compound according to Claim 27 wherein R 7 is hydrogen, hydroxyl, alkoxyl, alkylthio, chloro, fluoro, bromo, alkyl and substituted alkyl wherein the substituent or substituents are: alkoxyl, or hydroxyl; and R 6 is: hydrogen; substituted and unsubstituted: alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl; wherein the substituent or substituents are selected from: hydroxyl, chloro, fluoro, bromo, oximino, alkoximino, ureido, amino, alkoxyl or alkylthio.

Claim 36

A compound according to Claim 28 wherein R 7 is hydrogen, hydroxyl, alkoxyl, alkylthio, mercapto, chloro, fluoro, bromo, alkyl and substituted alkyl wherein the substituent or substituents are: alkoxyl, or hydroxyl; and R6 is hydrogen; substituted and unsubstituted: alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl; wherein the substituent or substituents are selected from: hydroxyl, chloro, fluoro,.bromo, oximino, alkoximino, ureido, amino, alkoxyl or alkylthio.

Claim 37

A compound according to Claim 35 wherein R 7 is hydrogen, CH 3 or OCH 3 .

Claim 38

A compound according to Claim 36 wherein R 6 is selected from: H, wherein: y = 0 or 1; X = OH, NH 2 ;SH; n = 0 or 1; R = substituted or unsubstituted: alkyl, alkenyl or alkynyl having 1-6 carbon atoms wherein the substituent is R 1 ; R 1° = alkoxyl, carboxyl, CF 3 , OH, H, linear or branched alkyl bearing 1 or more hydroxyl groups, amino, aminoalkyl, Cl, F, Br, alkylthio, amidino, guanidino, oximino, phenyloxy, phenylthio,

Claim 39

A compound according to Claim 36 wherein R 6 is selected from:

Claim 40

A compound according to Claim 38 wherein R 8 is:

Claim 41

40 . A compound according to Claim 27 selected fron the group consisting of: (R = phenyl, m-aminomethylphenyl, o-, p- , m-hydroxyphenyl)

Claim 42

41 . A compound according to Claim40 wherein the aminoethylthio side chain, is replaced by a member of the group consisting of: n = 1, 3, 4, 5 or 6.

Claim 43

A process for preparing a compound according to Claims 1-40 or 41 comprising: halogenating.followed by cyclizing in the presence of base: to form: dehydrohalo g enating the resulting intermediate in the -presence of base to form: heating the resulting intermediate in the presence of a displacing agent to form: isomerizing the position of the double bond of the resulting intermediate to form: wherein X is halo.

Claim 44

43 . A process for preparing a compound according to Claims 1- 40 or 41 comprising treating: with a base capable of isomerizing the double bond to form:

Claim 45

44 . A process for preparing a compound of the formula: comprising reacting: with XSR 8 to yield followed by elimination of HX; wherein X is halo.

Claim 46

44 . A process for preparing a compound of the formula: comprising reacting: with XSR 8 to yield followed by elimination of HX; wherein X is halo.

Claim 47

A process for preparing a compound according to Claims 1-40 or 41 comprising reacting: with XSR 8 wherein X is halo.

Claim 48

An antibiotic pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claims 1-40 or 41 and a pharmaceutical carrier therefor.

Claim 49

A compound according to Claim 1 wherein R 7 is hydrogen and R 6 is