NZ213565A - Quaternary amine thiol compounds - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £13565 21 Priority Date(s): T&.

! Complete Specification Filed: | Class: &3M>9r$shfi&};fG7pA?9- .<#?. *?c. z?.7j?j.<rr. c OJMW Publication Date: ,. P.O.-Journal, No: .../.*?.' •23 JAN 1987 : •'•••••• J- i ««•<»«• i Under the provisions of Regu* lation 23.(1) the ......

Specification has been ante-dated) to (fiBfl.&y.-.. \4@L^ K.... m is NEW ZEALAND PATENTS ACT, 1953 Divided from No. 207346 No.: Date: COMPLETE SPECIFICATION QUATERNARY AMINE THIOL COMPOUNDS WWe, BRISTOL-MYERS COMPANY, a State of Delaware corporation having offices at 345 Park Avenue, New York, New York 10154, United States of America, hereby declare the invention for which j{XX"we Pray that a patent may ^be granted to ix$&/u.s, and the method by which it is to be performed, to be particularly described in and by the following statement: - 213565 The present invention is directed to intermediate compounds in a -new process for the preparation of carbapenem derivatives having a 2-substituent of the formula -S-A-R14 wherein A represents cyclopentylene, cyclohexylene or C -C 2 6 alkylene optionally substituted by one or more C -Calkyl 14 1 4 J . groups and R represents a quaternized nitrogen-containing aromatic or non-aromatic heterocycle attached to A through a quaternary nitrogen atom. This process is described and claimed in our New Zealand Patent Specification No. 207346.

The carbapenem derivatives prepared by the process of Specification No. 207346 are disclosed and claimed in U.S. Patent Specifications Nos. 4536335 and 4552696; the entire disclosure of each of these specifications is incorporated herein by reference.

U.S. Patent Specification No. 4552696 discloses preparation of carbapenem antibiotics of the formula IA g *1 wherein R is hydrogen and R is selected from the group consistinc of hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl and ■cycloalkyl-alkyl, 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, hetero--cyclyl and heterocyclylalkyl wherein the hereto atom or atoms in the above-named heterocyclic moieties are selected from the group ...--/.'•f'.'vy'r-"" -v"' 2 consistinc of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms ; wherein the' substituenz or substituents relative to 'the above-named radicals are selected from the croup ccnsis-ing of C^-Cg alkvl optionally substituted by ■amino, halo, hydroxy or carboxyl halo -OR 0 : ■ U 34 -OCNR R ' o '' 3 4--CNR R 3 4 -NR R • -SO-NR3R4 o II 3 4 .-NBCNR E / 0 3II 4 R CNR - —C02R3 =0 -OCR' -SR3 0 II S — SR. 0 II 9 -SR II O — cn -> ^»kiO « VvM*-0" " c£" y&f I y -n3 -0S03R3 -r0S02R3 -nk3SO2H4 3 A -NR C=NR 3 4 -NR C02R ; ; .-NO2 wherein, relative to the above-named substituents, the croups 3 A ♦' a and R are independently selected from hydrogen? alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl,; cycloalkyl alkyl and alkylcy cloalky 1, having 3-6 carbon atonis 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 1-5 carbon atoms ; and heteroaryl, heteroaralky1, heterocyclyl and heterocycly 1 alkyl wherein the beterc atom.or atoms in the above-named heterocyclic moieties are selected from the croup consisting of 1-4 oxyoeu, nitrogen or sulfur atoms and tie alkyl moieties associated with said heterocyclic moieties have 1—6 carbon atoms, .or R3 and taken together with the nitrogen to which- at least one is attached may form a 5-or 6-membered d ,1- — v. ->B. ■ q nitrogen-containing heterocyclic ring; R is as defined for R taken except that it may not bs hydrogen; or wherein R and R* together, represent: Cj-C^ a Iky li dene or C2~ClQ alky lidene substituted by hydroxy; A_is cyclopentylene, cyclohexylene or C2~<"6 alkylene optionally substituted by one or more C^-C^ alkyl groups; is hydrogen, an anionic charge or a conventional 2 13565 readily removable carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter anion; and represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring and attached to A through a ring nitrogen, thereby forming a quaternary ammonium group; and pharmaceutically acceptable salts thereof by the process shown in the following reaction scheme: r8 h coor diphenyl chlorophosphate > iii r8 h N. iv op(oc6h5)2 coor' hs-a-oh A = alkylene or Cc-Cr cycloalkylene D 0 V N s-a-oh ^COOR2 methanesulfonyl .chloride ■> ■ _ U.S.: Patent Specification No. 4536335 discloses preparation of carbape'nem antibiotics of the formula !8 H . \ IB g T wherein R is hydrogen and R ;is selected from the group consisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cycloalkyl-alkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl anc aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon, atoms; heteroaryl, heteroaralkv1, hetero-cyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are independently selected from, the group consisting of vv.:V:/^/rVs,«, ,' •' : '•■jf: r -- - , x^i ' .; -ViL C^-Cg alkyl optionally substituted by amino, halo, hydroxy or carboxyl halo -or3 O "34 -ocnr r 0 -. ■ ■ '■ ■ . -cnr3r4 ; -nrV- ' nr3 ■ \ nr3r4 -s02nr3r4 o " 3 4 -nhcnr r O 3 if 4 r cnr -co2r3 =0 O -ocr3 -SR3 O "9 -sr' ■ "0 " 9 -sr il ■ O -cn . -«3 3 -0s03r -oso7r3 3 4 -nr s02r ■- ■ ■*. vvv;;?.

-NR3C--=NR4 . 13 ■ .R • .• • . .

-NR3CC2R4 -NO2 • ;■ wherein, relative'to 'the above-named subs tituents, the crows R3 anc R4 are' independently selected from 'hydrogen; alkyl,-alkenyl and alkynyl, having-from"1-10 carbon atoms ; cycloalkyl, cycloalkvlalkyl and alkyIcycloalkvl, having 3-6. carbon atcms in the cycloaUcyl xing and 1-6 carbon, atoms' in the alkyl. moieties ;. phenyl; era Iky 1, ar alkenyl and aralkynyl wherein' the aryl moiet^-is phenyl and the aliphatic portion has 1-6 carbon atoms; and -heteroaryl, heteroaralkyl,• heterocyclyl and het'exjpcvclylalxyl vherein the hetero-atom or atoms in the above-named heterocyclic moieties are selected from the' group consisting .cf 1-4 oxygen , nitrogen or sulfur 'atoms and the'alkyl moieties associated with said heterocyclic, moieties have 1-6 "carbon atoms, or R3 and R4 taken together -with the nitrogen to which .at least one is attached may form a 5-or • 6-membered nitrogen-containing heterocyclic ring; R is as defined for R except that it may not be hydrooen; or 1 g vherein' R and R taken together represent C,-C,n alkyliaene or " 5^ ' -u C2-C10 alkyliaene substituted by hydroxy; R is. selected from the group consisting of substituted" and unsubstitutec:- alkyl, alkenyl and alkynyl, having from 1-10 carbon, atosls; cycloalkyl and cycle— alkylalkyl, having .3-6 carbon atcms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl'moieties; phenyl; aralkyl, aralkenvl and aralkynyl wherein the aryl moiety Vis phenyl and-the aliphatic portion has 1-6 carbon • atoms; heteroaryl, heter oar alkyl, hetero^- cyclyl and heterocyclylalkyl wherein the hetero atcro or atoms 'in the above-named heterocyclic moieties are selected from the grouo consisting of 1--4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties'have 1-6 S ' 5 carbon atoms; wherein the above-named R radicals are optionally substituted by 1-3 substituents independently selected frcm: ♦ 213565 Ki cl~cg alkyl optionally substituted by asiao, fluoro, chlcro, carboxyl, hydroxy or carbamoyl; fluoro, chloro or bromo; -OR3 ; * -0c02r3 ; -ocor3 ; -oconr3r4 ; -0s02r3 ; -oxo-; -nr3r4 ; r3conr4-- ; -NR3C02R4 ; 3 3 4 -nr conr r 3 4 -ks sojr .; -sr3 ; O t- 9 -S-K ; 0 O K S Q -s-r ; -so3r3 y -c02r3. ; 3 4 -conr r ; -CN; or phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C.-Cc alkyl, -OR3, -NR3*4 , 3 3 ■ 3 4 j -SO-.R , -CO_R or -CONR R , wherein R , R £nd 9 . d - R m such R subs tituents are as defined above- (Jfcj'l 11 3565 or R may represent a divalent phenylene or C^-C^ alkylene croup j cinec to the . .. e ring so as to form a bridged polycyclic group; A is cyclopentylene, or cyclohexylene' or C--C-. alkylene optionally substituted by one or more C^-C^ alkyl groups; R is hydrogen., an anionic charge or a.conventional readily removable carboxyl protecting group, provid-2 inc that when R is hydrogen or a protecting group, there is also present a counter ion; and represents a substituted'or unsubstituted mono-, bi- or polycyclic non-aromatic heterocyclic radical containing at least one nitrogen in the ring and attached to A through a ring nitrogen, thereby forming a quaternary ammonium group; . and pharmaceutical^ acceptable salts; thereof, by the process shown in the following reaction .■scheme1: .: ,8 H diphenvl chlorophosphate COOR 2' III .8 H IV ,P(<?C6H5>2 COOR HS—-A OH . —; ^ A=alkylene or C^-Cg cycloalkylene ,8 H N S—A—OH COOR2' raethanesulfonyl chloride : -:. ■ " > v VI S-A-0S02CH3 COOR -A-I COOR 2 ' ; I e + 6 Ag X II COOR optional * de-blocking I 'B COOR2 IB To elaborate on the prior art scheme, starting material III is reacted in an inert organic solvent with diphenyl chlorophosphate in the presence of a base to give intermediate IV. Intermediate^ IV is then reacted with a nercaptan reagent of the formula HS-A-OH in an inert organic solvent and in the presence of a base to give intermediate V. Intermediate V is then acylated with methanesulfonyl chloride in an inert organic solvent and in the presence of base to give intermediate VT which is reacted with a source of iodide . ions in an inert organic solvent to give intermediate II. Intermediate II is reacted with the desired amine in an inert organic solvent and in the presence of silver ion to produce the quaternized product I ' A or I'B which may then be deblocked to give the corresponding de-blocked carbapenem of ;Formula IA or IB.

The above-described process has several disadvantages. Thus, for example, the process involves several steps which advantageously could be reduced in number. The overall reaction yield is also quite low and the quaternization step is performed on the entire carbapenem compound. It would be desirable to have a new process for producing compounds of Formula IA or IB which (1) involves fewer -reaction steps, (2) gives higher yields, (3) allow the quaternized amine to be formed first and then attached to the carbapenem nucleus at a later'stage in the synthesis anc (4) can be used to more easily form quaternary amine products with a wide variety of amines, i.e. amines with steric hindrance end those with / ■ low pK^ values.

^ ^ O c^ftv> New Zealand Patent Specification Wo. 207346 provides a novel process for the preparation of carbapenem derivatives of the formula 8 2 wherein R is hydrogen and R is selected from the group consisting of hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cycloalkyl alkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; -aralky 1, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heterc-aralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substitiients relative to the above-named radicals are selected from the croup consisting of „ . . ,-f. — ,% ... v-'-im 2 C^-Cg alkyl optionally substituted by anino, halo, hydroxy cr carbo;<yl ■ halo -or" ? 3 A -OCNR R -S02NR-3R4 -NHOvR3R4 ■■ 0 3" 4 r cnr --co2RJ: - f: -OCR" -SR3 O // 9 -SRy 0 // 9 -sr?.. II O — CK ; : -NV f irv.*.

:?A> 'V ^ .vV/v -V;' L-: •:> -• ■ 3 213565 -oso-r J 3 -0s02r -NR3502R4 4 -NrC=KR I3 3 4 -nr c02r -no2 wherein, relative to the above-named substituents, the groups 3 A- R and R are lnaepenaently selected from hvdrooen; tlicyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl,' cy cloalkylalky1 a_nd alkyIcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in -the al3cyl moieties; phenyl; aralkyl, &ralkenyl and aralkynyl vherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atones; and heteroaryl, heteroaralkyl, heterocyclyl anc heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the croup consisting of 1-4 c>:ygen, nitrogen or sulfur atoiss and the, alkyl moieties associated with said heterocyclic moieties have 3 4 1-6 carbon atcms, or R .anc R taken together with the nitrogen to which at least one is attached may form a 5-or 6-membered 9 3 nitrogen-containing heterocyclic ring; R is as defined for R 1 8 except that it Tnay not be hydrogen; or wherein R~ and R taken together represent C2-C1Q alkylidene or C2~C10 alkylidene substituted by hydroxy; A is cyclopentylene, cyclohexylene cr C2-Cg aUcylene optionally substituted by one or more alkyl groups; is hydrogen, an anionic charge or a conventional readily removable 2 carboxyl protecting group, providing that when R is hydrogen or a protecting group, there is also present a counter 2 1 17 . 14 . . . anion; and R is a quaternized nitrogen-containing aromatic or non-aromatic heterocycle attached to A through, a ring nitrogen, thereby forming a quaternary ammonium group, or a pharmaceutically acceptable salt thereof, which process comprises reacting an intermediate of the formula coor IV wherein R and R are as defined above, R is a conventional, readily removable carboxyl protecting group and L is a. conventional leaving group, with a thiol compound of the formula- \ hs-a-r 14 ,e ■ Y1-1 wherein A and R are as defined above and X is a counter anion in an inert solvent and in the presence of basej to produce a , \ carbapenem product of the formula s-a-r COOR 14 ,e '14 g A, R and X are as defined above and, if ,2' wherein R , R , R desired, removing the carboxyl protecting group R" to give the corresponding de-blocked compound of formula I, or a pharmaceutically acceptable salt thereof.

The carbapenem compounds of Formula I are potent antibacterial agents or intermediates useful in the preparation of such agents.

The compounds of general Formula I above contain the carbapenem. nucleus . -• \ 0 4 and may thus be named as l-carba-2-penem-3-carboxylic acid derivatives. Alternatively, the compounds may be considered to have the basic structure ^ and named as 7-oxo-l-azabicyclo(3.2.0)hept-2-ene-2-carboxylie acid derivatives. While the present invention includes•compounds wherein the relative stereochemistry of the 5,6-protons is cis as well as trans, the preferred compounds have the 5R,6S (trans) stereochemistry as in the case of thienanycin.

The compounds of Formula I may be unsubstituted in the 6-position or substituted by .substituent groups previously disclosed for other carbapenem derivatives. More specifically. may be hydrogen and R^" may be hydrogen or a non-hydrogen substituent disclosed, for example, in European Patent Application 8 1 38,869 (see definition of Rg). Alternatively, R and R taken together may be C2_C10 alkylidene or C2"C10 alkylidene substituted, •for example, by hydroxy.

The present invention provides the intermediates of Formula VII and processes for preparing such intermediates.

More specifically the present invention provides quaternary amine thiol compounds of the formula HS- A-——R14 X® wherein A is cyclopentylenej cyclohexylene or R10 R12 -C- R11 R13 in which R^, R^, R"^ and R^"3 are each independently hydrogen 0 i or C-L~C4 alkyl, X is a counter anion and R represents a substituted or unsubstituted mono, bi- or polycyclic aromatic or non-aromatic heterocyclic radical containing at least one nitrogen in the ring and attached to A through a ring nitrogen, thereby forming a quaternary ammonium group, and a process for preparing such quaternary amine thio compounds, which process comprises reacting a sulfide of the formula wherein R"1"^, R^, R^ and R^ are each independently hydrogen or alkyl with a strong acid and either (a) a heteroaromatic amine of the. formula whe rein represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in the ring capable of being; quaternized and bonded .to a carbon atom of substituent A or (b) a heterocyclic amine of the formula R16 wherein represents a substituted or unsubstituted mono-, bi- or polycyclic non-aromatic heterocyclic radical containing at least one nitrogen in the ring capable of being quaternized by substituent R^ ajid bonded to a carbon atom of substituent A and R represents either (a) an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, hetero-cyclyl or heterocyclyl-aliphatic radical or (b) a divalent phenylene or C^-C^ alkylene group joined to the ring so as to form a 'bridged polycyclic group.

The radical A in the compounds of Formula VII may be cyclopentylene cyclohexylene or alkylene of the formula R 4 .11, R12 I -C- ,13 in which R C,-C .11- 12 13 R and R are each independently hydrogen ^ alkyl. A preferred embodiment comprises those compounds Formula VII in which' substituent A is -CHCK_-, tv. or -CH_CH- ■ . ; 2l»y In the case of certain compounds of Formula vil having a cycloalkylene or branched alkylene A substituent, one or more -• additional assymmetric carbon atoms may be created which result in formation of diastereoisomers. The present invention include mixtures of such diastereoisomers as well as the individual purified diastereoisomers. 3L» 3S<o5 - 22 -14 The quaternized R substituent may be an optionally substituted mono-, bi- or polycyclic aromatic or non-aromatic heterocyclic radical containing at least one nitrogen in the ring and attached to A through a ring nitrogen, thereby forming a quaternary ammonium group. 14 One preferred class of R. substituents may be represented by the general formula which is meant to define a substituted or unsubstituted mono-, bi- or polycyclic heteroaryl radical containing at least one nitrogen in the ring and attached .to a carbon atom.of substituent A through a ring nitrogen, thereby forming a quaternary ammonium group. The heteroaryl radical may be optionally substituted7by such substituents as alkyl, alkyl substituted by hydroxy, amino, carboxy or halo, C^-Cg cycloalkyl, C^-C^"alkoxy, C^-C^ alkylthio, amino, C^-C4 alkylamino, di(C^-C4 alkyl)amino, halo, C^-C4 alkanoylamino, alkanoyloxy, carboxy, O II -C-OC1~C4 alkyl, hydroxy, amidino, guanidino, trifluoromethy1, phenyl, phenyl substituted by one, two or three amino, halo, hydroxy1, trifluoro methyl, C^-C^ alkyl or C^-C^ alkoxy groups, heteroaryl and hetero aralkyl'in which the hetero atom or atoms in the above-named heterocyclic moieties ,are selected from the group consisting of 1-4 0, N or S atoms and the alkyl moiety associated with hetero-aralkyl has 1-6 carbon atoms.

The heteroaryl radical attached- to substituent A is preferably a 5- or 6- membered aromatic heterocyclic radical containing a quaternized nitrogen atom (which is directly bonded to a carbon atom of the alkylene or cycloalkylene radical) and, optionally, one or more additional hetero atoms selected from 0, N or S. While, in general, any heteroaryl radical bended to A 213565 O via a quaternized nitrogen atom is found to produce biologically active carbapenem derivatives/ a preferred embodiment comprises compounds in which represents a radical selected from the group consisting of J (a) ' wherein R , R and R are independently selected from hydrogen; C^-C4 alkyl; C^-C^ alkyl substituted .by. hydroxy, amino, carboxy or halo; C^-Cg cycloalkyl; C^-C^ alkoxy; C^-C^ alkylthio; amino; C^-C^ alkylamino; diCC^-C^ alky1)amino; halo; C^-C^ alkanoylamino C^-C^ alkanoyloxy; carboxy; /' 0 II '• ; , -C-OC^-C^ alkyl? hydroxy, amidino; guanidino; trifluoromethyl; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl/trifluoromethyl/C^-C4 alkyl or C^-C^ alkoxy groups; and heteroaryl and heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said hetero-aralkyl moiety has 1-6 carbon atoms; or wherein two cf R , R. or R^ taken together may be a fused saturated carbocyclic ring, a fused aromatic carbocyclic ring, a fused saturated heterocyclic ring or a fused heteroaromatic ring, (b) or "'•11 'j.'-.. : ;fZ: optionally substituted on a carbon atom by one or more sub- ■, stituents independently selected from C^-C^ alkyl; C^-C^ alkyl substituted by hydroxy, amino, carboxy or halogen; C^-Cg cycloalkyl; C^-C^ alkoxy; alkylthio; amino; C^-C^ alkylamino; . di (C^-C^ alkyl) amino; halo; alkanoylamino; C^-C^ alkanoyloxy; o \ >; : ■ '-"'.V-v carboxy; -C-OC^-C^ alkyl; hydroxy; amidino; guanidmo; trifluoromethyl; phenyl; phenyl substituted by one, two or three amino, halo, hydroxy1, trifluoromethyl, C^-C^ alkvl or alkoxy groups; and heteroaryl or heteroaralkyl in which the heteroatom .or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms ' and the alkyl moiety■associated with said heteroaralkyl moiety ' has 1-6 carbon atoms, or optionally substituted so .as ' to form a ;* fused carbocyclic or heterocyclic ring; optionally substituted on a carbon atom by one or more substituents independently selected from C^-C^ alkyl; C^-C^ alkyl substituted by hydroxy, amino, carboxy or halogen; C^-C^ cycloalkyl; C^-C^ . alkoxy; C^-C^ alkylthio; amino; C^-C^ alkylairtino; di (C^-C^ alkyl) -amino; halo; C-^-C^ alkanoylamino; C^-C^ alkanoyloxy; carboxy; - ■ J ' ■■■":■ : " - ^-:V -C-OC^-C^ alkyl; hydroxy; amidino; guanidino; trifluoromethyl; • ' phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, <-i-C4 alkyl or C^-C^ alkoxy groups; and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said, heteroaralkyl - optionally substituted on a carbon atom by one or more substituents independently selected from C^-C^ alkyl; C^-C^ a.lkyl substituted by hydroxy, amino, carboxy or halogen; C^-C^ cycloalkyl; alkoxy ; C^-C^ alkylthio; amino; C^-C^ alkylamino; di (C^-C^ alky 1)-amino; halo; C^-C'4 alkanoylamino; C^-C^ alkanoyloxy; carboxy; 0 .

II ■■ ' -C-OC^-C^ alkyl; hydroxy; amidino; guanidino; trifluoromethyl; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C^-C^' alkyl or C^-C^ alkoxy groups; and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the: alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused -- carbocyclic or heterocyclic ring; :u: --'4, r>- r; wl- '5? - 26 (e) or O . wherein X is 0, S or NR'in which R is C^-C^ alkyl or phenyl, said radical being optionally substituted on a carbon atom by one or more substituents independently selected from" C^-C^ alkyl; C^-C4 alkyl substituted by hydroxy, amino, carboxy or halogen; 'C3-Cg cycloalkyl; C^-C^ alkoxy; Ci-C4 alkylthio; • amino; ;C]_~C4 alkylamino; di(C^-C4 alkyl)amino; halo; C^-C4 alkanoylamino; C^-C4 alkanoyloxy; carboxy; . '• 0 . "V: vv 7 II ■■ • ' . ' " -C-OC^rC4 alkyl; hydroxy; amidino; guanidino; trifluoromethyl; phenyl; phenyl substituted by one, two or three amino, halo, • hydroxyl, trifluoromethyl, C^-C4 alkyl or C^-C4 alkoxy groups; and heteroaryl or heteroaralkyl in which the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen; nitrogen or sulfur atoms-and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms, or optionally substituted so as to form a fused carbocyclic or heterocyclic ring; ■(f) o © N- •igfe! or N N- wherein X is 0, S or NR in which R is alkyl or phenyl, said radical being optionally substituted on a carbon atom by one or more substituents independently selected from Cj[-C4 alkyl; C^-C^ alkyl substituted by hydroxy, amino, carboxy or. halogen; C^-Cg cycloalkyl; a^oxY> Ci-C4 alkylthio;-amino; alkylamino; di{C^-C4 alkyl)amino; halo; C^-C^ alkanoylamino C^-C4 alkanoyloxy; carboxy; 0 ' ' ■ V.'- II -C-OC^-C^ alkyl;-hydroxy; amidino? guanidino; trifluoromethyl; phenyl; phenyl substituted by one, two or three amino, halo, hydroxyl, trifluoromethyl, C^-C4 alkyl or C^-C^ alkoxy groups; and heteroaryl or heteroaralkyl in which the hetero atom cr atoms in the above-named heterocyclic-moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms; and . e .■■■ ® wherein R is C2.~C4 alkyl or phenyl, said radical being optionally substituted on the carbon atom by a substituent selected from C^-C alkyl; alkyl substituted by hydroxy; amino, carboxy or halogen C3-Cg cycloalkyl; C^-C^ alkoxy; C^-C^ alkylthio; amino; C^-C^ alkylamino; di(C^-C^ alkyl) amino; C]_~C4 alkanoylamino; .carboxy; ?l ' -C-OC^-C^ alkyl; hydroxy; amadino; guanidino; trifluoromethyl; phenyl, phenyl substituted -by one, two or three amino, halo, 'hydroxyl, trif luoromethyl, C^-C4 alkyl or C^-C4 alkoxy groups; and heteroaryl or heteroaralkyl in which the hetero atom or :atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety associated with said heteroaralkyl moiety has 1-6 carbon atoms.

A particularly preferred embodiment of the present invention comprises preparation of compounds wherein represents a radical of the formula , R' in which R5, R6 and 3? are independently selected from the group consisting of hydrogen, C^-C^ alkyl, C^-C^ alkoxy, C^-C^ alkyl substituted by a hydroxy group, C^-C^ alkylthio, amino, carboxy and carbamoyl. r»v j='• :.;f •«' °5? r / 'c, 1 j5o-> A most preferred embodiment of the present invention comprises preparation cf compounds wherein represents a radical of the formula » 6 in which R^f R^ and R^ are independently selected from the group consisting of hydrogen, C^-C^ alkyl, C^-C^ alkoxy, C^-C^ alkyl substituted by a hydroxy group, C^-C^ alkylthio and amino.

Another preferred embodiment of the present invention comprises preparation of compounds wherein represents a radical of the formula ■«' : ; N-=rr-—sea.

Another preferred embodiment of the present invention comprises preparation of compounds wherein represents a pyridiniurn radical..

A most preferred embodiment of the present invention comprises the preparation of compounds of the formula © HS A—N ) wherein represents 213565 "CH2CH2 e/s~\ a, N ) "Ca2 (1) (3) (5) -ch (7) "ch °CH3 (9) 2 2 w (11) -chch-, n I * ch3 \= (2) (4) (6) (io) (12) R 02T S • diastex-eoisomers • NH„ (13) -ch2ch2®n \ or (14) SCH. e ( 8 } -CH2CH2 -ch2ch2en ch.

-CH2CH2®N sch. ^s. J1-CE.

R,R or S,S diastereoisomers at two assymmetric carbons of the cyclohexyl group. / 14 .

Another preferred class of quaternized R substituents may be represented by the general formula . 16' R in. which R^® is selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl and cvcloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl and araIkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moieties associated' with said heterocyclic moieties have 1-6 carbon atoms; wherein the above-named radicals are-optionally substituted by 1-3 substituents independently selected from: C^-Cg alkyl optionally substituted by asiino, fluoro, chloro, carboxyl, hydroxy or carbamoyl fluoro, chloro or bromo; -OR3. ; ' -0C02R3 .7.. -ocor3 ; ; • -oconr3r4 ? -osd2r3 ; -OXO-; "m3„4 ■-NR R ; 33conr4- ; ' " .> • • •' 3 " 4 -nr cozr ; 3 34 -nr conr r ; ; 3 4 -NR S02R . ; -sr3 ; .. ■ o ^ -r q -S-R ; ■ 0 O 1 • e . -s-r -S03R3 ; .

-C02R3 ; . . . 3 A ' '■ •" -conr r 7 -CN; or phenyl optionally .substituted by 1-3 fluoro, 3 '' ■ 3 4'' chloro, bromo, c^-cg alkyl, -or , -nr r , -so^r3 , -co_r3 ■ or -conr3r4, wherein r3 , r4 ..and 9 jne R in such R substituents are'as defined abovs, =7"" 1 •'■sit':'. <f 1, ^ & % <3 O < or R^ may represent a divalent phenylene or C^-C^ alkylene group joined to the ring so as to form a bridged polycyclic group and represents a substituted or unsubstituted mono-, bi- or polycyclic non-aromatic (which may be fused to another aromatic or non-aromatic ring) heterocyclic radical containing at least one nitrogen in the ring and attached to A through a ring nitrogen ^thereby.-forming a quaternary ammonium group. The heterocyclic radical- ■ may be saturated or unsaturated (with 1-2 double bonds) and may contain up to two additional hetero atoms in addition to the quaternary nitrogen, such additional hetero atoms being selected from 0, S(0)TO, N, NR15 or NS17R18 wherein m is 0, 1 or 2, R15 is hydrogen, optionally substituted C,-Cc alkyl or ODtionally substitut; 17 18 " . phenyl and R and R are each independently optionally substituted C^-Cg alkyl or optionally substituted phenyl.

In a preferred embodiment \ r i w ■ '4 •.

I'1 represents a non-aromatic 4-7 membered, preferably 5- or 6- memberedv N-containing' heterocyclic ring containing Q-2 double bonds and. 0-2 additional hetero-atoms selected from O, S (O) , N, 17 18 15 m NR or NR R wherein m is O, 1 or 2, R is hydrogen, C^-Cg alky; optionally substituted by 1-2 substituents indeDendentlv selected 3 34 3 * " from -OR , -NR R , -CO _R , oxo, phenyl, fluoro, chloro, bromo, 3 3 ^ -SO^H and -CONR R or phenyl optionally substituted by 1-3 substituents independently selected from C.-C- alkyl, - . -3 -I 1 6 1 A OR' fluoro, chloro, bromo,. -SO^R" a u -NR R , -CO-jR2 and" -C0NR3R4 and R17 and R18 ar e' each independently C.-C alkyl optionally substituted bv " 3~4 -cd2.^, A U o 1-2 substituents independently selected from -OR, -NR"R oxo, phenyl, fluoro, chloro, bromo, -S03RJ and -CONR3R4 or phenyl % $ ^ tT2 ,f gr £ r? ^ . a k 3 , J (>.. j \/"-v?v f's-s&x _ .. . !'W optionally substituted by 1-3 substituents independently selected . 7 4 3 from C,-Cc alkyl, -OR , -NR R , fluoro, chloro, bromo, -SO,R , ^ ^ a 3 4 is -CO R and -CONR R , wherein R and R in such heterocyclic NR or NR1 Ri8 groups are as defined above In connection wi-th the R16 substituent. In such preferred embodiment the ring may be optionally substituted by 1-3 substituents independently selected from (a) c,-cc alkyl ootionally substituted bv 1-2 substituents mdepencently selected from fluoro, chloro, bromo, -or , -ocor3, -oconr3r4, oxo; -nr3r4, -nr3cor4, -nr3conr3r4, -nr3s02r4, -sr3, -s03r3, -c02r3 and -conr3r4'; (b) C2~C6 a-^en-yoptionally substituted by 1-2 substituents independently selected from fluoro, chloro, bromo, -or3, -ocor3, — 0c0nr3r4, oxo, -nr3r4, -nr3cor4, .-nr3conr3r4, -nr3s02r4, -sr3, -s03r3, -c02r3 and -c0nr3r4; : (c) c2~Cg alkynyl optionally substituted by 1-2 substituents independently selected from fluoro, chloro, bromo, -or , —ocor3, -oconr3r4, oxo, -nr3r4, -nr3cor4, -nr3conr3r4, -nr3s02r4, -sr3, -s03r3, -c02r3 and -conr3r4; (d) c,-cg .cycloalkyl optionally substituted by 1-2 substituents , . • 3 independently selected from fluoro, chloro, bromo, -OR , -ocor3, -oconr3r4, oxo, -nr3r4, -nr3cor4, -nr3c0nr3r4 , -nr3s02r4, -sr3, -s03r3, -c02r3 and -conr3r4; . ' . (e) cycloalkylalky1 having 3-6 carbon atoms in the cycloalkyl ring and lr6 carbon atoms in the alkyl moiety, optionally substituted by 1-2 substituents independently selected from fluoro, chlorof bromo, -or3, -ocor3, -oconr3r4, oxo, -nr3r4, -nr3cor4, -nr3conr3r4, -nr3so_r4, -sr3, -so,r3, -co-r3 and 34 ^ J 2 .-conr r ; 2 13565 (f) heteroaryl wherein the hetero.atom or atoms are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms, optionally substituted by 1-2 substituents independently selected from fluoro, chloro, bromo, -OR"*, -OCOR3, -OCONR3R4, oxo, -NR3R4," -NR3COR4",- -NR3CONR3R4, -NR3S02R4, -SR3, -S03R3,- -C02R3 and -CONR3R4; preferred heteroaryl radicals are 5- or 6-merabered aromatic heterocyclic. rings; (g) heteroaralkyl wherein the hetero atom or atoms are selected from t£ie group "consisting of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety has 1-6 carbon atoms, optionally substituted by 1-2 substituents independently selected frora 3 3 3 4 fluoro, chloro, bromo, -OR , -OCOR , -OCONR R , oxo, 34 3 4 3 34 3 4 3 3 -NR R , -NR COR , -NR CONR R , -NR SO-R , -SR , -SO-.R , 3 3 4 -COjR and -CONR R ; preferred heteroaralkyl are those in which the heteroaryl radical is a 5- or 6-membered r- aromatic heterocyclic ring and the alkyl moiety has 1-2 carbon atoms; (h) heterocyclyl wherein the hetero atom or atoms are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms, optionally substituted by 1-2 substituents independently selected from fluoro, chloro, bromo, -OR3, -OCOR3, -OCONR3R4, oxo, -NR3R4, -NR3COR4, -NR3CONR3R4,' -NR3S02R4, -SR3, -S03R3, -C02R3 and -CONR3R4; preferred heterocyclyl are 5- or 6-membered saturated or unsaturated rings; (i) heterocyclylalkyl wherein the hetero atom or-atoms are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur a.toms and the alkyl moiety has 1-6 carbon atoms, optionally substituted by 1-2 substituents independently selected from fluoro, chloro, bromo, -OR3, -OCOR3, -OCONR3R oxo, -NR3R4, -NR3COR4, -NR3CONR3R4, -NR3S07R4, -SR3, -SO^R3 3 3 4 -C02R and -CONR R ; preferred heterocyclylalkyl are those in which the heterocyclyl moiety is a 5- or 6-membered saturated or unsaturated ring; (j) fluoro, chloro or bromo; (k) -OR3 7 ■' (1) -0C02R3 ; (m) ■; -OCOR3 ; (n) -OCONR3R4 ; (o) -OSOZR3 ; (p) oxo ; .. (q) -NR3R4 ; '(r) ' R3CONR4-; (s) -NR3C02R4 ; . (t) -NR3CONR3R4 ; (u) -NR3S02R4 ; (v) -SR3 ; . (w) O ■■ ' r g ■ • ■ ■ ■ -S-R ; (x) o o • ■ 7 q -S-R ' (y) ' -SO3R3 ; ; (2) -co2R3 ? ■ (aa) -CONR3R4 ; (bb) -CN; or (cc) phenyl optionally substituted by 1-3 fluoro, chloro, broao , .C1-C6 alkyl, -OR3, -NR3R4, -S03R3, .-C02R3 or -C0NR3R4. 3 4 9 . ■ The R > *R and R substituents mentioned\above are as defined i: connection with substituent r\ m o . -H : ■ ■ r:~^ ti ,j r 38 ring as defined above is a nori-aromatic heterocycle group.

This ring, however, may be fused to another ring which may be a saturated or unsaturated- carbocyclic ring, preferably a .C^-C^ carbocyclic ring, a phenyl ring, a 4-7 membered heterocyclic (saturated or unsaturated) ring containing 1-3 hetero atoms selected from 0, N, S(0)m, NR15. or NR17R18 or a 5-6 membered heteroaromatic ring containing 1-3 hetero atoms selected 0, S (0) , "IS 17 1 O 1 e 1 7 Vfl ' : m N, NR or NR .R in which m, R , R ' and R are as defined above. ■ y- The R^ substituent of the non-aromatic R^"4 radical may be either (a) an optionally substituted C^-Cg alkyl, C2~Clo alkenyl, C2~C10 'a-l-kynyl, C3~C6 cycioa^ky-' C3-C, cycloalkyl-C^-Cg alkyl, phenyl, phenyl-C^-Cg alkyl, phenyl-C^-C^ alkenyl, phenyl-C^-Cg alkynyl, heteroaryl, heteroaralkyl in which the alkyl moiety has 1-6 carbon atoms, heterocyclyl or hetero- • cyclylalkyl in which the alkyl moiety has 1-6 carbon- atoms or (b) a divalent phenylene or C^-C4 alkylene group joined to the' ; 2 1 35 6 5 $■• CE^? P=5» jp ffj* &s'- _ 39 _ w-: < .r VV:.

X!"; > faring so as to form a bridged ring polycyclic group, e.g. a quinuclidine group. The heteroaryl (or heteroaryl portion of • heteroaralkyl) substituent may be a mono-, bi- or polycyclic aromatic heterocyclic group containing 1-4 0, N or S atoms; preferred are 5- or 6-membered heterocyclic rings such as thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxazolyl, pvridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl and pyrazolyl. The heterocyclyl (or heterocyclyl portion of heterocyclylalkyl) substituent may be a mono-, bi- or polycyclic saturated or unsaturated non-aromatic heterocyclic group containing 1-4 0, N or S . atoms ;'■• preferred are- 5- or 6-membered heterocyclic rings such as morpholinyl, piperazinyl,. piperidyl, pyrazolinyi, :pyrazolidinyl, . . imidazolinyl, imidazolidinyl, pyrrolinyl and pyrrolidinyl... T In the case where the R~° substituent is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl; phenyl",, phenyl- -alkyl, phenyl alkenyl, phenyl alkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl group,: such groups may be . optionally substituted by 1—3 substituents independently • . -- selected from:'' (a) C^-Cg alkyl optionally substituted by, preferably 1-3, • amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups ; ..y'r ■(b) fluoro, chloro or bromo; . (c) ' -OR3 ,* (d) -OCO.R3 ; |rv; ■ • H; 3 ' (e) -OCOR ; (f) -OCONR3R4 ; (c) -0S02R3 ; (h) -OXO 7 (i) -NR3R4 ; (j) R3CONR4- ; (k) -NR3C02R4 ; . (1) -nr3conr3r4 1 7, ' ■ W (m) -NR3S02R4 j (n) -SR3 ; (o) -SOR9 ; (p) -SC2R9 ; (q) -S03R3 ; (r) -C02R3 ; (s) -CONR3R4 ; (t) -CN ; or (u) phenyl optionally substituted by 1-3 substituents independently selected from fluoro> chloro, bromo, C^-Cg alkyl, -OR3, -NR3R4, -SO,R3, -CO-R3 or -CONR3R4 , wherein, ■ . relative to the above-named R substituents, the groups R3 and R4 are independently selected from hydrogen; alky1, alkenyl and alkynyl, having•1-10 carbon atoms; cycloalkyl, cycloalky lalkyl and alkylcycloalkyl, having • ; ' • 3-6 carbon atoms in the cycloalkyl ring and 1-5 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; and heteroaryl, heteroaralkyl, heterocyclyl .and heterocyclylalkyl wherein ^ the heteroaryl and heterocyclyl group or portion "of" a group is as defined above for and the alkyl moieties associated with said heterocyclic moieties have 1-6 ■ ■ 3 4 ■ ■■■-■' carbon atoms; or R an d R taken together with the nitrogen to which at least one is attached may form a 5- or 6-membered nitrogen-containing heterocyclic (as;defined 16 . q . ■ ..' '3 above for R ) ring; and R is as defined above for R except that it may not be hydrogen. A most- preferred R substituent is C^-Cg alkyl, especially methyl.

In the case where R^Is a divalent phenylene or C^-C^ alkylene group,, such group is bonded to another atom of the ring so as to form a bridged polycyclic ring, e.g. a quaternized quinuclidine ring of the- formula A particularly . preferred."embodiment'of the present invention comprises preparation of compounds wherein S , N fr ©// . Y ch3 / e ■N V CH, N* ^h3 ' ~e- s—^ o ' ' / /, - ■ 'CHr NrY \ / — CH3 #4 or wherein Y is hydrogen, C-^-Cg alkyl,"hydroxy, -SC^-Cg alkyl/ carboxyl, carbamoyl, chloro, bromo, iodo/ fluoro or phenyl. } • 4-,.: A still more preferred embodiment of the present invention comprises preparation of compounds wherein represents CH" CH f~ ' CH.

—N \ s->o CH,. 4- J-CH- CH. , 9 J=H3 N' ■^Sch-3 : CH '^r\ —n a CH N e \ NH or A still more preferred embodiment of the present invention comprises preparation of compounds wherein o repres ents in which Y is hydrogen, C^-Cg alkyl, hydroxy, -S-C-^-Cg alkyl, carboxyl, carbamoyl, chloro, bromo, iodo; fluoro or phenyl. Within this preferred subclass, the preferred compounds are those in which A is . .. ... . 7.

A most preferred erabodiaent. of the present invention • comprises.preparation of compounds wherein ' represents Within this preferred subclass , the preferred compounds are those in which A is -CH„CHn-. 2. JL A most preferred embodiment of the present invention comprises preparation of the compounds of the formula HS- R16/^ ^N -ch2ch2 — wherein reoresents ch-- e CH. \_y CH N-CH3 or CH.

—N N ® \ / "-CH (both c- arid. S- ■ diastereoisoraers) ch3 The thio intermediates of Formula VII may be prepared, for example, by reacting a sulfide of the formula or villa VTIIb, / „ 12 v R"v—-p_C R ,11 ,13 viii c wherein R"^, R^, and are each independently hydrogen or C^-C^ alkvl with a heteroaromatic amine (as defined above) of th formula i t*--- ■13 or a non-aromatic heterocyclic amine (as defined above) of the formula and a strong acid. The reaction may be carried out in the presence or absence of an inert organic solvent which is preferably a non-polar organic solvent such as methylene chloride, benzene, xylene, toluene or the like. Where the amine-and sulfide reagents are liquids or where a solid amine is soluble in a liquid sulfide reagent, it is preferred to carry out the reaction without use of an additional solvent.

The particular strong acid used in the reaction is not critical and may be, for example, such .strong inorganic or organic acids as hydrochloric, hydrobroiaic,• methanesulfonic, p-toluenesulfcnic, trifluoromethanesulfonic, etc.

Formation of the quaternary amine thiol intermediate VI.I may be carried out at a temperature in the range of from substantially -20°C to substantially 100°C- Preferred temperatures are -generally in the range of about 50-70°C.

.The sulfide reagent, aromatic amine and acid are preferably employed so that the sulfide and acid are used in approximately equimoiar amounts with the amine being1used in excess, e.g. two to three moles of ; amine per mole of sulfide or acid.• 1 The quaternary amine thiol intermediate will have a counter anion associated with it which will be determined by the particular acid employed. It is, of course, possible to. substitute at this point a different counter anion by conventional procedures for use in the subsequent reaction with carbapenem intermediate TV.

The following Examples illustrate but do not limit the scope of the present invention.

Ex an'Die 1 A. 1-(2-mere auto ethyl)uyridiaiuj aethanesulfolate Do a suspension of pyridiniun nsthanesulfonate in pyridine.' prepared by -the dropvise addition of: nethanesulfonic. acid (1.95 cL,: 0.03 sol) . to pyridine (8. 0 mL, 0.099 sol) with-cooling, was added " ethylene sulfide (1.S6 oL, 0.033 mol) - The resulting nixture was stirred at 55*C for 16 h and concentrated under reducedpressure to a thick syrup which vas sixedwith few aL of water. £he solution was poured on top of a column (40 x 16 c=i) of y-bondapak C-18 which was eluted with water. Lyophyli^ation of the appropriate fractions gave a colorless syrup 6.5 g (9H) , ir (filn) V : 2300-2600 (br, SH) , *• in&^c ~ • 1635 (pyridiniun), 1490, 1200 (sulfonate), 1063, 1060, 1045, 791, 780 cm 1, 1Hmr . (DHSO-cf.) q: 2.32 (33, s, CT SO,~), 2.61 2.70 , 2.73, 2.82 (1H, 3 part of A^B svsten, SH), 3.07 (2H,a [with t>20, 3. OS (2X, j=6.5 _Kz) ] , CF.2S) , A. 76 (2H, t, £=6.5 Hz, CH2N+) , ■ 8.19 (2K, ra, H=i of ! pyridiniu=0 , 8. 6 (1H, .ti, Ko of pyridiniu.-n) , 9.08 (2H, dd, £=5.8 Hz, ,v £-1.4 Hz, Ho of pyridiniim) , uv (H O) \ : 206 (£5230) , 258 (C3760) ir.p a IT\2.X- ♦ 2 13565 method a 3 • 1- (2-niexcaDtoethvl) ovridiniun chloride HsO ? emu tit S-l CI An acueous solution of crude 1- {2-nercaptoethylJpyridiaixs: methanesulfonate (9.4 g/ 0.04 sol) was poured on top of col\= (2.5 x 41 era) of pemutit S-l CI - The col-cm was eluted with water at a rate of 0.5 riL per nin tad the appropriate'fractions were combined and lyophylized giving a yellowish syrcp 7.0 g (100*) which was used as it was for the next step, 1 ?*~r (D^O) 0: 3.22 (2K, n, CL^S) , 4.83 (a, 'CHjN +) , 8.13 (2H, a. Ha of pyridiniun) , 8.7 (IH, s:," Hp of pyxidinivn) , 9.0 ppm (2H, n, Ho of METHOD 3 A ci" Cl To a precooled (ice bath) pyridine (5.6 mL, 70 jrmol) was added pyridine hydrochloride (4.05 g, 35 mmol) and ethylene sulfide (2.1 mL, 35 mmol). The mixture was heated at 65°C and stirred for 75 min to give a two phases system. The lighter phase was remove.d. The remaining oil was washed with ether (5 x 10 jnL) and pimped / under high vacuum to give the title compound (90-100\). yzi 48 - i Example 2 1- (2-nercaotoethyl)-3,5-dimethylpyridinimn raethanesulfonate HsO + HsOH — y US' To a suspension of 3,5-lutidir.ium aethajiestilfonate in 3,S- lutidine prepared by.the addition of methauesulfonic acid (0.65 iL, 0.010 doI) to cold 3, 5-lutidine (2.51 mL, 0.022 no 1) vras" added : ethylene sulfide (0.655 kiL, 0.011 mol). The resulting hixture . was stirred under a nitrogen atmosphere at 55*C for 24 h, cooled to 23 *C and diluted with water (5 aL) and ether (5 aiL) . The organic layer was separated and-the aqueous solution was washed with, ether (6x4 R\L) . The traces of ether were removed under vacuus and the solution was applied on top of acoluan (2.5 x 6.0 ca) of p-boncapak C-18. Tne col'wTJi was eluted with water and iyoohilization of the appropriate fractions gave a colourless syrup 2.4 g (91*) j Mr (filn) V .* 2520 (SH) , 1628 (pyridinium),1600, 1495/ 1325, 1305, 1233, 1200 max (sulfonate), 1040, 938, 765, 680 ra"1; lKsir (DMS0 i ) <5: 2.31 (3K, 6 s, CH^SO^ ), 2.47 (6H, s, CH^.on pyridiniun), 2.57, 2166, 2.69, 2.78 (IK, • 3 part of system, SH) , 3.C6 (2K, mlwith D20 added (2H, t, £=6.5 Hz) ] , CH2S) , 4.65 (2H, t, £=6.5 Hz, CH2N+), 8.34 (IH, s, Kp of pyridiniuni) , 8.79 (2H, s, Ho of oyridiniura) ; uv (H„0) X : 271 ■ 2 jo.ax (C4860) my. Ana_l. calcd. for C10H17NO3S2-0.5H20: C 44.09, H 6.66, N 5.14, S 23.54; found: C 44.26, H 6.49, N 5.17^ S 24.18. vv 7- ~,'1\ j ir." ■■ 2 o - 49 -Example 3 3-Hydroxynethyl-l- (2-rarcaptoethyl) pyridlniurii trif luororoe thane sulfonate CH2°H + CJ^SO^H A. -> HSO^CJ^N Trif luorome thanesulfonic acid (1.327 oL, 0.015 aol) was added dropwise to 3-pyridinenethanol (2.91 xaL, 0.030 sol), followed lay ethylene sulfide {0.89 ini, -0-015 _:nol) . She resulting homogeneous mixture was heated (oil bath) at 50-70°C un'der'H for 20 b- .The reaction LXture was the.- taken up in H^O (15 mL) .and extracted" with CH2C12 (5x5 "riL) •' , The acrueous phase was concentrated -en vacuo arsd then applied to a C reverse-Dhase' cblunui. Elution with H_0 followed • io 2 ■ by evaporation of the relevant fractions gave a pale yellow oil.: This material was rechrociatographed to give a nearly -colourless oil. : After drying in vacuo (?2°5^ afforded the product (4.50 g, 94*) as a viscous oil. ir (film) v s 3450 (s, OH), 2560 (w, SH) era-1;' x>fcnr (^-acetone) 6: 9.10-8.05 (a, 4H, aroreatic) , 5.01 ft, J=5. 5 Hz, 2H, N-CK ) 4.93 (S, 2H, -CH2 OH), 4V43(br S, IH, -OH) , 3.43-3.18 (n, 2H, S-CH^ , 2.34-2.10 (ra, IH, SH). 213565 f' i 50 - Example 4 4-Hydroxyme thyl-I- (2-merca?toetbyl) oyridiniun trif luoro:=ethanesuLf onatt CS.OE 2 + OF^SCTH A -}■ .,'HSCH CH h To a solution of 4-pyridinenethanol (1.625 g, 0.015 col) . : in 10 nL of CH^Cl^/ at 0*C under was added dropwise triflucre— ne thanesulfonic acid. (1. 327 mi., • 0.015 aol) . A yellov—bzowa oil rapidly separated out.. An. additional equivalent of 4-pyridine- / aethanol (1.625 g, 0.015 riol) was added to this, nixture and the .v solvent was jeaoved under reduced pressure to give an oil. 3t> this oil was added ethylene sulfide (0. 891 mL, 0.015 nol) and' the - resulting homogeneous mixtruxe was heated (oil bath) at about 60*C for 3 h. The reaction mixture was then ta_ken up In 15 iri, of H^O and the acueaus solution was washed With (5 x .5 nL) . * After removing residual organic solvent -in vacuo the acueous solution was applied to a C reverse-phise colvr.n. Zlution with H O and subsequent evaporation of the relevant fractions afforded an oil,which was further dried -In ~vccul0 over ?2°5 to 5-ve product (4.64 c; 97*) as a colourless oil. ir ' (film) y :.3455 (s, OH) , 2565, (w, SH) c=T^; 3Hnmr (d -acetone) fi: 9.0"!, 8.18 (A3q, _J=6-B Hz, 4K, aromatic) , 5-. 03 6 (s, 2H, .CK20H)/ 4.96 (t, J.= 6.5 V.=., 2K, . Jv-CH ):., 4.09 (br S, IH, -OH) , 3.5-3.1 (m, 2H, S-CH2)2.25 (brs, IK, -SH) . ^ ' Example 5 1- (2-ner'c-apt:e>ethyl) -2—giethyloyridiniua oethanesulfonate A + N { I > + his OH 55 *C, 21 h HsO To a suspension, of 2-=ethylpyridiniunaathinesulfonate \ . in 2-nathylpyridi_ne prepared by-the addition of meth&nesulfcnic ■acid (0.65 rnL, 0.010"riol) to.cold 2-aethylpyridine (2.17 nvL, 0.022-nol)" was added ethylene sulfide (0.655 nL, 0.011 =>ol). reaction cixture was stirred under a nitrogen atmosphere at 55°C for 21 h, cooled to 23°C and diluted with water' (5 mL) . The aqueous solution was washed with ether (S pc 4 cL) paped to remove traces of organic solvents and poured on top of .a coluan '(2. 5' x 10.0 a) of y-bondapaJc C-18. "Erie coluan -was el'uted with water and lyophiii-zation of the appropriate fractions gave 2-13 g (85%) of the titlev : compound, .'if (film) Vwy; 2520 (SH) , 1823 • (pyridiniun) 1574, 1512, 1435 .1412, 1195 (sulfonate)", 1038 en"1, *}>=r (EtiSO-d + D O) a: 2.37 (3=, ® * * s, C33S03"),-2.83 (3H,.s, 'c^' on pyridiniua) , 3-09 (2H, J=6.9 Hz, Ca2'S) , 4.71 (2H, t, J-6.9 Hz, , 7.93 (2H, ra/ Hni of. pyridiniua) , 8.44 (IH, n, Hp of pyridiniira)*, 8.89 (IH, m, Ho of pyridiniun), uv (H O) x : 266 (£3550) r.y. 2 _ inZX . : Example 6 A. 1- (2-mercaptoe'thvl) -4-jnethvlpvridinium jnethanesulfonate A' r \\ /v /N .v.s0 + ))— +MsCH " 55°C, 24 h To a suspension of 4;-picoliniuamethanesulforiate in-4--picoline prepared by "the addition of methane sulfonic acid (0.65 nl,, 0.010 nol) -to 4-picoline' (2.14 nl<, '0.022 nol) . ia cooling wis\ acded ethylene sulfide (0.-555 kI», ' 0.011-iaol). The reaction roxture vas stirred under a nitrogen atnasphefe- at 55°C for 24 h, cooled to 23"C and diluted with water (5 clL) and ether (10 nL) The organic layer was separated and the aqueous layer was washed with ether (5x5 —*r) 'and applied on top of a colra (2.5 x 10 era) of y-bondapak 'c-l&-after traces of ether have been removed under reduced pressure. Elution of the column with 15% acetonitrile 85% vater. isixture cave after'lyophylization of the appropriate fractions a colcriess syrup 2.66 g (100%) , ir (fil=0 V : 2500 (SH) , 1640 (pyridiniua), • UliX " 1572, 1520, 1478, 1200 (sulfonate), 1040, 833 and 768 erf1,- ^Har (D.MSO-C? ) 6: 2.31 (3H, s, CH-SO,"), 2.62 (s, C3_ on oyridinics), ■ b 3 3 3 2.2-2; 9 (4H, SK, CH^ on pyridinivsa) , 3.04 (2K, ra, CH^S) ■■ A. 66- (25, t, J=5.4 Hz, G?2N ) , 8.01 (2H, d, J=6.6. Ez, Ha of pyridiniun)/ 8.89 (2H, d, £=6.6 Hz, Ko "of pyridiniim) , uv (H_0) A : 255 (£4100), 221 ■ ~~ 4 »■. TTt&^C (C7544) ir.p. - v\ 7 .</ B . I- (2-nercaptoethyl) -4-r.ethyl?yridiniun p^toluenesulfonate /\ + tif )V— + pXsOH •— >.

To a -suspension'.of •pr-toluenesulfcnic acid'(1-72 g, 0.01 nol). in benzene "(6.5 mL) was added 4-picoline (1117 aL, 0.012 mol). The resulting rdxtvre was stirred under a ■ nitrogen atmosphere at. 23 "C for 30 rdn, treated with ethylenesulfide . (0.65 mL, 0. Oil mol) and / stirred at 75" for 24 h. More ethylenesulfide (0.65 . nL, 0.011 aol) vas added and the stirring was continued at 75°C for 24 h more. . • The reaction mixture was cooled to 23*C and diluted with water ' (5 =1.) * and ether (3 mL) . The aqueous layer was separated and washed vith ' ether (3 x 8 .mL) . ' The traces of organic solvents were reaoyed " tinder vacuum and .the compound was chroma to graphed on p-bondapak C-13j with water as eluting solvent to give 2.94 g (90^) of the title co-pound as a colorless syrup; ir (film) v : 2S10 (SH) 1640 (pyr.i-dir.ium) , 1595, 1582, 1475, 11200 (sulfonate) , 1031, 1010. 818 <=a""5. :Krr.r (U".SO, d-) 6: 2.29 (3K, s, CH* on pvridinium), 2.61 (s, C3* ?h), © 3 . —3 ■ , 2.4-2.8 (4K, SH, CH3?h), 3.03 (2H, m (addition of .D^ gave at, £=6.4 Hz, at 3.04], CH^S) , 4.68 (2H. t, £=6.4 Hz, CH2N+) , 7.11, 7.49 (4H, 2d, J=*7.9 Hz, Phenyl) , 8.00 (2H, d, £=6.5 Hz,:Ezi of pyridinitza), 8.39 (2H, d, £-6.5 Hz, Ho of pyridiniumj , nv (H O) x .- 256 (e-4315), "l,l—. a , KftX 222 (£17045) my a .. i-.y.-.; " $ Example 7 2 13565 A. 4-Methvlthiooyridine* /y^\\ 1) Mel/EtOH \vJ/ H —* \^rr_/ 2) NaOH 4-Mer cap topyridi_ne • (S.55 g, 50.0 iedoI; Aldrich) was dissolved in boiling abs. ITtOH(50 aL). The insoluble material vas removed by filtration over Celite. ' The filtrate vas heated to re-dissolve, and when it cooled to ca. 50*C, methyl iodide (3.17 nL# 51.0 ictoI; Aldrich) was added at once. The mixture was cooled to : crystallize. Filtration of the. solid gave 6.77 g (26.7 caol, y. 53.5\) of the title compound as the hydriodide: 1Hrr (D^O) o: 2.70 (3H", s, -SCH ) and 7.65-7.77-8.35-8.43 ppm (42, type, arc^atic Hs); ir (Nujol) V- : 1615, 1S85 (aromatic) and 780 ca w (S.O) x 2 x : 227 (C2.02 x lbw) and 298 ran (el.64 x 10V). max The hydriodide (6.33 g, 25.0 ncriol) was dissolved in E^O • (40 mL) and the insoluble material was. removed and washed with H^O (10 mL) . To the filtrate was added at 0-5® NaOH pellet (5 g) and extracted with E^O (3 x 25 mL) , saturating the aqueous layer with NaCl. The combined organic, extracts were washed with brine (x 2), dried (MgSO^) and evaporated, yielding 2.92 g (23.4 r=nol, overall yield 50*) of the title' compound as an oil: 1Rmr (OCl^) 6: 2.48 (2H, s, -SCH^) and 7.03-7.13-8.38-8.48 ppa (4H, A^B^typearomatid-ris) ; ir (fila) V : 1580 and 800 cm \ nax / •Preparation of this compound was reported Jby King and Ware, J. Chem. Soc., 873 (1239). The procedure, described in this ref ererv was followed. 4-Methylthio-N- (2-wercaptoethyiyoyridiniua nethanesulfonate V OJjSOJH 50-60' 4-Jiethylthiopyridine (2.75 g, 22.0 rraol) was adde'd slowly to methanesulfonic acid*- (0.65 ml., 10.5 m=iol) by cooling in an ice-bath. To this solid was- added ethylene sulfide* (0.66 aL/ 11.0 raol, Aldrich) and the mixture was heated at 50-60*C for 21.h.

As reaction proceeds the solid went to solution. After cooling, "the reaction mixture vas dissolved in K^O (5 mL) and washed"with rt^o (5 x 4 ejX) . The cloudy aqueous layer was filtered civer Celite : and the filtrate was purified by reverse phase sijica gel colu=m . „ chromatography (C micro bondapack 10 g) eluting with H_0. Sach ■ ' IS . "* 2 fraction of 10 s>X was collected". Fractions 2 and 3 were combined and repurified by the reverse phase coluan. Fraction 2 gave 1.253 ^ (4.48 mool, y. 42.6%) of the title compound as a viscous oil: 1Hm= (EMS'O-cf', CFT-20) 6: 2.32 (3H, s, HeSoQ , 2.-72 (3H, s,--Site) , 2.68 (IK, a, •SH) , 2.9-3.2 (3H, a, -C-^S-) , 4.59 (2H, t, J-6.4 Kz, -CH2^, 7.97 (2H, "d", J=7.2 Hz, arcmatic-Hs) and 8.72 ppn (25,. "d", J»7-2.Ejz, aroaatic-Hs); ir (neat) V i 1630, 1200 (bz, , nax • J :>r, -SO®) , 7 -85 and 770 ca -1 * These reagents were distilled prior to use, 2 13565 Example 8 1-(2-mercaPtoethvl)-3-methoxypvridiniuin inethanesulfonate added drop-rise methanesulfor.ic acid (0.216 eL', 3.05 E=ol) and ethylene sulfide (0.19 mL, 3.2 ntnol) . The mixture vas then heated at 60 *C for 18 h, cooled to 20 ®C, diluted vith' water (10 ru.) ind . washed with ether (3 x- 10 nL) - The aqueous phase vas pv=ped under high vacua for 15 nin and poured on a C reverse phase 18 ^ column. The 'title compound vas eluted vith vater. The appropriate fractions were conbined and evaporated under high vacuum to give the desired thiol (61.6 ng, yield-76.3V); ir (CJ CI ) V i2550 (v, SH) 2 2 tv.X and 1620, 1600, 1585 ca (ra, a.ro.-natic) ; JHxr (EMS0 d.) o: 8.90-7.90 o (4H, m, aromatic C-H) , 4.72 (2H, t, £=6.6 v.z, cd^+) , 4.01 (ZH, s, OC-y , 3.5-3.0 (m, hidden CH^S) , 2.66 (IH/ cd, J=9.5 Hz, J=7.5 Hz, SH) and 2.31 rom (3H, s, CH-SO-,-) . * j i J Example 9 3-Methylthio-l— (2-aerca?toethyl)uyridir.ivjtt ch lor ice- SHe + E CI • To a solution of-3-aethylthiopyridine1 (2.00 g, 0-016 aol) in 10 sli of ether vas added 15 rr.L of 1 i* HCl and the nixture,vz.s veil shaken. .The aqueous phase vas separated", washed vith 10 ruL of ether ana then evaporated. The residual hydrochloride vas then dried -tJl vacii£ (P^O^)' to give a white solid.- - To this solid' . hydrochloride vas added 3-methylthiopyridlne (1.83 sV 0.015 aol) and ethylene sulfide (0.89 aL, 0.015 nol) -end the resulting rijcture vas heated (oil bath) at S5-S5"C under for 15 h- This cive a slightly turbid oil vhich vas taken up in 125 nX. of - HO and v^shed vith CH^Cl^- The acueous solution vas concentrated to about 2^ M: and then a fev drops,of acetonitrile were added to azke. the nixture homogeneous. Toe resulting aqueous solution vas applied to a C . 1 ''-18 reverse-phase colcr.-i. Eluticn >-ith and s-ohsecuer.t evaporation of the relevant fractions afforded the product (2.66 g 8C\) as a pale yellov, viscous oil. ir (filo) vnay' 2410 (br, -SH? c=i-1; ^Hnr-r (rfg-DMSO+D^O) o: 8.88-7.88 (jn, 4H, aromatic)', 4.70 (t, J«5.5 Hz, 2H, K-C52), 3.08 (skewed-t, _J=6.5 Hz, 2H, S-CH2), 2.64 (s, 3H, S-Me). 1 Prepared by the nethod of J.A. Zoltewiez and C. Kisi, J. Crc. Chen. 34, 765 (1969). - 58 -Example 10 , / 7 1- ( 2-mercaptoethyl) -2 ,'6-dimethvlpyridiniura inethanesulfonate + Hsoa ,100'C, 42 h ■ MS MsO tf^i | j A mixture of 2,6-diaethylpyridine • X19.2 mL, 0.165 sol) tad meth'anesulfonic acid. (3-27 eiL, 0.050 mol) vas stirred .for 25 rin, ; treated with ethylene sulfide (4.17 mL,_: 0.070 rol)_ and stirred at 100*C-for 42 h under a nitrogen ataosphere. \After cooling to 25*0/ the reaction mixttire vas diluted vdth eth4r (45 ri) and vater (30 mL) ,2he two layers vera separated and .the organic layer vas extracted' / vith water (2 x'5. nL). The aqueous layers were •ccr-Vned, filtered-through a Celite pad, washed with sther- (2 x 15 nL) K pumped to 'rersove the traces of organic solvents and "poured-on top of a: col-j^j • (3.0 x 12 era) of p-bondapak C-18. Slution vith 3v acetonitrile. 97% water mixture gave after lyophyliration of '.the appropriate fractions 2.5 g of the impure title compound as a syrup. It vas repurified by hplc (y-bondapak C-18) to give 0.90 g (7%) of the title compoted. ir (film) \> : 2520 .(SH), 1640 and 1625 (pyridiniim), 1585, 1490, ■ . max ■ ■ * 1200 cm 1 (sulfonate), 'h-tit (OiSO-tf, + DO) o: 2.36 (33, s, Q SO "l • ' ® 2 ■ 3 3 4.62 (2K, m, CH^N ), 7.74 (2K, Ja, Ka of pyridinicm) , 8.24 (IK, n, Hp of pyridiniuBi), uv (H20) 272 (4080)my Example 11 2-Methylthio-3-methy 1-1- (2-mercaptoethyl) imidazolicza trifluoromethanesulfonate : ~ ; ' SMe + C?3S03H + Zs HSCE2C32%'^N\_Me SMe' ' ■ A—/ C?3S03 Tri fl-uoromethanesulf onic acid (1.38 mL, 0.015 xnol) was added dropwise to 2-methylth.io-I-methyliaidazole^ (4.0 g) , 0.03 niol) at 0'C under. • Ethylene sulfide {0.9 mL/ 0.015 mol) was then added and the mixture was: heated at 55°C under Nj for-24 h. The reaction mix tare was triturated with ether (3x) and the residue was taken up in acetone, filtered and evaporated. This gave the product (4.2 g, 82%) as a semi-crystalline solid which -was used as such without further purification. ir(film) v : 25 50 (w, sh) cn 'Hnmr 3.X (dg-acetone) 6: 7.97 (s, 2H) , 4.66 (t, J=7 Ez , 2H, methylene) , .4.17 (s , 3H, N-Me) , 3.20 (d of t, J=7 Hz, J'«9 Hz, 2H , methylene), 2.72 (s, 3H, S-Me), 2.20 (t/ J=9 Hz, IH, -SK) . 1.

Prepared as per A. Wohl and W. Marckwald, Chem. 3er. 2.2 , 1353 (1889) .

Example 12 2 1 3-Amino-1-(2-mercaotoethyl)pvridinium chloride ESCSgCHg.' M O 3-Aminopyridine (1.50 g, 0 .016 mol) was taken up in 15 mL of 1 N.methanolic HCl and the resulting solution was evaporated to give the hydrochloride as an oil•. To this oil was added 3-aminopyridine (1.32 g, 0.015 mol) and ethylene sulfide (0.89 ml, 0.015, mol) and the resulting mixture was heated (oil bath) at 60-65°C under for 2 h. Another equivalent of ethylene sulfide (0.89 ml, 0.015 ir.ol) was added and heating was continued at 55-65°C for 65 h. The reaction nixture1was washed.with CH^Clj and then taken up in (25 ml). The aqueous solution was applied to a C^g reverse-phase column which was eluted with ^0. , Evaporation of the relevant fractions gave the product (1.26 g, 44%) as a colorless, viscous oil. ir (film) Vroax: 3180 (N^ ) cm ^; 'Hn mr (dg-DMSO) 0 : 8. 19-7. 59 (m, 4H, aromatic) , 4. 59 (t, J=6. 2 Hz, 2H, N-CI-Lj ) ,' 3. 5 (br s , 2 H, -NHj ) , 3. 2 0-2. 77 (m, 3H).

Example 13 ^ *** dZ-1- (2-mercapto-2-methylethyl) pyridinium methanesulfonate 'dZ-1- (2-narcapto-l-methylethyl)pyridiniun inethanesulfonate S3 // + N ( )\ + MsCH " >■ ' / vV MsO MsO • ES Methanesuifonie acid (1..95.mi, 0.030 mol) was added slowly to cold "pyridine (7.'S3, 0.097 mol) and the resulting mixture vas stirred at 40"C for 15 min, treated with c££-propylenesulfide (2-59 mL,. 0.033 mol) and stirred at 60*C.under a nitrogen atmosphere for 90 h. Pyridine was'removed under vacuum; the residue was mixed with water and purified by chromatography (hplc, Prep. 3ondapak C-18). The appropriate fractions were combined and lyophilised giving <££-1-(2-mercapto-2-methyi- ethyl)pyridinium inethanesulfonate 1.14 g (15%) as a colorless syrup; ir (film) V : 2520 (.SH) , 1640 (pyridix.ium) , 1180 (s, CH.SO ~), 1040 niix ^ 3 (CH,SO,")ct"V 'xinvr (DMSO d\) 6: 1. 25 {d; J=6.8 Hz, 3H, CT,CHS) , 2.30 (s, 2 3 & ■ — : ■ . ' • ; J ■ 2hj a so"), ,2.90 (d, J=8.S Hz, IH, SH) , 3-2-3,7 Cn, CSH) , a. 52 tad, J =12.9 Hz, J=8.4 Hz, CHCH_N+), 4.37 (dd, J =12.9 Hz, J=6.0 Hz, CHCH N+) —gem —2 •. ■ . ••. -s. —2 8. 0-8.4 (m, 2H, Hm. of pyridinium) , 8.5-8.8 (m, IH, Hp of pyridinium) , 9.04 (dd, J=1.4 Hz, J=6.7 Hz, 2H, Ho of pyridinium), uv fH2°' ^max: 208 (cS267) , 259 (E3338), Anal. calcd. for C H lffl.S -2H O; C 37.8B, H 6.71, N 4.91, !•) J * • S 22.47; found: C 37; 49, H 6.85, N 4 .86, S 22.09 and c££-l-(2-Eiercapt:o-*l-methylethyl) pyridinium inethanesulfonate 0.82 g. {ll\) as a colourless syrup; ir (film) v : 2500 (SH) , 1628 (pyridinium)., 1180 (sulfonate, CIS X • 1035 (sulfonate)' cm"1, JHmr (DMSO d ) 6s 1.69 (d, o=6.8 Hz, 3H, 6 q^cW") , 2.31 (s, 3H, CH3SQ3") , 3.0-3.3, (a, 2H, C^S) , 4.2-5.2 (m, IH, CHN+) , 8.0-8. 4 (m, 2H, Hm of pyridinium) , 3.5-S.3 (a, IH, Kp of pyridinium), 9.0-9.2 (m, 23, Ho of pyridinium), uv (E.O) X s 209 / 2 max (£4987), 258 (£3838).' Anal, calcd. for-CgH^NO^-1. 5E20: C 39.11, ' H 6.56, N 5.07; fpund: C 29.13, H 5.92, N 5.20. 1 Example 14 di-l- ( 2-mercapto-l-cyclohexyl)pyridinium nethaj-iesulforiate O + N + Hs OS HsO . >5ethanesuLf onic acid [0.65 mL, 0.01 mol) was added drppwise to pyridine (2.42 mL, 0.03 .mol) witS cooling. The nixture was stirred under a nitrogen ataosphere for. 10 nin, treated with ^-cyclohexene- sulfi.de-. [1.377 g (85* pure), 0.0102 mol) and stirred at 72*C for 25 h.

The excess of pyridine was removed under vacutsa and the traces were • codistilled with water. The residue vas ziixed with water and chramato- graphed.through prepbondapaDc- C-18 column' (5 x. 13 c=n) with 0-2\ acetonitrile in water as eluting solvent giving after lyophiliration a colourless syrup 1.57 g (53*) , ir (film) 2500 (SK), 1625 (pyridiniua), 1190 (so ") , :K=r (DMSO 'O <5: 1.2-2.5 (=s, 8H, cyclohexyl H), 2.32 (s, 3H, ), 2.82 fd/ £=9. 8 Hz, SH), 3.0-3.5 (m, IK, CHSH), 4.2-4.9 (m, IH, CHN+) , 8.0-8.3 {ra, 2H, Km of pyridinium), 8.4-8.8 (n, IR, Hp of pyridiniun), 8.9-9.3 (m, 2H, Ho of pyridinium) , uv (H_0) X : 214 (E5365) , 258- (C3500) 2 wax - - .

Anal, calcd. for C12H19N03S2*H2°: C <5.88, H 6.88, N 4.56; found: C 46.61, H 6.4 6, N 4.65.

Example 15 N-methyl-N-(2-mercaotoethy1)thioraorpholinium methanesulfonate / \ 1) Ms OH MeN S -> 2> A To precooled (ice bath) N-methylthiomorpholine* (5.00 g, 42.7 mmol) was added methanesulfonic acid (1.47 mL", .5 mmol) and ethylene sulfide (1.30 mL, 21.4 mmol). The mixture was heated at 65°C for 24 h and diluted with water (25 mL) . The aqueous solution was washed with diethyl ether (3 x 25 mL) , pumped under vacuum and poured over a silica gel reverse phase column? the title compound being eluted with water. The appropriate fractions were combined and evaporated to afford the thiol as an oil (4.80 g, yield 86%); ir (film) '• 2550 cm-1 (w, SH) ; ^mr (DMSO d,) <5 : 3.25-2.95 (6H, m, max. _ o CH2N®), 3,32 (3H, s, CH3N ); 3.20-2.65 (7H, m, CH2S, SH) and 2.32 ppm (3H, s, CH^SO^) • *J.M. Lehn and J. Wagner. Tetrahedron, 26, 4227 (1970) Example 16 1-Me thy 1-1- (2-mercaptoethyl) morpholinium trifluoromethane-sulfonate + CFSOH * /S\ ) HSCH^ CH-,N 3iU3n / \ — ' 2 2 To N-methylmorpholine (3.29 mL/ 0.0 30 mol) was added dropwise trifluoromethanesulfonic acid (1.327 mL, 0.015 mol) at °C, followed by ethylene sulfide (0.89 mL, 0.015 mol). The resulting yellow-brown solution was heated (oil bath) at 50-60°C under for 18 h. Volatile material was then removed in vacuo and the residual oil was taken up in 10 mL of 1^0. The aqueous solution was washed with diethyl ether (3 x 5 mL) and then residual organic solvent was removed in vacuo. The resulting aqueous solution was applied to a C-^g reverse-phase column which was eluted with KjO, then 5% acetonitrile-K20 and finally 10% acetonitrile-H^O. Evaporation of the relevant fractions afforded a white solid which was dried in vacuo (P^O^) to give the product (1.92 c, 41%). ir (K3r)v : 2560 (-SH) cm "S ^Hnmr (dc-acetane) ■ nia-x ■ b 6: 4.25-3.6 (m, 8H), 3.49 (s,'3H, N-Me), 3.35-2.7 (m, 5H). ~ - 65 -Example 17 2 13565 A. 1- (2-acetylthioethy 1) -1, 4-dimethylpiperazinium bromide -N N- Y_/ Acetone 50°C ' A solution of 2-bromoethyl thiolacetate *(2.20 g, 0.012 mol) and 1,4-dimethylpiperazine (1.95 mL, 0.014 mol) in acetone (4 mL) was stirred at 50°C for 65 h. After cooling to °C, the liquid phase was decanted from the gum which was triturated twice in diethyl ether; a hygroscopic yellowish powder, 3.2 g (90%) was obtained; ir (Nujol) v : 1685 (C=0 of ^ ^ max thioester) cm ; Hmr (D20) 6: 2. 37, 2. 39 (2s, 6H, CH^O, , 3.18 (s, 3H,. ) *B. Hansen, Acta Chem. Scand. 11; 537-40 (1957) B. 1,4-dimethyl-l- (2-mercaptoethyl)piperazinium bromide hydro-chloride Br HCl A — , Br , HCl A solution of 1- (2-acetylthioethy 1)-1,4-dimethylpiperazinium bromide (1.1 g, 3.7 mmol) in 6N hydrochloric acid (4 mL) was heated at 80°C under a nitrogen atmosphere for 1 h. The solution was concentrated under reduced pressure to .give a white powder, 0.41 g (38%), *Hmr (DMSO, d,,) 6: 2.90 (s, u on o ,N /H —\ / C- lf )' 3-26 (s, y+ \CH3 —/ \— -3 ) .

Anal, calcd. for CgH^l^SBrCl- H20: C 31.03, H 7.16, N 9.05, S 10.35; found: C 31.62, H 7.46, N 9.19, S 10.19. --fe;.... 2 ®5^ Example 18 A. 1- (2-ace tylthioethy 1) -1,4, 4-trimethyloiperazinium bromideiodide Kel ^-OH, 55-60cC CH 3 ' A suspension of 1- (2-ace tylthioethy 1)-1,4-dimethylpiperazinium bromide (1.48 g, 5.0 mmol) in isopropyl alcohol (10 mL) •was treated with me thy liodide (0. 373 mL, 6 .0 mmol) and heated at 55-60°C for 30 h. The solvents were evaporated tinder reduced pressure; the residue was triturated in hexane and the solid was filtered, 1.85 g. The solid was dissolved in hot water (8 mL) and the solution was diluted with acetone until turbidity (70-80 mL) . Two successive ... crystallizations gave 1.5 g, mp 220-5°C dec. , 68% of the title compound; ir (K3r) v = : 169 2 cm"1 (C=0) ; ^Hmr (D-O) 6: 2.40 (s, 3H, . jn aX £ CH -COO) , 3.37 (s / N-CH-) , 3.39 (s , N-rCH-) , 3.99 (s) ; uv (H-O) X. .

J J * O ul&X 226 (el3144) . Anal, calcd for C-^H^l^OSBrl: C 30 . 0 8, K 5.51, N 6.38? found: C 30.48, H S.53, N 6.86.

£ A"! (2-mercaptoethyl) -1, 4 , 4-trime thvlpjperaziniun- bischloride , •HCl 6N Persiutit /^..4 S-l CI" 213565 A mixture of 1-(2-acethylthioethyl)-1,4,4-trimethyl-piperazinium bromideiodide (1.84 g, 4.19 mmol) and 6N hydrochloric acid (15 mL) was heated at 57°C under a nitrogen atmosphere for 2.5 h. The solution was concentrated under reduced pressure to dryness. The solid was suspended in water (10 mL) and the well— stirred suspension was treated with perrautit S-l Cl until a solution was obtained. The solution was pour.ed on a column' (1.2 x 60 cm) of perroutit S-l Cl . The column was eluted with water (1.5 mL/min). The appropriate fractions were combined and lyophilize< to give a white powder, 0.93 g, mp 190-191°C/ 85%; ir. (nujol)vm : * IucLX 2460 (SH) ; iHmr (D20) <5: 3.4 (s, N-CH3) , 3.45 (s, N-CH3) , 4.07 (s) . Anal, calcd for CgH22N2SCl2* 0.75 H20: C 39. 34, H 8.62, N 10. 20 , S 11.67; found: C 39.48, H 8.39, N 10.55, S 11.15. r" - r. ■. . 'i \■ . ic. . f :■/' , ■ ■' ■:... - 68 - •

Claims (3)

WHAT WE CLAIM IS: 213565 I I ,o"~\

1. A process for the preparation of a quaternary amine thiol compound of the formula ,14 HS- -R X 9 wherein A is cyclopentylene, cyclohexyiene or 10 12 R' 11 13 in which , R"^, and are each independently hydrogen © 14' or C1-C4 alkyl, X is a counter anion and R represents"a substituted or unsubstituted mono, bi- or.polycyclic aromatic - or non-aromatic heterocyclic radical containing at least one nitrogen in the ring and attached to A through a ring nitrogen, thereby forming a quaternary ammonium group, which process comprises reacting a sulfide of the formula or ?0'AC^E I11 i" 12 If w- wherein R"*"0, R^"\ and R"^ are. each independently hydrogen or Ci -C . alkvl with a strong acid and either, (a) a heteroaromatic 14.- J amine of the formula wherein represents a substituted or unsubstituted mono-, bi- or polycyclic aromatic heterocyclic radical containing at least one nitrogen in > the ring capable of being quaternized and bonded .to a carbon atom of substituent A or (b) a heterocyclic amine of the formula ,16 wherein represents a substituted or unsubstituted mono-, bi- or polycyclic non-aromatic heterocyclic radical containing at least one nitrogen, in the ring capable of being quaternized by substituent R^ and bonded to a carbon atom of substituent A and represents either (a) an optionally substituted aliphatic, cycloalipfoatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic radical or (b) a divalent phenylene or C^-C^ alkylene group joined to the ring so as to form a -bridged polycyclic group. - 70 - 213565

2- The process according to Claim 1 wherein the reaction is carried out at a temperature in the range of from' ..substantially -20°C to substantially 100°C. ' 3- The process according to Claim 1 or Claim 2 wherein the strong acid is hydrochloric, hydrobromic, methanesulfonic,' p-toluenesulfonic or trifluoromethanesulfonic. \4.• The process according to Claim 1 wherein'the reaction is carried out in the presence of a non-polar organic solvent . 5". The process according to Claim :4 wherein the non-polar organic solvent is methylene chloride, benzene, xylene or toluene. 5 . The process according to Claim 1, 2 or "3 wherein^, when the amine and sulfide reagents are liquids or when the amine reagent is a solid, the sulfide reagent is liquid and the solid amine is soluble in the liquid sulfide reagent, the reaction is. carried out without additional solvent. 7 . A quaternary amine thiol compound of the formula ,14 Xv HS — A -— R ,e - -5 e-n c \, VII wherein A is cyclopentylene, cyclohexylene or R10 H12 '■i . i ■ ■ . —c ——-C — . R11 i13 .; in which R^°, R11, R~^ and R~3 are each independently hydrogen 0 14 or C^-C^ alkyl, X is a counter anion and R represents a substituted or unsubstituted mono, bi- or polycyclic aromatic or non-aromatic heterocyclic radical containing at least one _ nitrogen in the ring and attached to A through a ring nitrogen.,, thereby forming a quaternary ammonium group. ^ . Vi .. 213565

3. A process according to claim 1 substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 18. ] dated this s( day of gcjmmj* tv a. j/pa^k'&.'sdn;'.-'' per agents for the applicants ; y q 1 - * v ■■r. o- ■ ' Ma \ %, 1 f :<.y; • =--^.=-7^