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PCX 



WORLD IKTELLKTUAL PROPERTY ORGANIZATION 
iDtemadoDaJ Bureau 




(51) International Patent Classification ^ : 




(11) International Publication Number: 


WO 95/15966 


C07D 501762, A61K 31/545 


Al 








(43) International Publication Date: 


15 June 1995 (15.06.95) 



(21) International Application Number: PCT/CA94/(X)669 

(22) Internationa] Filing Date: 6 December 1994 (06.12.94) 



(30) Prionty Data: 

08/162,478 



7 December 1993 (07.12.93) US 



(71) Appticant: SYNPHAR LABORATORIES. INC. [CA/CA]; #24 

Taiho Alberta Center. 4290-91A Street, Edmonton, Albeita 
T6E 5V2 (CA). 

(72) Inventors: MAITI, Samarendra, Nath; 6756-39 Avenue, Ed- 

monton, Alberta T6K 1X8 (CA). FIAKPUI, Charles. Yao; 
188 South Ridge. EdmcHiton, Alberta T6H 4M9 (CA). 
REDDY, Andhc, Vcnkat, Narender, 1503-104 Street, Ed- 
monton. Alberta T6J 5T2 (O). CZAJKOWSKI, David. 
Paul; 3819-86 Street, Edmonton, Alberta T6K 0H7 (CA). 
MIC:EnCH, Ronald, George; 12 Braeside Terrace. Sher- 
wood Park. Alberta T8A 3V6 (CA). 

(74) Agent: RICHES. MCKENZIE & HERBERT; Suite 2900, 2 
Bloor Street East, Toronto. Ontario M4W 3J5 (CA). 



(81) Designated States: AM, AT, AU, BB, BG, BR, BY, CA, CH, 
CN, C2, DE. DK, EE, ES, FI, GB, GE, HU, JP, KE, KG. 
KP, KR. KZ, LK, LR. LT. LU, LV, MD. MG. MN, MW. 
NL, NO, NZ. PL, PT. RO, RU, SD. SE. SI SK, TJ, TT. 
UA, UZ, VN, European patent (AT, BE, Oi DE, DK, ES, 
FR, GB, GR, IE, IT. LU. MC. NL, PT, SE). OAPI patent 
(BF, BJ, CF, CG, CL CM, GA, GN, ML. MR, NE. SN. TD, 
TG), ARIPO patent (KE. MW, SD, SZ). 



PuMKhed 

With intemananal search report 



(54) Title: 2-SPmO(2^SPIROCYCLOALKYL)CYCLOPROPYL CEPHALOSPORIN SULFONES AS ANTIINFLAMMATORY AND 
ANTTDEGENERATTVE AGENTS 

(57) Abstract 

2-spiro(2*-spirocycloaIkyl)cycloiwopyI cephalosporin sulfonc compounds, mcdiods of treating patients for elastase inhibition, and 
processes for preparipg such compounds. 



FOR THE PURPOSES OF INFORMATION ONLY 



Codes used to identify States party to the PCT on the firont pages of pamphlets publishing international 
applications under the PCT. 



AT 


Austrii 


GB 


United Kingdan 


MR 


Maisitania 


AU 


Australia 


GE 


Georgia 


MW 


Malawi 


BB 


Barbtdos 


GN 


Guinea 


ME 


Nigct 


BE 


Belgian} 


GR 


Greece 


NL 


Netbertands 


BF 


Burkina Faso 


HU 


Hungary 


NO 


Norway 


BG 


Bulgaii 


IE 


farUnd 


HL 


New Zealand 


ai 


Benin 


rr 


Italy 


PL 


Poland 


BB 


Brazil 


JP 


lapAB 


PT 


Ponugal 


BY 


BeUns 


K£ 


iCenya 


RO 




CA 




KG 


Kyxgystas 


RU 


Russian Fedcntion 


CF 


Ceotra] A&icaD Rqxibtic 


KP 


DoDOcmic People** RcpiAlic 


SD 


Sudan 


CG 


Congo 




of Kocca 


SE 


Sweden 


CH 


Switzeriand 


KR 


Republic of Korea 


SI 


Slovenia 


a 


COledlvoire 


KZ 


Kazakbitaa 


SS 


Slovakia 


CM 


CamoooD 


U 


Liecfatetulein 


SN 


Senegal 


CN 


China 


LK 


Sri Lanka 


TO 


Chad 


CS 


CzecboslovakiB 


LU 


LuxcndMurg 


TG 


Togo 


CZ 


Czecfa RepiAlic 


LV 


Latvia 


TJ 


Tajikistan 


DE 


Gennany 


MC 


Monaco 


TT 


Trinidad and Tobago 


DK 


DcDoiafk 


MD 


RqwbUc of Moldova 


UA 


Ukraine 


ES 


Spain 


MG 


Madigascar 


US 


United States of America 


n 


Hnlattl 


ML 


Mali 


uz 


Uzbekistan 


FR 


Ranoe 


MN 


Mongolia 


VN 


Viet Nam 


GA 


Gabon 











wo 95/15966 



PCT/CA94/00669 



10 



20 



2-Spiro{2'-spirocycloal)cyl)cyclopropyl Cephalosporin Sulfones 
as Antiinflsunmatory and Antidegenerative Agents 

FIELD OF THE INVENTION 
The present invention relates to novel 2-spiro(2'- 
spirocycloalkyl) cyclopropyl cephalosporin sulf one derivatives 
as potent elastase inhibitors and to processes for their 
preparation. 



BACKGROUND OF THE INVENTION 

Human leukocyte elastase (HLE) is a member of the 
family of serine proteases. It is carried by the azurophilic 
granules of hximan polymorphonuclear leukocytes and released 
15 into the extracellular space. Elastase, like other serine 
proteases, have a catalytic triad composed of three 
juxtaposed amino acid residues : aspartate (Asp-102) , 
histidine {His-57) , and serine (Ser-195) . Through either a 
"charge relay" or a "proton relay" mechanism, the three 
residues catalyze a proton extraction via oxyanion attack 
(ser-195) on an amide carbonyl group. The end result of this 
reaction is a degradation of peptide bonds. 

Under noarmal conditions, the proteolytic activity 
of HLE is controlled by several natural protease inhibitors. 
25 The primary guardian against connective tissue destruction 
is a-1 protease inhibitor (a-PI) . Although a-Pl associates 
with HLE very quickly and irreversibly, several pathological 
conditions may arise when a-PI levels are genetically low, or 
when Q-PI has been oxidized or degraded, or when access to 
30 HLE is restricted. The disease states resulting from 
uncontrolled elastase activity include: pulmonary emphysema, 
rheumatoid arthritis, adult respiratory distress syndrome 
(ARDS) , cystic fibrosis, and other related syndromes. 

35 SUMMARY OF THE INVENTION 

The present inventors synthesized 7 a-substituted 
2-spiro(2'-spirocyclo- alkyl)- cyclopropyl cephem sulfones 
and found from studies that these compounds are potent 
elastase inhibitors and that they are useful in the 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/GA94/00669 



prevention, control and treatment of inflammatory conditions, 
particularly rheumatoid arthritis, osteoarthritis, cystic 
fibrosis, chronic bronchitis and emphysema. 

5 DETAILED DESCRIPTION OF THE INVENTION 

In accordance with the present invention, there is 
provided novel 7 a-substituted 2-spiro(2 '-spirocycloalkyl) 
cyclopropyl cephalosporin sulfones having anti-elastase 
activity. Such derivatives, or elastase inhibitors, are 

10 useful in the prevention, control and treatment of 
inflammatory conditions, particularly emphysema, rheumatoid 
arthritis, osteoarthritis and cystic fibrosis, chronic 
bronchitis and emphysema. 

In one aspect, the present invention relates to a 

15 7 a-substituted 2-spiro (2 '-spirocycloalkyl) cyclopropyl 
cephalosporin sulf one of the structural formula (I) : 



20 




25 

Wherein Rj is COOR4, COR5, -C(R5)=N-0R^, CONR^Rg 
R4is hydrogen; Cj^ branched or straight alkyl; alkenyl; 
Cj^ alkanoyl Cj^ alkyl; Cj^ alkanoyloxy alkyl; alkoxy 
Cj^ alkyl; halogenated Cj^ alkyl; -CH2-phenyl; -CH(phenyl)2; 

30 the phenyl groups may further be substituted with at least 
one of alkyl, Cj^ alkoxy, nitro. 

The preferred groups representing R^ include 
hydrogen, methyl, ethyl, tert-butyl, allyl, methoxyethyl, 
benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, 2,2,2- 

35 trichloroethyl. 



2 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



R5 is hydrogen; Cj^ straight or branched alkyl; 
alkenyl; alkynyl; C^^ cycloalkyl; C^jj, aryl; aralkyl; a 

monocyclic or fused polycyclic saturated or unsaturated 
heterocyclic group containing from 1 to 4 of any one or more 
5 of the heteroatoms selected from N, S and O. 

The preferred groups representing R5 include 
hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- 
butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, 
cyclohexyl, ethenyl, propenyl, ethynyl, phenyl, benzyl, 
10 thienyl, furyl, pyridyl, pyrimidinyl, imidazolyl, triazinyl, 
triazolyl, tetrazolyl, thiazolyl, thiadiazolyl. 

The substituent R5 in the formula -C{R5)=N-0R^ has 
the same meaning as described above. 

The substituent is hydrogen or a hydrocarbon 
15 residue which may be substituted. In the formula -C(R5)=N- 
ORg, the ORg group may be in "syn" or "anti" configuration. 
The hydrocarbon residue may be exemplified by Cj^ straight or 
branched alkyl, alkenyl and C^^ cycloalkyl group, 

Substituents of these hydrocarbon residues may be 
20 exemplified by hydroxyl group, Cj^ cycloalkyl group, mercapto 
group, amino group, halogen atom, cyano group, carboxyl 
group, Ci.g alkoxycarbonyl group, c^jq aryloxycarbonyl group, 
C7.12 aralkyloxycarbonyl group, C3.5 alkenyloxycarbonyl group, 
^6-10 aryl group, a 5- (or 6-) membered heterocyclic group 
25 containing from 1 to 4 of any one or more of the heteroatoms 
selected from N, S and O (examples of which include but are 
not limited to thienyl, furyl, pyridyl, pyrimidinyl, 
thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, 
imidazolyl, triazolyl, tetrazolyl, and the like). 
30 The number of the substituents on the above 

mentioned hydrocarbon residue is not restricted to one and 
may be plural which are the same or different. 

More preferred examples of the substituted 
hydrocarbon residues include Cj.j alkyl groups substituted by 
35 halogen, hydroxy, amino, carboxyl, Cj^ alkbxycarbonyl. 
Examples of the substituted hydrocarbon residues include 
2-hydroxyethyl , 2-aminoethyl , 2-f luoroethyl , 2-chloroethyl , 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



2-broinoethyl , carboxymethyl , l-carboxy-l-methylethyl , 1- 
carboxycyclopropy 1 , l-carboxycyclobuty 1 , methoxycarbonyl- 
methy 1 , ethoxycarbonylmethyl , tert-butoxycarbonylmethyl , 
l-methoxycarbonyl-l-methylethyl, 1-ethoxycarbonyl-l- 
5 methy lethyl , i-tert-butoxycarbonyl-l-methyl-ethyl , 1- 
benzyloxycarbonyl-l-methylethyl, 1-pivaloyloxycarbonyl- 

1-methy lethyl . 

R-y is hydrogen; Cj^ alkyl; cycloalkyl; C^,^^ 

aryl; C7.12 aralkyl; Cj^ alkoxycarbonyl Cj^ alkyl; carboxyl Cj^ 

10 alkyl; a five or six-member ed heterocyclic group containing 
from 1 to 4 of any one or more of the heteroatoms selected 
from N, O and S (examples of which include but are not 
limited to pyridyl, pyrimidinyl, pyrazinyl, triazinyl, 
imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl, 

15 benzothiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, 
benzimidazolyl^ triazolyl, tetrazolyl, and the like). 

Rg is also selected from the above mentioned 
substituents as defined for R7; however, they may be the same 
or different. 

20 R7 and Rg in the formula CONR7Rg may combine to form 

a heterocyclic ring which may contain at least another 
heteroatom selected from N, S or O (examples of which include 
but are not limited to piperazinyl, morpholinyl, 
thiomorpholinyl, piper idinyl, pyrrolidinyl, and the like). 

25 The said heterocyclic ring may be substituted at the carbon 
atom or at the nitrogen atom which is different from the 
nitrogen atom having binding arm with the CO group in the 
formula CONR7Rg. Examples of such substituents include 
hydroxy 1, hydroxy alkyl, C^^ alkyl, alkenyl, 

30 alkynyl, Cj^ cycloalkyl, Cj^ alkoxy, alkoxy alkyl, 

azido, cyano, halogeno q^ alkyl, carboxyl, carboxy Cj^ 
alkyl, Ci.g alkoxycarbonyl, Cj.g alkoxycarbonyl Cj^ alkyl, 
azido Cj^ alkyl, cyano Cj^ alkyl, amino, guanidino, amino Cj^ 
alkyl, mono-Cj^ alkylamino, di-Cj^ alkylamino, mono-Cj^ 

35 alkylamino q^ alkyl, di-Cj^ alkylamino Cj^ alkyl, halogen 
atom, carbamoyl^ diethoxyphosphinyl Cj^ alkyl, dihydroxy- 
phosphinyl q^ alkyl, mercapto, mercapto Cj^ alkyl, sulfo. 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



sulfo Cj^ alkyl, Cj^ alkylthio, Cj^ alkylthio alkyl, 
^6-10 arylthio, C^^io aryloxycarbonyl, C7.,2 aralkyloxycarbonyl, 
C1.5 alkanoyl, C2.5 alkanoyl Cj^ alkyl, C2.5 alkanoyloxy, C2.5 
alkanoyloxy Cj^ alkyl, or a heterocyclic group • 
5 There may be the same or different plural of the 

above mentioned substituents, without limiting to the case of 
single substituent. The heterocyclic group means a 5- or 6- 
membered ring containing one to several heteroatoms, such as 
nitrogen atom (which may be oxidized) , oxygen atom or sulfur 

10 atom, or a condensed ring thereof, which possesses a binding 
arm at the carbon atom. 

More specifically, the above substituents are: 
hydroxy, carboxy, tert-butoxycarbonyl , azido, amino 
hydroxymethyl, hydroxyethyl, bromoethyl, cyano, carboxamide, 

15 guanidino, diethyl-phosphinylmethyl, diethylphosphinylethyl, 
dihydroxyphosphinyl-methyl , dihydroxyphosphinylethyl, 1,2,3- 
tr iazole , tetrazole . 

In the structural formula (I) , R2 is hydrogen, 
chloro, bromo, fluoro, hydroxy, Cj^ alkoxy, trif luoromethyl, 

20 Ci_6 alkyl, €2^ alkenyl, alkynyl, C^^ cycloalkyl, or -CHjX, 
wherein X is hydroxy, chloro, bromo, Cj^ alkoxy, Cj^ 
alkanoyloxy, -OCONHj, -OCONHCj^ alkyl, amino, -NHCj^ alkyl, 
-N(Cj^ alkyl) 2, a quaternary ammonium group (for example, NH^, 
NHZ2, N23 where 2 represents lower alkyl, aryl or aralkyl; 

25 the nitrogen atom may also be the part of the heterocyclic 
system) • 

In the structural formula (I) , R2 also represents 
-CH2YR9, wherein Y is S or N. 

When Y is sulfur, may be hydrogen or the residue of a 
30 thiol compound. The term "residue of a thiol compoxind" means 
a residue obtained by omitting the -SH group from a thiol 
compound. Preferred thiol compounds are heterocyclic thiols. 
Examples of such heterocyclic groups that might be mentioned 
are: an unsaturated 5 to 8 membered heteromonocy<:lic group 
35 containing at least one of the heteroatoms selected from N, 
O or S; an unsaturated 5 to 8 membered heteromonocyclic group 
containing 2 to 4 nitrogen atoms; an unsaturated 5 to 8 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



membered heteromonocyclic group containing 1 "to 2 sulfur 
atoms and 1 to 3 nitrogen atoms; an unsaturated 5 to 8 
membered heteromonocyclic group containing 1 to 2 oxygen 
atoms and 1 to 3 nitrogen atoms • 
5 The above mentioned heterocyclic rings may be 

substituted further with one or more of the following 
radicals such as Cj^ alkyl, -COOH, -COOCi^ alkyl, -OH, 
-CH2COOH, -CHjCOOCi^ alkyl halogen, or the like. The 
substituents may be at the carbon atom or at the nitrogen 
10 atom. 

In the formula -CH2yR9, when Y is nitrogen, 
represents the residue of a nitrogen containing heterocyclic 
ring system. More specifically, Y together with R9 forms a 
heterocyclic ring where Y is nitrogen which is part of the 

15 heterocyclic system. The above mentioned heterocycles may be 
further substituted with one or more of the functional groups 
selected from chloro, bromo, fluoro, hydroxy, carboxy, 
carbomethoxy, carboethoxy, cyano, amino, hydroxyalkyl, 
substituted amino, carboxamido and the like. 

20 The preferred groups representing R2 in the 

structure (I), include: hydrogen, chloro, bromo, hydroxy, 
methoxy, methyl, trif luoromethyl, vinyl, hydroxymethyl, 
chloromethyl, bromomethyl, azidomethyl, acyloxymethyl, 
carbamoyloxymethyl , 1,2, 3-tria2olylmethyl , 1,2, 4-triazol-l-yl 

25 methyl, imidazol-l-yl methyl, pyrazol-l-yl methyl, thiazolyl- 
thiomethyl , isothiazolylthiomethyl , tetrazolylthiomethyl , 
triazinylthiomethyl, l-substituted pyridinium-4-ylthiomethyl, 
2 , 3-cyclopenteno-l-substituted pyridinium-4-ylthiomethyl , 
pyridyl-2-ylthiomethyl , pyridyl-4-ylthiomethyl , 1,3,4- 

30 thiadiazolylthiomethyl, 1,2,3-thiadiazolylthiomethyl, 1,2,4- 
thiadiazolylthiomethyl , lH-1 , 2 , 3-triazolylthiomethyl , 4H- 
1 , 3 , 4-tr iazolylthiomethyl , 2H-1 , 2 , 4-tria2olylthiomethyl , 
s-triazolo[l,5-a]pyrimidinylthiomethyl, lH-triazolo[4 , 5-e] 
pyrimidinylthiomethyl , pyr idinium methyl , 2 , 3-cyclopenteno 

35 pyridinium methyl, N-methylpyrrolidium methyl, N-methyl- 
piperidinium methyl. 



6 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



10 



Preferred substituents on the heterocyclic rings 
are: methyl, hydroxy, oxo, amino, carboxyl, carboxymethyl, 
methoxycarbony Imethy 1 , ethoxycarbonylmethyl , tert- 
butoxycarbony 1 methyl , hydroxymethyl , hydroxyethyl , 
dimethy laminomethy 1 . 

R3 is hydrogen, C,^ alkoxy, more preferably R3 is 
methoxy and ethoxy. 

In the structural formula (I), n is 0, 1, 2, 3 or 
4. More specifically, n is 1, 2, or 3. 

The present invention also includes the salts of 
those compounds of cephem (I) . Among the salts of the 
compound (I) ^ especially pharmaceutically acceptable salts 
are used when the compound (I) is applied as an anti«elastase 
agent and other salts are utilized as intermediates for 
15 synthesis. Examples of the salts of compound (I) include the 
inorganic base salts, ammonium salts, organic base salts, 
basic amino acid salts, inorganic acid addition salts, 
organic acid addition salts. Inorganic bases that can form 
the inorganic base salts include alkaline metals (e.g. 
20 sodium, potassium) and alkaline earth metals (e.g. calcium, 
magnesium); organic bases that can form the organic base 
salts include procaine, 2-phenylethylben2ylamine, 
dibenzylethylene-diamine, ethanolamine, diethanolamine; 
inorganic acids that can form the inorganic acid addition 
25 salts include hydrochloric acid, hydrobromic acid, phosphoric 
acid, nitric acid, sulfuric acid; organic acids that can form 
the organic acid addition salts include p-toluenesulfoni<: 
acid, methanesulfonic acid, trif luoroacetic acid, acetic 
acid, formic acid, oxalic acid, maleic acid, succinic acid; 
30 basic amino acids that can form the basic amino acid salts 
include lysine, arginine, ornithine and histidine. Among 
these salts, the base salts (i.e. inorganic base salts, 
ammonium salts, organic base salts and basic amino acid 
salts) mean base salts which can be formed when an acid group 
35 such as carboxyl or sulfo group is present in the structural 
formula (I). The acid addition salts (i.e. inorganic acid 
addition salts and organic acid addition salts) mean acid 
addition salts which can be formed when a basic group, (such 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



as amino, piperazine, guanidino, monoalkylamino, di- 
alkylamino, cycloalkylamino, arylamino, cyclicamino or 
nitrogen - containing heterocyclic group) is present in the 
structural formula (I) . 
5 The present invention also includes those compounds 

of the structural formula (I) that have suitably 
pharmaceutically acceptable in vivo hydrolysable esters, 
namely those esters which hydrolyze in the human body to 
produce the parent acid or its salt* Examples of such 

10 metabolically unstable, non-toxic esters include C1.5 
alkanoyloxymethyl ester, C2.5 alkanoyloxyethyl ester, Cj^ 
alkoxy Cj^ alkyl ester or l-(Cj^ alkoxycarbonyloxy) Cj^ alkyl 
ester, more specifically acetoxymethyl ester, 1-acetoxyethyl 
ester, 1-acetoxybutyl ester, 2-acetoxyethyl ester, 

15 pivaloyloxy- methyl ester, methoxymethyl ester, ethoxymethyl 
ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1- 
ethoxyethyl ester, ethoxycarbonyloxymethyl ester, 1- 
(ethoxycarbonyl) ethyl ester, tert-butoxycarbonyloxymethyl 
ester, 1- (tert-butoxycarbonyloxy) ethyl ester, and other such 

20 ester groups which have been or can be used in the penicillin 
and cephalosporin art. 

The method for preparing the cephem sulfone (I) of 
this invention is described in the following process: 

25 0 0 



30 




The starting compound (II) can be easily prepared 
35 by a known method [e.g. US Pat. Appln. No. 685,960 (pending), 
US Pat. Appln. No. 747,762 (pending), US Pat. Appln. No. 
4,547,371] or one analogous thereto. 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



The cephem sulfone (I) can be prepared by carrying 
out a cycloaddition reaction of the compound (II) with a 
cycloalkyl diazo derivative of the formula (III) wherein the 
symbols have the same meaning as described before. 
5 The diazo derivative (III) is usually used in an 

amount of 1 to 5 moles, preferably 1 to 2 moles, per 1 mole 
of the compound (II). The reaction is conducted at -40*C to 
50*C, preferably at to 30*C, and most desirably at 

-10**C to lO'C. The reaction time varies depending on the 

10 species of the compounds (II) and (III) , the kind of solvent 
(also the mixing ratio, if a mixed solvent is used) , the 
reaction temperature, etc., being usually 1 minute to 10 
hours, preferably 15 minutes to 3 hours. 

The present invention also includes the following 

15 compounds (IV) , (V) and (VI) which are obtained from the 
cycloaddition reaction. 



20 



25 



30 




SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



10 



More specifically, the most preferred embodiments 
of the present invention is comprised of the following 
compounds; but it should be understood that the present 
invention is not limited to such specific compounds. 

t-Butyl 7 a-methoxy-2-spiro(2 '-spirocyclopentyl) 
eye lopropy 1-3 -me thy 1-3 -cephem-4-carboxy late- 
ly 1-dioxide; 

t-Buty 1 7 a-methoxy-2 -spiro { 2 ' -spirocyclohexy 1 ) 
cy clopropy 1-3 -me thy 1-3-cephem- 4- carboxy late- 
ly 1-dioxide; 

15 7 a-Methoxy-2-spiro ( 2 ' -spirocyclopentyl) 

cyclopropyl-3-methyl-3-cephem-4-carboxylic acid 
-1, 1-dioxide, and its sodium salt; 

7 a-Methoxy-2-spiro (2 ' -spirocyclohexyl) 
20 cyclopropyl-3-methyl-3-cephem-4-carboxylic acid 

-1, 1-dioxide, and its sodium salt; 

7 a-Methoxy-2-spiro ( 2 ' -spirocyclopentyl) 
cyclopropyl-3-methyl-3-cephem-4-[{ (4-N- 
25 methyl ) piperaz ine } carboxamide ] -1 , 1-dioxide , and 

its hydrochloride salt; 

7 a-Methoxy-2-spiro (2 ' -spirocyclopentyl) 
cyclopropyl-3-methyl-3-cephem-4- [ { (4-t- 
30 butoxycarbony 1 ) piperidine} carboxamide ]- 

1, 1-dioxide; 



7 a-Methoxy-2-spiro (2 ' -spirocyclopentyl) 
cyclopropyl-3-methyl-3-cephem-4- [ { (4- 
35 carboxy) piperidine} carboxamide ]-l, 1-dioxide, and 

its sodixim salt; 



10 

SUBSTITUTE SHEET 



PCT/CA94/00669 



7 a-Methoxy-2-spiro ( 2 ' -spirocyclopentyl ) 
cylopropyl-3-inethyl-3-cephein-4- [ { (4-N-t- 
butoxycarbonylmethyl) pipera2ine}carboxainide] -1 , 1- 
dioxide; 

7 Q-Methoxy-2-spiro (2 '-spirocyclopentyl) 

cylopropyl-3-inethyl-3-cephein-4- 1 { (4-N-acetic 
acid)pipera2ine)carboxainide]-l, 1-dioxide, and its 
sodium salt; 

7 a-Methoxy-2-spiro (2'-spirocyclohexyl) 
cylopropyl-3-methyl-3-cephem-4-[{ {4-N- 
methyl) piperazine ) carboxamide] -1 , 1-dioxide, and 
its hydrochloride salt; 

7 a-Methoxy-2 -spiro ( 2 ' -spirocyclohexyl ) 
cyclopropyl-3-inethyl-3-cephein-4- [ { (4-N-t- 
butoxycarbonyl methyl) piperazine } -carboxamide ]- 
1, 1-dioxide; 

7 a-Methoxy-2 -spiro ( 2 ' -spirocyclohexyl ) 
cyclopropyl-3-methyl-3-cephem-4-[ { (4-N-acetic 
acid) piperazine) carboxamide]-!, 1-dioxide, and its 
sodium salt; 

t-Butyl 7 a-methoxy-2-spiro (2 ' -spirocyclopentyl) 
cyclopropyl-3- [ (2 , 5-dihydro-6-hydroxy-2-methyl-5- 
oxo-1 , 2 , 4-tria2in-3-yl ) thiomethyl ] -3-cephem-4- 
carboxylate-1, 1-dioxide and its sodiiim salt; 

t-Butyl 7 a-methoxy-2-spiro (2 '-spirocyclopentyl) 
cyclopropyl-3- [ ( 1-methyl-l , 2,3, 4-tetrazole-5- 
yl ) thiomethyl ] -3 -cephem-4 -carboxylate-1 , 1-dioxide ; 

t-Butyl 7 a-methoxy-2-spiro(2 '-spirocyclopentyl) 
cyclopropyl-3- [ (2-methyl-l, 3 , 4-thiadia2ole-5- 
yl) thiomethyl ] -3 -cephem-4 -carboxylate-l, 1-dioxide; 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



t-Buty 1-7 a-inethoxy-2 --spir o ( 2 ' -spirocyclopenty 1 ) 
cyclopropyl-3- [ (pyridyl-4-yl) thiolnethyl]-3-cephem- 
4 -carboxylate-1 , l-dioxide ; 

5 t-Butyl-7 a-iDethoxy-2-spiro(2'-spirocyclopentyl) 

cyclopropyl-3 (pyridyl-2-yl) thioInethyl]-3-cephel^- 
4-carboxylate-l, 1-dioxide; 

t-Butyl-7 a-niethoxy-2-spiro(2 '-spirocyclopentyl) 
10 cyclopropyl-3-broinomethy l-3-cephein-4-carboxy late- 

ly 1-dioxide; 

t-Butyl-7 a-niethoxy-2-spiro(2'-spirocyclopentyl) 
cyclopropyl-3 - acetoxymethyl- 3 - cephein-4- 
15 carboxylate-1, 1-dioxide; 

7 a-Methoxy-2-spiro (2 ' -spirocyclopenty 1 ) 
cyclopropyl-3- [ (2, 5-dihydro-6-hydroxy-2-iaethyl-5- 
oxo-1, 2 , 4-triazin-3-yl) thioJnethyl]-3-cephem-4- 
20 piperidine carboxamide-l, l-dioxide, and its sodium 
salt; 

7,7-Dihydro-2-spiro(2'-spirocyclopentyl) 
cyclopropyl-3-inethyl-3-cephein-4-[ { (4- 
25 carboxy ) piperidine } carboxamide ] -1 , 1-dioxide , and 

its sodiuia salt; 



7,7-Dihydro-2-spiro(2 ' -spirocyclopenty 1 ) 
cyclopropyl-3-inethyl-3-cephein-4- [ (N-methyl-N- 
30 acetic acid) ]carboxainide-l, 1- dioxide, and its 

sodium salt; 



7 a-Methoxy-2-spiro (2 ' -spirocyclopenty 1 ) 
cyclopropyl-3- [ (2 , 5-dihydro-^-hydroxy-2-methyl-5- 
35 oxo-1 r 2 , 4-tria2in-3-yl) thiomethyl] -3-cephem-4- 

[ { (4-carboxy) piperidine} -carboxamide ] -1, l-dioxide, 
and its sodium salt; 



12 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



7 a-Methoxy-2-spiro (2 ' -spirocyclopenty 1) 

cyclopropyl-3-inethyl-3-cephein-4-inethylcarbonyl- 
1,1-dioxide; 

7 a-Methoxy-2-spiro (2 ' -spirocyclopentyl ) 
cyclopropyl-3-iDethyl-3-cephem-4- [4 ' - (methyl) -4 
(methoxy imino) ] -1 , 1-dioxide ; 



7 a-Methoxy-2-spiro (2 ' -spirocyclopentyl) 
cyclopropyl-3-inethyl-3-cephein-4-[ { (4- 
carboxamide) piper idine } carboxamide ] -1 , 1-dioxide ; 

7 a-Methoxy-2-spiro (2 '-spirocyclopentyl) 
cyclopropyl-3-methyl-3-cephein-4-[{ (4- 
cyano ) piper idine } carboxamide ] - l , 1-dioxide ; 

7 a-Methoxy-2-spiro (2 ' -spirocyclopentyl) 
cyclopropyl-3-methyl-3-cephem-4-[{ (4- 
hydroxy ) piper idine } carboxamide ] -1 , i-dioxide ; 

7 a-Methoxy-2-spiro (2 ' -spirocyclopentyl) 
cyclopropyl-3-methyl-3-cephem-4-[ { (4- 
hydroxyethy 1 ) piper idine } carboxamide ] -l , 1-dioxide ; 

7 Q-Methoxy-2-spiro (2 ' -spirocyclopentyl) 
cyclopropyl-3-methyl-3-cephem-4-[{ (4- 
bromoethy 1 ) piper idine } carboxamide ] -1 , 1- dioxide ; 

7 a-Methoxy-2-spiro (2 ' -spirocyclopentyl) 
cyclopropyl-3-methyl-3-cephem-4-[{ (4- 
diethoxyphosphinylethyl)piperidine}-carboxamide]- 
1, 1-dioxide. 



BIOLOGICAL EVIDENCE 
35 The in vitro test data on anti-elastase activity of 

exemplary derivatives having the structural formula I are 
shown in Table I herebelow: 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 




TABLE I 

IC50 VALUES OF 2-SPIRO f 2 ^ -SPIR0CYCL071LKYL) CYCLOPROPYL 
CEPHALOSPORIN SULFONES AGAINST HLE 



COMPODMD 


»1 


»2 


^^3 


n 


IC50 (nM) 


1 


COOBu' 


CH3 


r 

CH3O 


2 


4, 17 


2 


o 


CH3 


CH3O 


2 


27.3 


3 


0 H Ci^ 


CH3 


CH3O 


2 


24.4 


4 


^"s^** COOH 

o 


CH3 


CH3O 


2 


139.0 


5 


y-N^-COOH 
0 


CH3 


CH3O 


2 


58.1 


6 


COOBU* 


CH3 


CH3O 


3 


3.47 



14 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



COMPOUND 




^2 


R3 


n 


IC50 (nM) 


7 


Vn^N -CH3 
0 


CH3 


I 

CH3O 


3 


6.40 


8 


V^C^^ COOBu' 
0 


CH3 


CH3O 


3 


8.37 


9 


V^,N^ COOH 
0 


CH3 


CH3O 


3 


27.0 


10 


0 H r 0 ® 


CH3 


CH3O 


3 


8.4 


11 


COOBu^ 


CH2OAC 


CH3O 


2 


9.1 


12 


COOBU* 


CH, 
1 

^f^,H 
0 


CH3O 


2 


15.0 


13 


COOBu^ 


-cHz— s-<;^ 


CH3O 


2 


9.4 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



COMPOUND 




^2 


»3 


n 


IC50 (nM) 


14 


COOBU^ 


1 


CH30 


2 


15.3 


15 


COOBu^ 


K — N 


CH30 


2 


10.3 


16 


o 


CHj 
1 

0 


0CH3 


2 


32.4 


17 


Vn^~V"Coobu* 
o ^ 


CH3 


H 


2 


870 


18 


o 


CH3 


0CH3 


2 


10.7 


19 


1 

N 

OCHj 


CH3 


0CH3 


2 


80.7 



16 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



COMPOUND 








n 


IC50 (nM) 


20 


0 


CH3 


OCH3 


2 


8.4 


21 


><£> 

0 


CH3 


OCH3 


2 


3.9 


22 


C00CHph2 


CH3 


H 


2 


478 


23 


Vn — CHaCOOH 
0 1 


CH3 


OCH3 


2 


75 


24 


^iT" N_coONa 
0 


1 

0 


OCH3 


2 


34 



ENZYME ASSAY FOR INHIBITION OF HLE 



ENZYME: 

SUBSTRATE: 

REACTION 
MIXTURE: 



Purified 
cells. 



elastase from human white blood 



MeO-succinyl-L-alanyl-L-alanyl-L-prolyl-L- 
valine-p-nitroanilide 

10 mM phosphate buffer {pH 7.6) 

500 mM NaCl 

10% dimethylsulfoxide 

0.35 mM substrate 



17 

SUBSTITUTE SHEET 



wo 95715966 



PCT/CA94/00669 



The enzyme activity was determined by monitoring 
the increase in absorbance at 410 nm caused by the hydrolysis 
of chromogenic substrates. Inhibition of enzyme by the 
compounds described were determined after a 10 minute 
5 preincubation with the enzyme in the reaction mixture minus 
substrate. Reaction was initiated by the addition of 
substrate* The concentration of human letikocyte elastase 
used for assay was at 10 nM. 

For therapeutic administration, a compound having 

10 the structural formula I, is used in the form of conventional 
pharmaceutical preparation which contains said compounds as 
an active ingredient in admixture with a pharmaceutically 
acceptable carrier such as an organic or inorganic solid or 
liquid excipient which is suitable for oral, parenteral or 

15 external administration. The pharmaceutical preparations may 
be in solid form such as capsule, tablet, ointment, etc. or 
in liquid form such as solution, suspension or emulsion. 
There may be included in the above preparation auxiliary 
substances, stabilizing agents, wetting or emulsifying 

20 agents, buffers and the other commonly used additives. 

In general, a daily dose of between 0.2 mg and 150 
mg, or even more per kilogram of body weight, per day may be 
administered to a patient. However, the dose level may vary 
and will depend upon a variety of factors such as the 

25 activity of the specific compound employed, the age, body 
weight, sex, diet, time of administration, route of 
administration , etc . 

The following examples are provided to demonstrate 
the operability of the present invention. 

30 

EXAMPLE 1 

t-Butyl 7 tt-methoxy-2-9piro(2 ^-spirocvclopentvl) cycloproDVl" 
3-methYl"3-cephem-4-carboxvlate*l,l*dioxide 

35 To a suspension of anhydrous magnesium sulfate (3.5 

g) in ether (50 ml) cooled to -15 ^'C was added silver oxide 
(5.10 g) , followed by cyclopentanone hydrazone (2.16 g) . A 
solution of potassium hydroxide in methanol (1 ml) was added 



18 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



dropwise. Within three to five minutes, a deep red color was 
developed. The reaction mixture was filtered quickly through 
a small bed of Celite. To the filtrate, a solution of t- 
butyl 7 a-methoxy-2-methylene-3-methyl-3-cephem-4- 
5 carboxylate-l,l-dioxide in methylene chloride (100 ml) was 
added and the reaction mixture was stirred at room 
temperature for 2 hours. The mixture was filtered through 
Celite and the filtrate was concentrated to dryness which was 
purified over a silica gel column using a mixture of hexane- 

10 ethyl acetate. 

The first eluting component was: 
t-Butyl-7 a-methoxy-2 (Z) • ( (cyclopentyl) methylene] -3-methy 1-3- 
cephem-4-carboxylate-l,l-dioxide (1.23 g, 28.1%); NMR 
(CDCI3): S 6.35 (d, IH, J=10.7 Hz); 5.23 (d, IH, J=1.4 Hz); 

15 4.67 (d, IH, J=1.4 Hz); 3.68-3.84 (m, IH) ; 3.57 (s, 3H) ; 2.07 
(s, 3H); 1.55 (s, 9H) ; 1.25-1.80 (m, 8H) . 

The second eluting component was: 
t-Buty 1-7 a-methoxy-2 -spiro ( 3 ' -spirocyclopentyl ) cyclopropyl- 
3-methyl-3-cephem-4-carboxylate-l, 1-dioxide. ^H NMR (CDCI3) : 

20 S 4.87 (d, IH, J=1.5 Hz); 4.57 (d, IH, J=1.5 Hz); 3.55 (s, 
3H); 2.14 (s, 3H) ; 1.83 (d, IH, J=6.4 Hz); 1.62-2.00 (m, 8H) ; 
1.53 (s, 9H) ; 1.48 (d, IH. J=6.4 Hz). 

The third eluting component was: 
t-Butyl-7 a-methoxy-2 (E) -[ (cyclopentyl)methylene]-3-methyl-3- 

25 cephem-4-carboxylate-l,l-dioxide (0.41 g, 8.88%). ^H NMR 
(CDCI3): 6 6.73 (d, IH, J=10.8 Hz); 4.96 (d, IH, J=1.6 Hz); 
4.63 (d, IH, J=1.6Hz); 3.48 (s, 3H) ; 2.75-2.88 (m, IH) ; 2.23 
(s, 3H); 1.48 (s, 9H) ; 1.18-2.07 (m, 8H) . 

The fourth eluting component was: 

30 t-Butyl-7 a-methoxy-2-spiro (2 '-spirocyclopentyl) cyclopropyl- 
3-methyl-3-cephem-4-carboxylate-l, l-dioxide (1.65g, 37.67%) . 
^H NMR (CDCI3): S 5.10 (d, IH, J=1.8 Hz); 4.57 (d, IH, J=1.8 
Hz); 3.56 (s, 3H) ; 1.95 <d, IH, J=6.5 Hz); 1.76 (s, 3H) ; 1.56 
(s, 9H); 1.60-1.96 (m, 9H) . 

35 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



EXAMPLE 2 

t-Butvl^7 tt-methoxv*2^spiro f 2 ^-spirocvclopentvl) cyclopropvl''^ 
3* f > 3 , 4-tetra2ole*S'>vl) thiomethvn ^3*cephem*4- 

carboxvlate^l » l^'dioxide 

5 

Step A: 

To a solution of t-butyl-7 a-inethoxy-2-spiro(2 
spirocyclopentyl ) cyclopropyl-3-methyl-3 -cephein-4 -car boxy late- 
ly 1-dioxide (Example 1, 761 mg, 1.9146 minols) in carbon 

10 tetrachloride (35 ml) was added N-bromosuccinimide (374.8 mg, 
2.1060 mmol) followed by AIBN (15.7 mg, 0.0957 mmols) . The 
mixture was heated to reflux at 90 •>C for 21 hours; cooled to 
0«*C, the precipitated solid was removed by filtration. The 
filtrate was concentrated under reduced pressure to give a 

15 crude mass (1.15 g) which was chromatographed over a silica 
gel column using methylene chloride as eluant to give 670 mg 
(73.5%) of t-butyl-7 a-methoxy-2-spiro (2 '-spirocyclopentyl) 
cyclopropyl-3-bromomethyl-3-cephem-4-carboxylate-l, 1-dioxide. 
NMR (CDCI3) : 5.14 (d, IH, J=2.0 Hz); 4.60 (d, IH, J=2.0 

20 Hz); 4.35 (d, IH, J=10.8 Hz); 3.57 (s, 3H) ; 3.32 (d, IH, 
J=10.8 Hz); 2.16 (d, IH, J=7.2 Hz) ; 1.65 (d, IH, J=7.2 Hz); 
1.60 (s, 9H) ; 1.55-2.00 (m, 8H) . 

Step B: 

25 To a solution of t-butyl-7 a-methoxy-2-spiro (2 ' - 

spirocyclopentyl) cyclopropyl-3-bromomethyl-3-cephem-4- 
carboxylate-l,l-dioxide (Example 2, step A; 100 mg, 0.2099 
mmol) in acetonitrile (2 ml) was added l-methyl-5-mercapto- 
1,2,3,4-tetrazole (24.38 mg, 0.2099 mmol) followed by 

30 triethylamine (64 m1# 0.4618 mmol). After stirring at room 
temperature for 1 hour, the solvent was removed under reduced 
pressure and the residue was dissolved in methylene chloride; 
washed with dilute hydrochloric acid, followed by dilute 
sodium bicarbonate solution, dried over anhydrous sodixim 

35 sulfate and concentrated to give a brown foam which was 
purified over a silica gel column using hexane-ethyl acetate 
mixture as eluant to give the title compound as a yellow foam 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



(81 mg, 76%) . NMR (CDCI3) : 6 5.12 (d, IH, J=l,9 Hz); 

4.60 (d, IH, J=1.9 H2); 4.26 (d, IH, J=13.0 Hz); 3.92 (s, 
3H); 3.80 (d, IH, J=13.0 Hz); 3.58 (s, 3H) ; 1.72-1.97 (m, 
lOH); 1.59 (s, 9H). 

5 

EXAMPLE 3 

t-Butvl-7 tt-methoxv*2-spiro(2^-9Pirocvclopentvl) cvelopropvl^ 
3-r (2-methvl-1.3,4-tbiadia2ole-5-vl) thiomethvn*3-cephem»4^ 
carboxylate-l^ 1-dioxide 

10 To a solution of t-butyl-7 a-methoxy-2-spiro(2'- 

spirocyclo-pentyl) cyclopropyl-3-broinoinethyl-3-cephein-4- 
carboxylate-l,l-dioxide (Example 2, Step A; 100 mg, 0.2099 
mmol) in acetonitrile (2 ml) was added 5-methyl-2-mercapto- 
1,3,4-thiadiazole (27.7 mg, 0.2099 mmol), followed by 

15 triethylamine (64 mL, 0.4618 mmol). After stirring at room 
temperature for 4 hours, the solvent was removed under 
reduced pressure and the residue was dissolved in methylene 
chloride, washed with dilute hydrochloric acid, dilute sodium 
bicarbonate solution, water and brine, dried over anhydrous 

20 sodium sulfate and concentrated to give a brown foam which 
was purified over a silica gel column using hexane-ethyl 
acetate mixture as eluant to give 54 mg (50%) of the title 
compound as a light yellow foam. ^H NMR {CDCI3) : S 5.12 (d, 
IH, J=1.9 Hz); 4.59 (d, IH, J=1.9 Hz); 4.20 (d, IH, J=13.0 

25 Hz); 3.96 (d, IH, J=13.0 Hz); 3.57 (s, 3H) ; 2.72 (s, 3H) ; 
1.94 (d, IH, J=9.3 Hz); 1.73-1.96 <m, 9H) ; 1.58 (s, 9H) . 

EXAMPLE 4 

t-ButYl-7 a-methoxv-2-3Piro (2 ^-spirocvclopentvH cvclcpropvl^* 
30 3-r (Pvridvl-2-vl) thiomethvn-3-cephem-4-carboxvlate-l, 1- 
dioxide 

To a solution of t-butyl-7 a-methoxy-2-spiro(2'- 
spirocyclo-pentyl) cyclopropyl-3-bromomethyl-3-cephem-4- 
carboxylate-l,l-dioxide (Example 2, Step A; 100 mg, 0.2099 
35 mmol) in acetonitrile (2 ml) were added 2-mercapto pyridine 
(23.6 mg, 0.2099 mmol) and triethylamine (64 /xL, 0.4618 
mmol) . The reaction was worked up in the same manner as 



21 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



described in Example 3 . The title compound was obtained' as 
a white foam (54 mg, 51%). NMR (CDCI3) : S 8.37-8.39 (m, 

IH) ; 7.44-7.52 (m, IH) ; 7.16-7.20 (m, IH) ; 6.95-7.02 (m, IH) ; 
5.12 (d, IH, J=1.9 Hz); 4.58 (d, IH, J=1.9 Hz); 3.93 {ABq, 
5 2H, J=13.25 and 22.15 Hz); 3.57 (s, 3H) ; 1.64-1.96 (m, lOH) ; 

1.57 (s, 9H). 

EXAMPLE 5 

t-Butyl-? tt^methoxv-2-3Diro (2 ^-sDirocvclopentvll cvclcpropvl* 
10 3»r (pvridvl-4-vl) thiomethvn"3-cephem*4-carbcxvlate-l.l- 
dioxide 

The reaction was done in the same manner as 
described in Example 4 by using 4-mercapto pyridine. The 
yield of the title compound was 60 mg (57.7%). ^H NMR 
15 (CDCI3) : S 8.42 (d, br, 2H) ; 7.14 (d, br, 2H) ; 5.14 (d, IH, 
J=2.0 Hz); 4.61 (d, IH, J=2 . 0 Hz); 4.15 (d, IH, J=11.7 Hz); 

3.58 (s, 3H); 2.93 (d, IH, J«11.4 Hz); 2.075 (d, IH, J=7.3 
Hz); 1.56-2.06 (m, 8H) ; 1.536 (s, 9H) ; 1.43 (d, IH, J=7.3 
Hz) . 

20 EXAMPLE 6 

t"ButYl~7 a*methcxY"2-9Piro (2 ^-spirocvclopentvl) cvclopropvl'-' 
3-f (2 , S-dihYdro-6-hvdroxv-2-methvl-5-oxo-l> 2 , 4-triazin-3-vl) - 
thiomethvn-3«-eephem«>4-carboxvlate-l, l^dioxide 

25 Step A: 

To a solution of t-butyl-7 a-methoxy-2-spiro(2 '- 
spirocyclo-pentyl) cyclopropyl-3-bromomethyl-3-cephem-4- 
carboxylate-l,l-dioxide (Example 2, Step A; 200 mg, 0.4198 
mmol) in acetonitrile (5 ml) were added 2 ,5-dihydro-6- 
30 diphenylmethyloxy-2-methyl-3-mercapto-5-oxo-l, 2, 4-triazine 
(137 mg, 0.4198 mmol) and triethylamine (0,8396 mmol). The 
reaction mixture was stirred at room temperature overnight, 
diluted with ethyl acetate, washed with dilute hydrochloric 
acid, sodium bicarbonate solution, water and brine, dried 
35 over anhydrous Na2S04, filtered and concentrated to give a 
light brown foam. The product was purified over a silica gel 
column using hexane-ethyl acetate mixture as eluant. The 



22 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



yield of the title compound was 170 mg (56.3%). NMR 
(CDCI3) : 6 7.30-7.46 {m, lOH) ; 6.75 (s, IH) ; 5.09 (d, IH, 
J=2.0 H2); 4.58 (d, IH, J=2.0 Hz); 3.9 (ABq, 2H, J=13.2 and 
23.0 H2); 3.62 (s, 3H) ; 3.56 (s, 3H) ; 1.61-1.96 (m, lOH) ; 
5 1.56 (s, 9H). 



Step B; 

To a stirred solution of t-butyl-7 a-inethoxy-2- 
spiro(2'-spirocyclopentyl) cyclopropyl-3-[ (2 , 5-dihydro-6- 

10 hydroxy-2-inethyl-5-oxo-l,2, 4-tria2in-3-yl) thioinethyl]-3- 
cephein-4-carboxylate-l,l-dioxide (from Step A, 146 mg, 0.2196 
mmol) in dry methylene chloride (5 ml) was added 
trifluoroacetic acid (204 liL, 1.2 mmol). The mixture was 
stirred at room temperature for 2.5 hours. The solvent was 

15 removed under reduced pressure and the residue was diluted 
with ether and treated with hexane. The precipitated white 
solid was collected by filtration, 81 mg (75%) . NMR 
(CDCI3): 6 5.11 (d, IH, J=1.9 Hz); 4,59 (d, IH, J^l.9 Hz); 
4.30 (s, br, IH); 3.79 (ABq, 2H, Ji=13.2 Hz, J2=28.3 Hz); 

20 3.75 (s, 3H); 3.58 (s, 3H) ; 1.99 (d, IH, J=7.0 Hz) ; 1.73-2.00 
(m, 9H) ; 1.58 (s, 9H) . 



E3CAMPLE 7 

7 a-MethoxY-2-spiro f2^-spirocvcloDentvl> cvclopropYl*"3- 
25 ffiethvl-3-cephem-4- f f f 4-carboxY) pjperidinel carboxamidel -1.1- 
dioxide 

Step A: 

A solution of t-butyl-7 a-methoxy-2-spiro(2'- 
30 spirocyclopentyl) - cyclopropy 1-3 -methy 1-3 -cephem-4 - 
carboxylate-1, 1-dioxide (Example 2, 0.50 g, 1,26 mmol) in 
formic acid (10 ml) was stirred at 50 for a period of 1 
hour and the formic acid was removed by freeze-drying. The 
residue was washed several times with a mixture of hexane- 
35 ether (9.5:0.5) and finally dissolved in methylene chloride. 
Evaporation of the solvent in vacuo gave a foam (0.408 g, 
95%). ^H NMR (CDCI3): S 8.03 (s, br, IH) ; 5.13 (d, IH, 



23 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



J=1.6 Hz); 4.62 (d, IH, J=1.6 Hz); 3.58 (s, 3H) ; 2.046 (d, 
IH, J=6.6 Hz); 1.67 (d, IH, J:=6.6 Hz); 1.56-2.00 (m, 8H) ; 
1.91 (s, 3H). 

5 STEP Bt 

To a stirred and ice-cooled solution of 7 a- 
inethoxy-2-spiro(2 '-spirocyclopentyl) cyclopropyl-3-inethyl-3- 
cephein-4-carboxylic acid-1, 1-dioxide (from Step A, 2.96 g, 
8.7 mmol) in dry methylene chloride (100 ml) under nitrogen 

10 was added oxalyl chloride (1.46 g, 1.13 mmol) followed by 
four drops of dimethyl formamide. The reaction mixture was 
stirred for 15 min. at 10 and at room temperature for 50 
min. Volatile materials were removed under reduced pressure. 
The solid obtained was dissolved in dry methylene chloride 

15 (100 ml) . To this solution, a solution of 4-t-butoxycarbonyl 
piperidine (1.61 g, 8.7 mmol) in methylene chloride (5 ml) 
was added, followed by triethylamine (0.934 g, 9.1 mmol). 
The reaction mixture was stirred at room temperature for 1.5 
hr, then diluted with 100 ml of methylene chloride. The 

20 methylene chloride solution was washed successively with 
sodium bicarbonate solution, brine and dried over anhydrous 
sodium sulfate. Evaporation of the solvent gave a light 
brown solid which was purified over a silica gel column using 
hexane-ethyl acetate mixture (3:2) as eluant. The title 

25 compound was obtained as a white solid (3.33 g, 75.5%). ^H 
NMR {CDCI3) : 6 5.11-5.14 (m, IH) ; 4.58-4.59 (m, IH) ; 4.31- 
4.50 (m, IH) ; 3.65-3.85 (m, IH) ; 3.54 and 3.55 (2s, 3H) ; 
2.90-3.20 (m, 2H) ; 2.35-2.55 (m, IH) ; 1.50-2.04 (m, 14H) ; 
1.58 (s, 3H); 1.45 (s, 9H) . 

30 

Step C: 

A solution of 7 a-methoxy-2-spiro(2'- 
spirocyclopentyl) cyclo-propyl-3-methyl-3-cephem-4-[ { (4-t- 
butoxycarbonyl) piperidine} carboxamide]-l, 1-dioxide (3.2 g, 
35 6.3 mmol) in anhydrous formic acid (200 ml) was stirred under 
nitrogen at 40-45*>C over a period of 1.5 hours and formic 
acid was removed by freeze-drying. The residual mass was 



24 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



digested with a mixture of hexane-ether (8.5:1.5); the 
precipitated solid was filtered off, 2.45 g (85.8%). NMR 
(CDCI3) : S 5.13-5.15 (m, IH) ; 4.60-4.61 (m, IH) ; 4.25-4.55 
(m, IH) ; 3.5-3.90 (m, IH) ; 3.54 (s, 3H) ; 2.90-3.25 (m, 2H) ; 
5 2.50-2.75 (m, IH) ; 1.51-2.10 (m, 14H) ; 1.53 and 1.58 (2s, 
3H) . 

EXAMPLE 8 

7 a-Methoxv-2-spiro (2 ^-spirocyclopentYl) cvcloBropvl-3-methYl*" 
10 3 -cephem-4 * f / ( 4 -N-methvl ) piperaz inel e ayhnva w ide 1 *1 . 1-dioxide 
hydrochloride 

Step A: 

To a stirred and ice-cooled solution of 7 a- 

15 inethoxy-2-spiro(2'-spirocyclopentyl) cyclopropyl-3-inethyl-3- 
cepheiD-4-carboxylic acid-1, 1-dioxide (Example 7, Step A; 2.75 
g, 8.06 mmol) in dry methylene chloride (100 ml) under 
nitrogen was added oxalyl chloride (1.36 g, 10.5 mmol) 
followed by three drops of DMF. The reaction mixture was 

20 stirred at 10 for 15 min and then at room temperature for 
50 min. The volatile solvents were removed under reduced 
pressure. The solid thus obtained was dissolved in 80 ml of 
dry methylene chloride and stirred under nitrogen. To the 
above solution was added a solution of N-methyl-piperazine 

25 (0.824 g, 8.06 mmol) followed by triethylamine (0.865 g, 8.46 
mmol) . The reaction mixture was stirred at room temperature 
for one hour, then diluted with methylene chloride (100 ml) ; 
washed successively with sodium bicarbonate solution^ brine, 
dried (Na2S04) and concentrated to give a light yellow foam. 

30 The product was purified over a silica gel column using ethyl 
acetate-methanol (9.5:0.5) as eluant; yield 1.96 g (57.5%). 

NMR (CDCI3): S 5.12 (d, IH, J=1.9 Hz); 4.60 (d, IH, J=1.9 
Hz); 3.55 (s, 3H) ; 3.5-4.0 (m, 4H) ; 2.33-2.50 (m, 4H) ; 2.33 
(s, 3H); 1.92 (d, IH, J=6.4 Hz); 1.56-1.93 (m, 8H) ; 1.55 (s, 

35 3H); 1.52 (d, IH, J=6.4 Hz). 



25 

SUBSTITUTE SHEET 



wo 95/15966 PCT/CA94/00669 



STEP B: 

1.96 g (4.63 minol) of 7 a-inethoxy-2-spiro(2'- 
spirocyclopentyl) cyclopropyl-3-inethyl-3-cephein-4- [ { (4-N- 
5 methyl ) piper az ine } carboxamide ] -1 , 1-dioxide ( from the previous 
step) was dissolved in dry methylene chloride (15 ml) . A 
stream of dry hydrogen chloride gas was bubbled through this 
solution and the reaction mixture was stirred at room 
temperature for 10 min. The reaction mixture was diluted 
10 with 50 ml of anhydrous ether. The precipitated white solid 
was collected by filtration, 1.9 g (89.2%). NMR (CDCI3) : 

6 5.09 (d, IH, J=1.7 Hz); 4.76-4.83 (m, IH) ; 4.62 (d, IH, 
J=1.7 Hz); 3.30-4.20 (m, 5H); 3.56 (s, 3H) ; 2.90-3.10 (m, 
2H) ; 2.81 (d, 3H, J=4.06 Hz); 1.96 (d, IH, J=6.5 Hz); 1.55- 

15 1.98 (m, 9H) ; 1.55 (s, 3H) . 

EXAMPLE 9 

7 tt-Methoxv-2-spiro (2^-spirocvclopentvl>cycloDropyl->3'^methYl- 
3-cephem-4-r i (4-N-aceticacid) piperazinelcarboxamide'^l, 

20 dioxide 

STEP A; 

To a stirred and ice-cooled solution of 7 a-methoxy-2- 
spiro (2 '-spirocyclopentyl) cyclopropyl-3-methyl-3-cephem-4- 

25 carboxylic acid-1, 1-dioxide (Example 7, Step A; 2.93 g, 8.6 
mmol) in dry methylene chloride (100 ml) under nitrogen was 
added oxalyl chloride (1.45 g, 11.2 mmol) followed by 4 drops 
of DMF. The reaction mixture was stirred at 10 ''C for 15 min 
and at room temperature for 45 min. The volatile materials 

30 were removed under reduced pressure. The residual light 
yellow foam was dissolved in methylene chloride and stirred 
under nitrogen. To this reaction mixture was added 4-(t- 
butoxycarbonyl methyl) piperazine (1.72 g, 8.6 mmol) dissolved 
in methylene chloride (2 ml) , followed by triethylamine 

35 (0.923 q, 9.03 mmol). The reaction mixture was stirred at 
room temperature for one hour and diluted with methylene 
chloride (100 ml). The organic layer was washed with soditim 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



bicarbonate solution, brine, dried (NajSO^) and concentrated 
under reduced pressure to give a light yellow foam. 
Purification of the product over a silica gel colxunn using 
hexane-ethyl acetate mixture as eluant gave the pure compound 
5 (3.3 g, 73.5%). NMR (CDCI3) : 6 5.09 (d, IH, J=2.0 Hz) ; 

4.56 (d, IH, J=2.0H2); 3.80-4.00 (m, IH) ; 3.51 (s, 3H) ; 3.4- 
3.7 (m, 3H) ; 3.12 (s, 2H) ; 2.56-2.70 (m, 4H) ; 2.26-2.40 
(m, IH); 1.62-1.98 (m, lOH) ; 1.52 (s, 3H) ; 1.43 (s, 9H) . 

10 STEP p; 

7 a-Methoxy-2-spiro (2 '-spirocyclopentyl ) 
cyclopropyl-3-methyl-3-cephem-4-[ { (4-N-t-butoxycarbonyl 
methyl)piperazine)-carboxamide]-l,l-dioxide (fromStepA; 3.2 
g, 6.1 mmol) was dissolved in anhydrous formic acid (150 ml) 
15 and the reaction mixture was stirred at 40-45 'C for 2 hours. 
Formic acid was removed by f reeze-drying. The residual gummy 
mass was digested with a mixture of hexane-ether (9:1). The 
precipiated solid was collected by filtration (2.06 g, 72%). 
'H NMR (CDCI3): 6 5.4-5.5 (br, IH) ; 5.11 (d, IH, J=2 . 0 Hz) ; 
4.60 (d, IH, J=2.0 Hz); 4.1-4.2 (m, IH) ; 3.5-3.75 (m, 3H) ; 
3.55 (s, 3H) ; 3.32 (s, br, 2H) ; 2.70-3.05 (m, 4H) ; 1.52-1.95 
(m, lOH) ; 1.56 (s, 3H) . 

EXAMPLE 10 

t-Butvl-7tt -methoxY-2-spiro (2 ^-spirocvclohexvl) cyclopropvl-3- 
methvl-3-cephem-4-carboxvlate-l , 1-dioxide 

To a suspension of anhydrous magnesium sulfate (4.0 
g) in dry ether (90 ml) cooled to -15 'C was added silver 
oxide (8.11 g) followed by cyclohexanone hydrazone (3.75 g, 
33.4 mmol). A solution of potassiim hydroxide in methanol 
(iml) was added dropwise. After stirring at this temperature 
for three minutes, a deep red color was formed. The 
reaction mixture was filtered rapidly through a small bed of 
Celite. To the filtrate a solution of t-butyl-7 Q-methoxy-2- 
methylene-3-methyl-3-cephem-4-carboxylate-l, 1-dioxide (2.20 
g, 6.7 mmol) in methylene chloride (50 ml) was added slowly. 
The reaction mixture was stirred at room temperature for 2 



30 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



hours, concentrated under reduced pressure and the crude mass 
was purified over a silica gel column using hexane-ethyl 
acetate mixture (6:3) as eluant to give the pure compound 
(1.1 g, 40%). NMR (CDCI3): S 5.05 (d, IH, J=2.0 Hz); 

5 4.63 (d, IH, J=2.0 Hz) ; 3.56 (s, 3H) ; 1.92 (s, 3H) ; 1.55 (s, 
9H) ; 1.23-2.40 (m, 12H) . 

EXAMPLE 11 

7tt-Methoxv-2"spirol2 ^'■'SPirocvclohexvl) cvclopropvl-3-methvl'" 
10 3-cephem-4*rf (4'*N-methvl)pipera2ine>carboxamidel-l,l-dioxide 



STEP A; 

t-Butyl-7 a-methoxy-2-spiro(2 '-spirocyclohexyl) 
cyclopropy l-3-methyl-3-cephem-4-carboxylate-l , 1-dioxide 

15 (Example 10, 2.133 g, 5.18 mmol) was dissolved in anhydrous 
formic acid (40 ml) and the reaction mixture was stirred at 
50**C for one hour. Formic acid was removed by f reeze-drying. 
The residue thus obtained was digested with hexane; hexane 
layer was decanted off. This process was repeated several 

20 times and the residue was pumped out to give a foam (1.67 g, 
91%). NMR (CDCI3) : 6 5.07 (d, IH, J=2 . 0 Hz); 4.65 (d, 

IH, J=2.0 Hz); 3.57 (S, 3H) ; 2.08 (s, 3H) ; 1.87 (d, IH, J=6.4 
Hz); 1.10-1.90 (m, IIH) . 

25 STEP B: 

To a stirred and ice-cooled solution of 7 a- 
methoxy-2-spiro(2'-spirocyclohexyl) cyclopropyl-3-methyl-3- 
cephem-4-carboxylic acid-1, 1-dioxide (from the previous step; 
0.2 g, 0.62 mmol) in dry methylene chloride (5 ml) under 

30 nitrogen was added oxalyl chloride (0.092 g, 0.71 mmol), 
followed by 2 drops of DMF. The reaction mixture was stirred 
at room temperature for 50 min. The volatile materials were 
removed under reduced pressure. The residual light yellow 
foam was dissolved in methylene chloride (10 ml) and stirred 

35 under nitrogen at O'^C. To this solution, N-methylpiperazine 
(0.124 g, 1.24 mmol) was added. The reaction mixture was 
stirred at ice-temperature for 30 min. and at room 



28 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



temperature for 30 min., diluted with 30 ml of methylene 
chloride. The methylene chloride layer was washed with 
water, brine, dried (Na2S04) and concentrated under reduced 
pressure to give a crude product which was purified over a 
5 silica gel column using ethyl acetate-methanol mixture as the 
eluant (0.163 g, 60%). NMR (CDCI3) : S 5.08 (d, IH, J=2.0 
Hz); 4.73 (d, IH, J=2.0H2); 3.54 (s, 3H) ; 3.40-3.90 (m, 4H) ; 
2.35-^2.50 (m, 4H); 2.31 (s, 3H) ; 1.80 (d/ IH, J=6.6 Hz); 1.64 
(s, 3H); 1.50 (d, IH, J=6.6 Hz); 1.17-1.89 (m, lOH) . 

10 

EXAMPLE 12 

t-Butvl-7 tt-methoxv-2-spiro f 2 ^-spirocvclopentyl) cvclopropyl- 
3-acetoxvmethYl-3-cephem-4-carboxvlate-l . I'^dioxide 

By using the same procedure as described in Example 
15 1, but using t-butyl 7 a-methoxy-2-methylene-3-acetoxymethyl- 
3-cephem-4-carboxylate-l, l-dioxide, the title compound was 
prepared. *H NMR (CDCI3) : 6 5.13 (d, IH, J=2.0 Hz); 4.60 
(d, IH, J=12.7 Hz); 4.60 (d, IH, J=2.0 Hz); 4.27 (d, IH, 
J=12.7 Hz); 3.57 (s, 3H) ; 2.08 (s, 3H) ; 2.01 (d, IH, J=6.9 
20 Hz); 1.55 (s, 9H) ; 1.50-1.99 (m, 9H) . 

EXAMPLE 13 

7 tt-Methoxy— spiro (2 ^-spirocYclopentyl) cvclopropvl-3-r <2 . 5- 
dihvdro-6-hvdroxv-2-methvl-5-oxo-l , 2 . 4-triazin'^3-yl1 
25 thiomethvn-3-cepbem-4-piperidipe carboxamide-1^ l^dioxide 

Step A; 

To a stirred and ice-cooled solution of 7 a- 
me t h oxy- 2-spiro(2'-spirocycl open t y 1 ) eye 1 opr opy 1-3 -me thy 1 - 3 - 

30 cephem-4-carboxylic acid -1, 1-dioxide (Example 7, Step A; 3.0 
g, 8.8 mmol) in dry methylene chloride (60 ml) under nitrogen 
was added oxalyl chloride (1.45 g, 11.43 mmol) followed by 
three drops of DMF. The reaction mixture was stirred at 10*»C 
for 15 min. and then at room temperature for 45 min. The 

35 volatile solvents were removed under reduced pressure. The 
resulting solid thus obtained was dissolved in methylene 
chloride. To this solution, a solution of piperidine (1.65 



29 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



g, 19.4 nunol) in methylene chloride (2 ml) was added and the 
mixture was allowed to stir for 1 hour at room temperature. 
The reaction mixture was then diluted with methylene chloride 
and washed with water followed by brine, dried over anhydrous 
5 sodium sulphate. Evaporation of the solvent in vacuo gave a 
yellow foam, which was purified over a silica gel column. 
Gradient elution of the column with a mixture of hexane-ethyl 
acetate gave pure 7 QE-methoxy-2 -spiro ( 2 ' - 
spirocyclopentyl) cyclopropyl-3-methyl-3-cephem-4-piperidine 
10 carboxamide-l,l-dioxide, as a white foam (2.5 g, 69.4%). % 
NMR (CDCI3) : 6 5.12 (d, IH, J«=2.0 Hz); 4.60 (d, IH, J=2.0 
Hz); 3.62-3.72 (m, 2H) ; 3.55 (s, 3H) ; 3.37-3.45 (m, 2H) ; 1.92 
(d, IH, J=6.4 Hz); 1.58-1.84 (m, 14H) ; 1.56 (s, 3H) ; 1.51 (d, 
IH, J=6.4 Hz) . 

15 

Step B; 

To a solution of 7 a-methoxy-2-spiro(2'- 
spirocyclopentyl) -cyclopropyl-3-methyl-3-cephem-4-piperidine 
carboxamide-1, 1-dioxide (2.41 g, 5.9 mmol) in anhydrous 

20 carbon tetrachloride (60 ml) was added N-bromosuccinimide 
(1.16 g, 6.5 mmol) followed by azoisobutyronitrile (0.097 g, 
0.59 mmol) . The reaction mixture was refluxed at 80*C for 24 
hr., cooled to room temperature and filtered through Celite. 
The filtrate was evaporated in vacuo to give a crude mass 

25 which was purified over a silica gel column. Gradient 
elution of the column with a mixture of hexane-ethyl acetate 
gave the pure product, 7 a-methoxy-2-spiro (2' -spirocyclo- 
pentyl) cyclopropyl-3-bromomethyl-3-cephem-4 -piper idine 
carboxamide-l,l-dioxide (1.31 g, 45.5%). ^H NMR (CDCI3) : & 

30 5.16 (d, IH, J«2.2 Hz); 4.62 (d, IH, J=2.0 Hz); 4.06 (d, IH, 
J=11.6 Hz); 3.78-3.90 (m, IH) ; 3.56 (s, 3H) ; 3.56-3.65 (m, 
2H); 3.43 (d, IH, J=11.6Hz); 3.32-3.35 (m, IH) ; 2.14 (d, IH, 
J=7.1 Hz); 1.65 (d, IH, J=7.1 Hz); 1.56-2.00 (m, 14H) . 



30 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



Step C; 

To a solution of 7 a-inethoxy-2-spiro(2'- 
spirocyclopcntyl)-cyclopropyl-3-bromomethyl-3-cephein-4- 
5 piperidine carboxamide-l, 1-dioxide (Example 13, Step B, 0*5 
g, 1.03 mmol) in acetonitrile (15 ml) was added 2-inethyl-3- 
mercapto-5-oxo-6-diphenylmethoxyl,2,4-tria2ine (0.67g, 2.05 
mmol) followed by triethylamine (0.228 g, 2.3 mmol). The 
reaction mixture was stirred at room temperature for 16 hr. 

10 and acetonitrile was evaporated in vacuo . The crude product 
was purified over a silica gel column using hexane-ethyl 
acetate mixture as eluant. The mass of the pure product was 
0.417 g (56%). NMR (CDCI3) : S 7.26-7.46 (m, lOH) ; 6.75 

(s, IH); 5.14 (br, s, IH) ; 4.62 (d, IH, J=2.0 Hz); 3.61 (s, 

15 3H); 3.56 (s, 3H); 3.56-3.90 (m, 4H) ; 3.24-3.47 (br, m, 2H) ; 
1.58-2.05 (m, 16H) . 

Step p; 

To a stirred and ice-cooled solution of 7 a- 

20 methoxy-2-spiro-(2'-spirocyclopentyl)cyclopropyl-3-[ (2,5- 
dihydro-6-diphenyl-methoxy-2-methyl-5-oxo-l,2,4-tria2in-3- 
yl)thiomethyl]-3-cephem-4-piperidinecarboxamide-l,l-dioxide 
(Example 13, Step C, 377 mg, 0.52 mmol) in anhydrous 
methylene chloride (4.5 ml) was added dry anisole (8.5 ml) 

25 followed by trif luoroacetic acid (13 ml). The reaction 
mixture was stirred at 0*'C for 1 hr. and evaporated in vacuo . 
The gummy residue was digested with a mixture of hexane-ether 
(2:1). The precipitated solid was dissolved in methylene 
chloride and evaporated in vacuo to give pure compound, 7 a- 

30 methoxy-2-spiro (2 ' -spirocyclo-pentyl) cyclopropyl-3- [ (2,5- 
dihydro-6-hydroxy-2-methyl-5-oxo-l , 2 , 4-tria2in-3-yl) 
thiomethyl] -3 -cephem-4 -piperidine carboxamide-1, l-dioxide, as 
a foam (260 mg, 89%). NMR (CDCI3) : S 5.15 (d, IH, J=2.0 
H2); 4.64 (d, IH, J=2.0 H2) ; 3.74 (s, 3H) ; 3.57 (s, 3H) ; 

35 3.57-3.85 (m, 4H) ; 3.37-3.47 (br, m, 2H) ; 1.98 (d, IH, J=6.8 
H2); 1.50-2.00 (m, 15H) . 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



EXAMPLE 14 

7 , 7'-Dihvdro-2"3Piro (2 ^ -spirocryclopentvl) cvclopropvl-3*>inethvl- 
3-cephein-4- T ^ (4-carboyv) piper idinel carboxamidel l . l^dioxide 

5 

Step A: 

To a suspension of anhydrous sodixam sulphate (40 g) 
in ether (200 ml) cooled to -10**C was added silver oxide 
(12*45 g) , followed by cyclopentanone hydrazone (5.28 g, 53.7 

10 mrnol) . A solution of potassium hydroxide in methanol (2 ml) 
was added dropwise. Within 5 minutes a deep red color was 
developed. The reaction mixture was filtered quickly thorugh 
a small bed of Celite. To the filtrate, a solution of 
benzhydryl 7 , 7-dihydro-2-methylene-3-methyl-3-cephem-4- 

15 carboxylate-1, 1-dioxide (11 g, 26.9 mmol) , dissolved in a 
mixture of methylene chloride and ethyl acetate was added. 
The mixture was stirred at room temperature for 1 hr. 
Evaporation of the solvent under reduced pressure gave a 
white solid which, upon purification by silica gel column 

20 chromatography using a mixture of hexane-ethyl acetate as 
eluant, gave benzhydryl 7 , 7-dihydro-2-spiro (2 ' • 
spirocyclopenty 1 ) -cyclopropy 1-3 -methyl -3 - cephem-4 - 
carboxylate-1, 1-dioxide (4.60 g, 35.1%). NMR (CDCI3) : S 

7.26-7.38 (m, lOH) ; 6.99 (s, IH) ; 4.65 (dd, IH, J=2.4 and 4.9 

25 Hz); 3.60 (dd, IH, J=2.0 and 15.0 Hz); 3.42 (dd, IH, J=4.0 
and 15.0 Hz); 1.71 (s, 3H) ; 1.95 (d, IH, J=6.6 Hz); 1.60 <d, 
IH, J=6.6 Hz); 1.54-1.96 (m, 8H) . 

Step B: 

30 A mixture of benzhydryl 7,7-dihydro-2-spiro(2'- 

spirocyclo-penty 1 ) cyclopr opy 1-3 -methy 1-3 - cephem-4 - 
carboxylate-1, 1-dioxide (3.0 g, 6.3 mmol) in methylene 
chloride (25 ml), anhydrous anisole (50 ml) and 
trif luoroacetic acid (75 ml) was stirred under nitrogen 

35 atmosphere at 0*»C for 1 hr. The reaction mixture was 
concentrated under reduced pressure and the residue was 
digested with hexane. The precipitated solid was filtered 
off, washed with hexane and air dried to give a white solid 

32 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



10 



(1.89 g, 96.4%). NMR (CDCI3) : ^ 6-45 (br, s, IH) ; 4.70 

(br, s, IH); 3.44-3.55 (m, 2H) ; 1.91 (s, 3H) ; 1.67-2.00 
(m, lOH) . 

Step C; 

To a stirred and ice-cooled solution of 7,7- 
dihydro-2-spiro(2'-spirocyclopentyl)cyclopropyl-3-inethyl-3- 
cephem-4-carboxylate-l,l-dioxide (Example 14, Step B, 1.29 g, 
4.14 mmol) in anhydrous methylene chloride (25 ml) under 
nitrogen was added oxalyl chloride (0.684 g, 5.4 mmol) 
followed by two drops of DMF. The reaction mixture was 
stirred at room temperature for 1 hr. The volatile materials 
were removed under reduced pressure. The residue was 
dissolved in anhydrous methylene chloride and stirred under 
15 nitrogen. To this solution, a solution of 4-tert- 
butoxycarbonyl piperidine (0.768 g, 4.14 mmol) in methylene 
chloride (1 ml) was added in one portion followed by triethyl 
amine (0.44 g, 4.4 mmol). The reaction mixture was allowed 
to stir at room temperature for 1 hr., diluted with methylene 
20 chloride, washed successively with water, sodium bicarbonate 
solution and brine. The organic layer was dried over 
anhydrous sodium sulphate, evaporated in vacuo to give the 
crude product which was purified by silica gel column 
chromatography using a mixture of hexane-ethyl acetate (1:4) 
25 as eluant. The pure compound, 7,7-dihydro-2-spiro(2'- 
spirocyclopentyl)cyclopropyl-3-methyl-3-cephem-4-[ { (4-t- 
butoxycarbonyl) piperidine }carboxamide] -1 , l-dioxide was 
obtained as a foam (1.14 g, 60%). NMR (CDCI3) : 6 4.66 

(dd, IH, J=2.4 and 4.6 Hz); 4.28-4.53 (m, IH) ; 3.75-3.97 (m, 
30 IH); 3.53-3.67 (m, IH) ; 3.37 (dd, IH, J=5.0 and 16.2 Hz); 
2.87-3.25 (m, 2H); 2.35-2.55 (m, IH) ; 1.53 and 1.59 (2s, 3H) ; 
1.50-2.10 (m, 14H) ; 1.45 (s, 9H) . 

Step D: 

35 A mixture of 7,7-dihydro-2-spiro(2'-spirocyclo- 

pentyl) cyclopropyl-3-methyl-3-cephem-4- [ { (4-tert- 
butoxycarbonyl) piperidine}carboxamide]-l, i-dioxide (Example 



33 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



14, Step C, 0.4 g, 0.84 mmol) and anhydrous formic acid (15 
ml) was stirred under nitrogen at 60«C for 2 hr. The 
reaction mixture was concentrated under reduced pressure and 
the residue was washed several times with hexane followed by 
5 a mixture of hexane-ether (1:1). The precipitated solid was 
filtered off and air dried to give the desired product (0.34 
g, 96%). NMR (CDCI3) : S 4.65 (dd, IH, J=2.4 and 5.0 Hz) ; 
4.20-4.60 (m, IH) ; 3.75-4.00 (m, IH) ; 3.59 (dd, IH, J=2.4 and 
16 Hz); 3.38 (dd, IH, J=5.0 and 16 Hz); 3.10-3.30 (m, 2H) ; 
10 2.90-3.10 (m, IH) ; 2.50-2.75 (m, IH) ; 1.53 and 1.59 (2s, 
3H); 1.50-2.20 (m, 13H) . 

EXAMPLE IS 

7 ,7-Dihvdro-2-spiro (2 ^-spirocvclopentvl) cyclopropvl^3-methyl* 
15 3-cephem-4-r (N-methvl-W-acetic acid) 1 carboxamidel^ l^dioxide 



Step A: 

To a stirred and ice-cooled solution of 7,7- 
dihydro-2-spiro(2'-spirocyclopentyl)cyclopropyl-3-methyl-3- 

20 cephem-4-carboxylic acid -1,1-dioxide (Example 14, Step B, 
0.51 g, 1.64 mmol) in anhydrous methylene chloride (15 ml) 
under nitrogen was added oxalyl chloride (0.27 g, 2.13 mmol) 
followed by two drops of DMF. The reaction mixture was then 
stirred at room temperature for 1 hr. and the volatile 

25 materials were removed under reduced pressure. The residue 
was redissolved in methylene chloride (15 ml) and stirred 
under nitrogen. A solution of tert-butylsarcosine (0.238 g, 
1.64 mmol) in methylene chloride (1 ml) was added followed by 
triethylamine (0.174 g, 1.72 mmol) and the reaction mixture 

30 was stirred at room temperature for 1 hr. The mixture was 
diluted with methylene chloride (50 ml) and washed 
successively with water, sodium bicarbonate solution and 
brine. The organic layer was dried over anhydrous sodiiim 
sulphate and evaporated in vacuo to give the crude product 

35 which was purified by silica gel column chromatography using 
a mixture of hexane-ethyl acetate (3:2) as eluant. The pure 
compound, 7 , 7-dihydro-2-spiro ( 2 ' -spirocyclopentyl) 
cyclopropyl-3-methyl-3-cephem-4- [ (N-methyl-N-t-butoxy- 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



carbonylmethyl) ]carboxamide-l, 1-dioxide was obtained as a 
white foam (0.33 g, 46%). NMR (CDCI3) : S 4.89 (d, IH, 

J=17.0 H2); 4.66 (dd, IH, J=2.5 and 5.03 Hz); 3.43 (d, IH, 
J=17.0 Hz) 3.61 (dd, IH, J=2.5 and 16.2 Hz); 3.38 (dd, IH, 
5 J=5.0 and 16.2 Hz); 3.07 and 3.09 (2s, 3H) ; 1.53-2.05 
(m, 9H); 1.90 (d, IH, J=6.3 Hz); 1.74 (s, 3H) ; 1.47 (s, 9H) . 

Step B: 

A mixture of 7, 7-dihydro-2-spiro(2 '-spiro- 
cyclopentyl) -cyclopropyl-3-inethyl-3-cephein-4-[ (N-methyl-N-t- 
butoxycarbonyl-methyl) ] carboxamide-l , 1-dioxide (Example 15 , 
Step A, 0.3 g, 0.68 mmol) and anhydrous formic acid (10 ml) 
was stirred under nitrogen at 50 ®C for 3 hr. The reaction 
mixture was concentrated under reduced pressure and the 
residue was digested several times with hexane followed by a 
mixture of hexane-ether (3:2). The solid was filtered off 
and dried to give the pure product (0.19 g, 73%). *H NMR 
(CDCI3): 6 5.20 (br, s, IH); 4.69-4.75 (br, m, 2H) ; 3.35- 
3.91 (m, 3H); 3.13 (s, 3H); 1.68 (s, 3H) ; 1.57-1.90 (m, lOH) . 

EXAMPLE 16 

7a-Methoyv-2-spiro(2 ^-spirocyclopentvl) cvclopropvl*3-r f2.S'' 
dihvdro-6-hvdroxv-2-methYl-S-oxo*l, 2 . 4-triazin-3-vl> - 
thiomethvl 1 -3 -cephem-4- f / ( 4-carboxv) pjperidine^ eaybovam^ i^o] - 
1,1-dioxide 

Step A; 

To a mixture of 7 a-methoxy-2-spiro(2'- 
spirocyclopentyl)-cyclopropyl-3-methyl-3-cephem-4-[ { (4-t- 
30 butoxycarbonyl) -piperidine}carboxamide]-l, i-dioxide (Example 
7, Step B, 5.91 g, 11.6 mmol) and N-bromosuccinimide (2.38 g, 
13.4 mmol) in carbon tetrachloride (200 ml) was added AIBN 
(0.19 g, 1.16 mmol) and the reaction mixture was heated at 
lOO^C for 24 hr. The reaction mixture was cooled and 
35 filtered through Celite. The filtrate was concentrated under 
reduced pressure and the crude product was purified by silica 
gel column chromatography using a mixture of hexane-ethyl 



10 



15 



20 



25 



35 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



acetate (7:3) to give the pure product (2,49 g, 37%). NMR 
(CDCI3) : 6 5.15 and 5.17 (2d, IH, J=2.3 Hz each); 4.62 (d, 
IH, J=1.7 Hz); 4.20-4.45 (m, IH) ; 3.98-4.17 (m, IH) ; 3.60- 
3.75 (m, IH); 3.56 (s, 3H) ; 3.42 (d, 2H, J=11.6 Hz); 2.95- 
5 3.15 (m, IH) ; 2.35-2.55 (m, IH) ; 1.50-2.15 (m, 14H) ; 1.45 (s, 
9H) . 

Step B: 

To a solution of 7 a-inethoxy-2-spiro (2 
10 spirocyclopentyl) -cyclopropyl-3-broinoinethyl-3-cephein-4-[ { (4- 
t-but oxy car bony 1) -piperidine}carboxamide] -l , 1 -dioxide 
(Example 16, Step A, 1.5 g, 2.6 mmol) in acetonitrile (30 ml) 
was added 2-methyl-3-mercapto-5-oxo-6-diphenylinethoxy-l,2,4- 
triazine (2-08 g, 6.4 mmol) followed by triethylamine (0.797 
15 g, 7.8 mmol). The mixture was stirred at room temperature 
for 72 hours. Solvent was removed under reduced pressure and 
the residue was purified by silica gel column chromatography 
using a mixture of hexane-ethyl acetate (1:1) to give the 
pure product (0.88 g, 41.5%). ^H NMR (CDCI3) : S 7.24-7.45 
20 (m, lOH) ; 6.75 (s, IH) ; 5.14 (d, IH, J=2.0 Hz); 4.62 (d, IH, 
J=2.0 Hz); 4.20-4.40 (m, IH) ; 3.50-3.90 (m, 3H) ; 3.61 (s, 
3H) ; 3.55 (s, 3H) ; 2.90-3.30 (m, 2H) ; 2.30-2.55 (br, m, IH) ; 
1.50-2.00 (m, 14H) ; 1.45 and 1.39 (2s, 9H) . 

25 Step C: 

To a stirred and ice-cooled solution of 7 a- 
methoxy-2-spiro (2 ' -spirocyclopentyl ) cyclopropyl-3- [ (2,5- 
dihydro-6-diphenylmethoxy-2-methyl-5-oxo-l , 2 , 4-triazin-3- 
y 1 ) thiomethy 1 ] -3 -cephem-4 - [ { ( 4 -t-butoxycarbony 1 ) piper idine } 

30 carboxamide]-l,l-dioxide (Example 16, Step B, 0.836 g, 
1 mmol) in dry methylene chloride (11 ml) was added dry 
anisole (20 ml) followed by trif luoroacetic acid (33 ml) . 
The mixture was stirred at 0*»C for 1 hr. and concentrated 
under reduced pressure- The residue was dissolved in small 

35 volume of methylene chloride and diluted with ether. The 
precipitated solid was filtered off and washed with hexane to 



36 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



give the title compound as a white powder (0.579 g, 95%). 
NMR (CDCI3): S 5.16 (br, s, IH); 4.66 (br, s, IH) ; 4.30-4.45 
(m, IH) ; 3.75 and 3.77 (2s, 3H) ; 3.56 (s, 3H) ; 3.40-4.00 (m, 
5 3H); 3.00-3.35 (m, 2H) ; 2.50-2.65 (m, IH) ; 1.50-2.15 (m, 
14H) . 

EXAMPLE 17 

7 a-Methoxv-2-sDiro (2 ^-spirocvclopentvl) cvcloprcpvl->3'"inethvl- 

10 3-cephem-4-inethvlcarbonYl'*l* l^dioxide 

To a stirred and ice-cooled solution of 7 a- 
inethoxy-2-spiro- (2 '-spirocyclopentyl) cyclopropyl-3-methyl-3- 
cephein-4-carboxylic acid-1, 1-dioxide (Example 7, Step A, 1.0 
g, 2.929 mmol) in dry methylene chloride (20 ml) was added 

15 oxalyl chloride (332 /il, 3.808 mmol) followed by two drops of 
DMF, the reaction mixture was stirred at ice temperature for 
15 min. and then at room temperature for 3 hr. Solvent was 
removed under reduced pressure. The residue was dissolved in 
dry THF (15 ml), cooled to -78*>C, cuprous iodide (587 mg, 

20 3.076 mmol) was added in one portion followed by methyl 
magnesium bromide (1.27 ml, 3 (M) in ether); cooling bath was 
removed and the mixture was stirred for 2.5 hr. Saturated 
NH4CI (1 ml) was added slowly to the mixture and volatile 
materials were removed under reduced pressure. The residue 

25 was suspended in methylene chloride and filtered through a 
small bed of Celite. The filtrate was washed with aq. NaHCOj 
solution, brine, dried over anhydrous sodium sulphate and 
concentrated. The crude product (800 mg) was chromatographed 
on a silica gel column using hexane-ethyl acetate (2:1) 

30 mixture as eluant to afford a yellow foam which on treatment 
with ether gave the pure compound, 7 a-methoxy-2-spiro(2'- 
spirocyclopentyl) cyclo-propy 1-3 -methy l-3-cephem-4- 
methylcarbonyl-l, 1-dioxide as a white foam (418 mg, 50% 
yield). ^H NMR (CDCI3) : 5.12 (d, IH, J^l.5 Hz); 4.62 (d, 

35 IH, J=1.5 Hz); 3.58 (s, 3H) ; 2.48 (s, 3H) ; 1.98 (d, IH, J=6.7 
Hz); 1.72 (s, 3H); 1.61 (d, IH, J=6.7 Hz); 1.50-1.99 (m, 8H) . 



SUBSTITUTE SHEET 



wo 95/15966 PCT/CA94/00669 



EXAMPLE 18 

7 a-Methoxv-2-spiro (2 ^-spirocvclopentYl) cyclopropvl-3*methvl*- 
3 -cephem-4 f 4 ^ - (methvl ) --4 ^ - (methoxvimino) 1 -1 . l-dioxide 

5 To a stirred suspension of 7 a-inethoxy-2-spiro(2 '- 

spirocyclo-penty 1 ) cyclopropyl-3 -methy l-3-cepheIn-4- 
lnethylcarbonyl-l,l-dioxide (Example 17, 418 mg, 1.232 mmol) 
in a mixture of THF (8 ml) and ethanol (5 ml) was added 
pyridine (204 ^1, 2.524 mmol) and methoxylamine hydrochloride 

10 (216 mg, 2.537 mmol). The mixture was stirred at room 
temperature for 4 days and then concentrated under reduced 
pressure. The residue was dissolved in EtOAc, then washed 
with water, dilute HCl, brine, dried over anhydrous Na2S04, 
filtered and then concentrated to give a yellow foam (310 

15 mg) . The crude material was purified over a silica gel 
column using hexane-ethyl acetate mixture as eluant. 

The fast e luting component was the minor isomer of 
4-t4'- (methyl) -4 '-(methoxyimino) ] ; 4 mg. 

NMR (CDCI3): 6 4.84 (d, IH, J=1.6 Hz); 4.53 (d, 

20 IH, J=1.6H2); 3.95 (s, 3H) ; 3.58 (s, 3H) ; 2.03 (s, 3H) ; 1.92 
(s, 3H); 1.79 (d, IH, J=6.3 Hz); 1.50-1.90 (m, 8H) ; 1.43 (d, 
IH, J=6.3 Hz) . 

The second major component was the major isomer of 
4-[4'-(methyl)-4-(methoxyimino) ] ; 110 mg. 

25 ^H NMR (CDCI3): S 5.09 (d, IH, J=1.9 Hz) ; 4.57 (d, 

IH, J=1.9H2); 3.95 (s, 3H) ; 3.55 (s, 3H) ; 2.05 (s, 3H) ; 1.92 
(d, IH, J=6.5 Hz); 1.58 (s, 3H) ; 1.52 (d, IH, J=6.5 Hz); 
1.50-1.90 (m, 8H). 

30 EXAMPLE 19 

7 Q-Methoxy*2-spiro (2 ^-spirocvclopentvl) cvclopropvl-a^methvl- 
3*cephem-4'*r f (4-*carboxamide}piperidine>carboxamidel *1, 1^ 
dioxide 

By using the same procedure as described in Example 
35 7, Step B, but using isonipecotamide instead of 4-t- 
butoxycarbonyl piperidine, the title compound was prepared. 



38 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



NMR (CDCI3): 6 5.73 (br, 2H) ; 5.12 (d, IH, J-1.6 Hz) ; 
4.47-4.74 (m, IH); 4.61 and 4.62 (2d, IH, J=2.0 Hz); 3.70- 
4.00 (m, IH); 3.55 and 3.54 (2s, 3H) ; 2.70-3.20 (m, 2H) ; 
2.30-2.50 (m, IH) ; 1.53-1.98 (m, 14H) ; 1.59 and 1.53 
(2s, 3H) . 

EXAMPLE 20 

7 tt-Methoxv-2>SDiro (2 ^-splr ocvclopentvl) evciloprcpY^^-^^methvl^ 
3-cephem-4- r f ( 4-c vano) piper idine^ carboxamidel -1 . l-dioxide 

A solution of 7 aE-niethoxy-2-spiro(2'-spiro- 
cyclopentyl) cyclo-propy 1-3 -methyl -3 -cephein-4- [ { (4- 
carboxainide)piperidine}-carboxamide]-l,i-dioxide (Example 19, 
100 mg, 0.23 mmol) in 5 ml of acetic anhydride was heated at 
110-115 *»C for 18 hr. The solvent was removed under reduced 
pressure and the residue was dissolved in methylene chloride, 
washed with water aqueous NaHC03 solution, brine, dried over 
anhydrous Na2S04, filtered and concentrated to give a light 
yellow foam, 75 mg (75%). ^H NMR (CDCI3) : ^ 5-13 and 5.12 
(2d, IH, J=1.9 Hz); 4.61 (d, IH, J=1.9 Hz); 4.00-4.20 
(m, IH); 3.20-3.70 (m, 3H) ; 3.54 and 3.56 (2s, 3H) ; 2.90-3.00 
(m, IH); 1.60-2.10 (m, 14H) ; 1.53 and 1.56 (2s, 3H) . 

EXAMPLE 21 

7 a-Methoxv-2-9Pir o (2 ^-spirocvclopentvl) evelopropvl-a-methvl- 
3-cephem-4 - r f ( 4-liv drcxvl pjperidinei carboxamidel -1 . i-dioxide 
By using the same procedure as described in Example 
7, Step B, but using 4-hydroxy piperidine instead of 4-t- 
butoxycarbonyl piperidine, the title compound was prepared. 
30 ^H NMR (CDCI3): 6 5.12 and 5.13 (2d, IH, J=1.7 Hz); 4.61 (d, 
IH, J=1.7 Hz); 3.90-4.30 (m, 2H) ; 3.60-3.85 (m, IH) ; 3.53 and 
3.55 (2s, 3H) ; 3.15-3.40 (m, 2H) ; 1.48-2.00 (m, 14H) ; 1.54 
and 1.57 (2s, 3H) . 



10 



15 



20 



39 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



EXAMPLE 22 

7 a-MethoxY-2"3piro (2 ^-spirocvclopentvl) cvcloproDVl"3'"methYl- 
3"cephem-4-rf (4-hvdroyyethvl)piperidinel carboxamidel 
5 dioxide 

By using the same procedure as described in Example 
7, Step B, but using 4 -hydroxy ethyl piperidine instead of 4- 
t-butoxy-carbonyl piperidine, the title compound was 
prepared. NMR (CDCI3) : S 5.12 (2d, IH, J=1.5 Hz); 4.55- 

10 4.70 (m, IH) ; 4.62 and 4.64 (2d, IH, J=1.9 Hz); 3.75-3.98 (m, 
IH) ; 3.71 (t, 2H, J=6.4 Hz) ; 3.53 and 3.54 (2s, 3H) ; 2.64- 
3.15 (m, 2H) ; 1.50-2.18 (m, 17H) ; 1.52 and 1.60 (2s, 3H) . 

EXAMPLE 23 

15 7 tt-Methoxv-2-spiro (2 ^-spirocvclopentvl) cvclopropvl*3-methvl- 
3**cephem-4^r / r4-bromoethvl) piperidine^carboxamidel 1* 
dioxide 

Bromine (23 ^1, 0.45 mmol) was added to a 
vigorously stirred solution of triphenylphosphine (123 mg, 

20 0.468 mmol) in 3 ml of dry CH3CN. A solution of 7 a-methoxy- 
2-spiro (2 '-spirocyclo-pentyl) cyclopropyl-3-methyl-3-cephem-4- 
[ { (4-hydroxyethyl) -piperidine}carboxamide] -1, 1-dioxide 
(Example 22, 200 mg, 0.442 mmol) in 2 ml of CH3CN was added 
to the mixture and the mixture was stirred at room 

25 temperature overnight. Solvent was removed under reduced 
pressure and the residue was purified over a silica gel 
column using hexane-ethyl acetate mixture as eluant. The 
title compound was obtained as a light yellow foam, 220 mg 
(97%). ^H NMR (CDCI3): 6 5.12 (d, IH, J=l,9 Hz) ; 4.55-4.73 

30 (m, IH) ; 4.59 and 4.61 (2d, IH, J=2.0 Hz); 3.70-3.90 (m, IH) ; 

3.54 (2s, 3H) ; 3.38-3.48 (m, 2H) ; 2.60-3.20 (m, 2H) ; 1.42- 
1.98 (m, 17H); 1.51 and 1.59 (2s, 3H) . 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



EXAMPLE 24 

7 a-Methoxv-2*3Biro (2 ' -spirocvclopentvl) cvclopropvl^^a-methvl* 
3-cephem*4- r f r 4-diethoxvpho3Pbinvlethvl ) piperidin^} 
5 carboxamidel*!^ l-'dicxide 

A solution of 7 a-inethoxy-2-spiro(2'-spiro- 
cyclopentyl) - cyclopropyl-3-methyl~3-cephein-4- [ { (4* 
broinoethyl)piperidine}-carboxainide]-l,i-dioxide (Example 23, 
660 mg, 1.28 mmol) in 4.7 ml of triethyl phosphite was heated 

10 at 110«C for 18 hr. Excess triethyl phosphite was removed 
under reduced pressure and the residue was purified over a 
silica gel column using ethyl acetate-methanol mixture as 
eluant to afford the product as a white foam; 300 mg (41%). 
NMR (CDCI3): S 5.12 and 5.13 (2d, IH, J=1.7 Hz); 4.56- 

15 4.70 (m, IH) ; 4.60 and 4.61 (2d, IH, J=1.9H2); 4.02-4.17 (m, 
4H) ; 3.70-3.95 (m, IH) ; 3.54 and 3.55 (2s, 3H) ; 2.58-3.15 (m, 
2H); 1.50-2.00 (m, 19H) ; 1.51 and 1.59 (2s, 3H) ; 1.32 (t, 6H, 
J=7.0 Hz) . 



41 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



What is claimed is: 

1. A 7o-substituted 2-spiro(2 '-spirocycloalkyl) 
cyclopropyl cephalosporin sulfone of the structural formula 
5 (I) 

O o 



10 




wherein Rj is COOR4, COR5, C(R5)=N-OR6 in which OR^ 
is in the "syn" configuration or the "anti" configuration, 
15 CONRyRg; 

R4 is hydrogen; Cj^ branched or straight chain 
alkyl; alkenyl; C^^ alkanoyl C^^ alkyl; C^^ alkanoyloxy 

Cj^alkyl; Cj^ alkoxy Cj^ alkyl; halogenated Cj^ alkyl; -CHj- 
phenyl; -CH (phenyl) j; the phenyl groups being unsubstituted 
20 or substituted with at least one of Cj^ alkyl, Cj^ alkoxy, 
and nitro; 

R5 is hydrogen; Cj^ straight or branched chain 
alkyl; alkenyl; Cj^alkynyl; €3^ cycloalkyl; C^jo aryl; 

aralkyl; a monocyclic or fused polycyclic saturated or 

25 unsaturated heterocyclic group containing from 1 to 4 of any 
one or more of the heteroatoms selected from N, S and O; 

R^ is hydrogen or a hydrocarbon residue which is 
unsubstituted or substituted at one or more positions with 
one or more hydrocarbon residue substituents which are the 

30 same or different; 

R7 and Rg are the same or different, and are 
selected from hydrogen; C^^ alkyl; C^^ cycloalkyl; C^jq aryl; 
€7,12 aralkyl; Cj^ alkoxy car bony 1 alkyl; carboxyl Cj^ 

alkyl; a five or six-membered heterocyclic group containing 

35 from 1 to 4 of any one or more of the heteroatoms selected 
from N, S and O; 

42 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



or R7 and Rg in the formula CONR^Rg may combine to 
form a heterocyclic ring component which may contain at least 
one other heteroatom selected from N, S and said 
5 heterocyclic ring component being unsubstituted or 
substituted, with one or more substituents which are the same 
or different, at the carbon atom or at the nitrogen atom 
which is different from the nitrogen atom having a binding 
arm with the CO group in the formula CONR^Rg; 
10 R2 is hydrogen, chloro, bromo, fluoro, hydroxy, Cj^ 

alkoxy, trif luoromethyl, Cj^ alkyl, alkenyl, alkynyl, 
Cj^ cycloalkyl, or -CH2X 

wherein X is hydroxy, chloro, bromo, Cj^ alkoxy, 
Cj^ alkanoyloxy, -OCONHj, -OCONHCj^ alkyl, amino, -NHCj^ 
15 alkyl, -N(Ci^ alkyl) 2, or a quaternary ammonium group; 

or R2 is -CH2YR9, wherein Y is S or N, wherein when 
Y is sulfur, R9 is hydrogen or the residue of a thiol 
compound obtained by omitting the -SH group from a thiol 
compound, and when Y is nitrogen, R9 is the residue of a 
20 nitrogen-containing heterocyclic ring system in which Y 
together with R9 forms a heterocyclic ring; 

n is 0, 1, 2, 3 or 4; 

R3 is hydrogen or Cj^ alkoxy; 

or a pharmaceutically acceptable salt or ester 

25 thereof. 



2. A 7 a-substituted 2 ' -spirocycloalkyl-2- 
spirocyclopropyl cephalosporin sulfone of formula (I) 



30 



^ vZV (CH2)n 



(I) 



35 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



Wherein Rj is COOR4, COR5, C(R5)=N-OR6, C0NR7Rg; 

R4 is hydrogen, C^^ alkyl or -CH (phenyl) 2 
R5 is hydrogen, C^^ alkyl or Cg.ioaryl 
is hydrogen or C^^ alkyl 
5 R7 and Rg are the sane or different and are 

hydrogen, Cj^ alkyl or carboxyl Cj^ alkyl 

or NR7Rg in the formula CONR^Rg is monocyclic 
heterocyclic ring group which has 1 or 2 nitrogen atom as 
hetero atom in its ring structure and which is unsubstituted 
10 or substituted with hydroxy, cyano, carboxamide, -COOCj^ 
alkyl, -COOH or Cj^alkyl which is unsubstituted or 
substituted by hydroxy, halogen, diethylphosphinyl, -GOOCj^ 
alkyl or -COOH 

R2 is Cj^alkyl which is unsubstituted or 
15 substituted by halogen or Cj^alkanoyloxy or Rj is -CH2SR9; 

R9 is a heterocyclic ring group which is 
unsubstituted or substituted with one or more radicals 
selected from C|^alkyl, -COOH, -COOCj^alkyl, -OH, -CHjCOOH, 
-CH2CO0Ci^ alkyl or halogen; 
20 R3 is hydrogen or Cj^alkoxy 

n is 0, 1, 2, 3, or 4, 
or a pharmaceutical ly acceptable salt thereof. 

3. A compound according to claim 1 which is 
25 selected from the group consisting of: 

t-butyl-7 o-methoxy-2-spiro(2 '-spirocyclopentyl) 
cyclopropyl-3-methyl-3-cephem-4-carboxylate-l, l-dioxide; 

30 t-butyl-7 a-methoxy-2-spiro (2 ' -spirocyclohexyl) 

cyclopropyl-3-methyl-3-cephem-4-carboxylate-l , l-dioxide; 

7 Q-Methoxy-2-spiro (2 ' -spirocyclop^ntyl ) 
cyclopropyl-3-methyl-3-cephem-4-carboxylic acid-1, l-dioxide 
35 and its sodium salt; 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



7 a-Methoxy-2-spiro (2 ' -spirocyclohexyl) cyclopropyl^ 
3-methyl-3-cephein-4-carboxylic acid-l, i-dioxide and its 
sodium salt; 

5 

t-butyl-7 a-methoxy-2--spiro (2 ' -spirocyclopentyl) 

cyclopropyl-3-acetoxyinethyl-3-cephein-4-carboxylate-l , i- 
dioxide; 

7 or-inethoxy-2-spiro (2 '-spirocyclopentyl) 
cyclopropyl-3-inethyl-3-cephein-4-[{(4-N-inethyl)piperazine} 
carboxainide]-l,l-dioxide and its hydrochloride salt; 

7 o-aethoxy2-spiro (2 '-spirocyclopentyl) 
15 cyclopropyl-3-©ethyl-3-cepheni-4-[ { (4-t-butoxycarbonyl) 
piper idine } carboxamide ] - l , 1-dioxide ; 

7 a-inethoxy-2-spiro(2 ' -spirocyclopentyl) 

cyclopropyl-3-inethyl-3-cephem-4-t{ (4-carboxy)piperidine} 
20 carboxamide]-!, 1-dioxide and its sodium salt; 

7 a-methoxy-2-spiro (2 ' -spirocyclopentyl) 

cyclopropyl-3-methyl-3-cephem-4-t{ (4-N-t-butoxycarbonyl- 
methyl ) piperazine} carboxamide] -1 , 1-dioxide ; 

25 

7 o-inethoxy-2-spiro (2 '-spirocyclopentyl) 
cyclopropyl-3-methyl-3-cephem-4-[{ (4-N-acetic acid) 
piperazine}carboxamide]-l,i-dioxide and its sodium salt; 

30 7 a-methoxy-2-spiro(2'-spirocyclohexyl)cyclopropyl- 

3 -methy 1-3 -cephem-4 -[{( 4 -N-methyl ) p iper a z ine } carboxamide ] - 
1, 1-dioxide and its hydrochloride salt; 

7 a-methoxy-2-spiro (2 ' -spirocyclohexyl) cyclopropyl- 
35 3-methyl-3-cephero-4- [ { (4-N-t-butoxycarbonylmethyl) piperazine} 
carboxamide ] -1 , 1-dioxide ; 



SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



7 a-inethoxy-2-spiro(2'-spirocyclohexyl)cyclopropyl- 
3-methyl-3-cephein-4-[ { {4-Nracetic acid) piperazine} 
carboxamidej-l, 1-dioxlde and its sodium salt; 

5 

t-butyl-7 a-inethoxy-2-spiro(2 '-spirocyclopentyl) 
cyclopropyl-3-broinomethyl-3-cephein-4-carboxylate-l , 1-dioxide ; 

t-butyl-7 a-inethoxy-2-spiro(2 '-spirocyclopentyl) 
10 cyclopropyl-3- [ (2 , 5-dihydro-6-hydroxy-2-inethyl-5-oxo-l ,2,4- 
triazin-S-yl) thiomethyl] -3 -cephein-4-carboxylate-l, 1-dioxide 
and its sodiuia salt; 

t-butyl-7 a-inethoxy-2-spiro(2 '-spirocyclopentyl) 
15 cyclopropyl-3 - [ ( l-methy 1-1 ,2,3, 4-tetrazole-5-yl) thiomethyl ] - 
3 -cephein-4-carboxylate-l, 1-dioxide; 

t-butyl-7 Q-inethoxy-2-spiro (2 '-spirocyclopentyl) 
cyclopropyl-3- [ {2-inethyl-l, 3 , 4-thiadiazole-5-yl) thiomethyl] - 
20 3-cephem-4-carboxylate-l, 1-dioxide; 

t-butyl-7 a-methoxy-2-spiro(2 '-spirocyclopentyl) 
cyclopropyl-3- [ {pyridyl-2-yl) thiomethyl ] -3-cephem-4- 
carboxy late-1 , 1-dioxide ; 

25 

t-butyl-7 a-methoxy-2 -spiro ( 2 ' -spirocyclopentyl ) 
cyclopropyl-3- [ (pyridyl-4-yl ) thiomethyl ] -3-cephem-4- 
car boxy late-1, 1-dioxide; 

30 7 a-methoxy-2 -spiro ( 2 ' -spirocyclopentyl ) 

cyclopropyl-3- [ (2 ,5-dihydro-6-hydroxy-2-methyl-5-oxo-l,2,4- 
triazin-3-yl) thiomethyl] -3-cephem-4-piperidine carboxamide- 
1, 1-dioxide, and its sodium salt; 

35 7,7-dihydro-2-spiro (2 '-spirocyclopentyl) 

cyclopropyl-3-methyl-3-cephem-4- 1 { {4-carboxy) piperidine} 
carboxamidej-1, 1-dioxide, and its sodium salt; 



46 

SUBSTITUTE SHEET 



wo 95/15966 PCT/CA94/00669 



7,7-dihydro-2-spiro(2' -spirocyclopentyl) 
cyclopropyl-3-iDethyl-3-cepheia-4- [ (N-methyl-N-^acetic acid) ] 
carboxainide-l,l-dioxide, and its sodixim salt; 

5 

7 a-methoxy-2-spiro (2 ' -spirocyclopentyl) 
cyclopropyl-3- [ (2 , 5-dihydro-6-hydroxy-2-inethyl-5-oxo-l, 2 , 4- 
triazin-S-yl) thiomethyl]-3-cepheia-4-( { (4-carboxy)piperidine}- 
carboxamide]-l,l-dioxide, and its sodium salt; 

10 

7 a -inethoxy-2-spiro (2 ' -spirocyclopentyl) 
cyclopropyl-3-inethyl-3-cepheiD^4-inethylcarbonyI-l, i-dioxide; 

7 a-inethoxy-2-spiro (2 ' -spirocyclopentyl) 
15 cyclopropyl-3-methyl-3-cephem-4- [ 4 (methyl) -4 
(methoxyimino) ]-l, 1-dioxide; 

7 a-methoxy-2-spiro (2 ' -spirocyclopentyl) 
cyclopropyl-3-methyl-3-cephem-4- 1 { (4-carboxamide) piperidine} 
20 carboxamide] -1 , 1-dioxide ; 

7 a-methoxy-2-spiro (2 ' -spirocyclopentyl) 
cyclopropyl-3-methyl-3-cephem-4- [ { {4-cyano) piperidine} 
carboxamide ] -1 , 1-dioxide ; 

25 

7 a-methoxy-2-spiro (2 ' -spirocyclopentyl) 

cyclopropyl-3-methyl-3-cephem-4-[{ (4-hydroxy)piperidine} 
carboxamide ] -1 , 1-dioxide ; 

30 7 ce-methoxy-2-spiro (2 ' -spirocyclopentyl) 

cyclopropyl-3-methyl-3-cephem-4- [ { ( 4 -hydroxy ethyl) 
piperidine}carboxamide]-l, l-dioxide; 

7 a-methoxy-2-spiro (2 ' -spirocyclopentyl) 
35 cyclopropyl-3-roethyl-3-cephem-4-[ { ( 4 -bromoethyl) piperidine} 
carboxamide ]-lr 1-dioxide; and 



47 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



7 a-inethoxy-2 -spiro (2 ' -spirocyclopenty 1 ) 
cyclopropyl-3-inethyl-3-cephein-4- [ { (4-diethoxyphosphinyl- 
ethyl) piper idine}-carboxajnide]-l, 1-dioxide. 

5 

4. A compound as recited in claim 1, wherein said 
hydrocarbon residue substituent is selected from the group 
consisting of €3^ cycloalkyl, carboxyl, Cj^g alkoxycarbonyl, 
C^jQ aryl, a five or six-membered heterocyclic group 

10 containing from 1 to 4 of any one or more of the heteroatoms 
selected from N, S and O. 

5. A compound as recited in claim 1, wherein R7 
and Rg in the formula C0NR7Rg combine to form a heterocyclic 

15 ring component which may contain at least one other 
heteroatom selected from N, S and 0, said heterocyclic ring 
component being substituted with one or more substituents 
selected from the group consisting of hydroxy, carboxy, tert- 
butoxycarbonyl , azido, amino, hydroxymethyl , hydroxyethyl , 

20 bromoethyl, bromomethyl, cyano, carboxamide, guanidino, 
diethylphosphinylmethyl , diethylphosphinyl ethyl , 
dihydroxyphosphinylmethyl , dihydroxyphsophinylethyl , 1,2,3- 
triazole, tetrazole, Cj^ alkylthio Cj^ alkyl, 
C^io arylthio Cj^ alkyl, and heteroarylthio Cj^ alkyl, 

25 

6. A compound as recited in claim 1, wherein said 
quaternary ammonium group is selected from the group 
consisting of NH3, NHZ2/ N23, where Z is lower alkyl, aryl or 
aralkyl, or a heterocyclic system containing a nitrogen atom. 

30 

7. A compound as recited in claim 1, wherein said 
thiol compound is a heterocyclic thiol. 

8. A compound as recited in claim 1, wherein n is 

35 1, 2 or 3. 



48 

SUBSTITUTE SHEET 



wo 95/15966 



PCT/CA94/00669 



9. A compound as recited in claim 1, wherein R3 
is methoxy or ethoxy. 

5 10. A compound as recited in claim 1, wherein said 

hydrocarbon residue is Cj^ straight or branched chain alkyl, 
alkenyl or Cj^ cycloalkyl. 

11. A pharmaceutical composition for controlling 
10 inflammatory or degenerative conditions in a mammal 

comprising an effective amount of at least one 2-spiro(2'- 
spirocycloalkyl)cyclopropyl cephalosporin sulfone of the 
structural formula (I) as defined in claim 1 or a 
pharmaceutical ly acceptable salt or ester thereof, in 
15 admixture with a pharmaceutically acceptable carrier. 

12. A method of treating inflammatory or 
degenerative conditions which comprises administering to a 
patient in need of such treatment an effective amount of a 

20 cephalosporin sulfone of the formula (I) as defined in claim 
1. 

13. A method as recited in claim 12, wherein said 
patient is an animal or a human being. 

25 



49 

SUBSTITUTE SHEET 



INTERNATIONAL SEARCH REPORT 



Int jonal Application No 

PCT/CA 94/00669 



A. <;i,A.s.sii K;ArioN or- suiui-cr maih;r 
IPC 6 C070501/62 A61K31/545 



According to Inicmational Patent (laicrification (IIH,') or to both naoonal classification and IPC 



B. rrP.LDSSI'ARCIII-D 



Minimum documentation searched (da-wificauon syvtcm followed by classificatjon symbols) 

IPC 6 C07D 



Documentation searched other than minimum documenuuon to the extent that such documents are included m the fields searched 



Electronic data base consulted during the international search (name of data base and. where practical, search temns u-scd) 



C. D0CUMI:NTS CONSIDHRHD to III- RELPiVANT 



Category* 


Otation of document, with indication, where appropnaie, of the relevant passages 


Relevant to claim No. 


A 


wo, A, 91 04977 (SYNPHAR LABORATORIES INC.) 

18 April 1991 

*Page 69-75: claims* 


1.11 


A 


WO, A, 92 17482 (SYNPHAR LABORATORIES INC.) 
15 October 1992 
*Page 33-41: claims* 


1.11 . 


A 


WO, A, 92 18474 (SYNPHAR LABORATORIES INC.) 
29 October 1992 
•Page 60-64: claims* 


1.11 


A 


CHEMICAL ABSTRACTS, vol. 86, no. 7. 
14 February 1977, Columbus, Ohio, US; 
abstract no. 43721d, 
page 539 ; column L ; 
see abstract 

& JP,A,7 676 285 (TEIJIN LTD.) 1 July 1976 

-/-- 


1.11 



HI 



l-urther documents arc listed in the eononuation of box C. 



I )( [ Patent family members arc listed in annex. 



Special categories of died docxuncnts : 

A* document defining the general stale of the art which is not 
considered to be of particular relevance 

E' earlier document but pubttshed on or after the international 
filing dale 

L' docimtcnt which may throw doubts on priority dairies) or 
which is dtcd to establish the publication date of another 
citation or other special reason (as specified) 

document referring to an oral disclosure, use, exhibition or 
other means 

P' document published prior to the international filing date but 
later than the priority date claimed 



T" later document published after the international filing date 
or priority dau and not in conflict with the application but 
dud to understand the prtndple or theory underlying the 
invention 

'X' document of particular relevance; (he daimed invention 
cannot be considered novd or cannot be considered to 
involve an inventive step when the document is taken alone 

'Y' document of particular relevance; the daimed invention 
cannot be considered to involve an inventive step when the 
docuntent is combined with one or more other such docu- 
ments, nich combination being obvious to a person skilled 
in the art. 

document member of the same patent family 



Date of the actual completion of the international search 

1 March 1995 


Date of mailing of the international search report 

-9. -03.95 


Name and mailing address of the ISA 

European Patent Office, P.B. S818 PatenUaan 2 
NL • 2280 HV Rijswijk 
Td. (+ 31-70) 340-2040, Tx. 31 651 epo nl. 
Far (+31-70) 340-3016 


Authorized officer 

Luyten, H 



Forai PCT/ISA^Q (second thrti) (iuly 1993) 



page 1 of 2 



INTERN A'J ION AL SEARCH REPORT 



(nil tunal Application No 

PCT/CA 94/00669 



C^ConUnuaUon) OOCU MINI'S CONSIDIiRRD TO Dli RliKnVANT 



Category " Citation of document, with indication, where appropnaic. of ihc relevant passages 



Relevant to claim No. 



CHEMICAL ABSTRACTS, vol. 86, no. 11. 
14 March 1977, Columbus, Ohio, US; 
abstract no. 72670s, 
page 621 ; column L ; 
see abstract 

& JP,A,7 680 890 (TEIJIN LTD.) 15 July 
1976 



1.11 



Fomi PCT/ISA,'3I0 (oontinuation of tccnnd iheet) (July 1992) 



page 2 of 2 



INTERNATIONAL SEARCH REPORT 



PCT/CA94/ 00669 



Box 1 Observations where certain claims were found unscarchabic (Continuation of item I of first sheet) 



This internauonal search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 
1. Claims Nos.: 

because they relate to subject matter not required to be searched by this Authority, namely: 

Although claims 12 and 13 are directed to a method of treatment of (diag- 
nostic method practised on) the human/animal body, the search has been 
carried out and based on the alleged effects of the compound/composition. 

Claims Nos.: 

because they relate to parts of the international application that do not comply with the prescribed requirements to such 
an extent that no meaningful international search can be carried out, specifically: 



□ 



Claims Nos.: 

because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). 



Box IJ Observations where unity of invention b lacking (Continuation of item 2 of first sheet) 



This International Searching Authority found multiple inventions in this international application, as follows: 



1. As all required additional search fees were timely paid by the applicant, this international search report covers all 
searchable claims. 

2. Q As aU searchable daims could be searches without effort justifying an additional fee. this Authority did not invite payment 

of any additional fee. 



3. As only some of the required additional search fees were timely paid by the applicant, this international search report 
covers only those claims for which fees were |aid. specifically claims Nos.: 



4. Q No required additional search fees were timely paid by the appBcanL ConsequenUy, this iniemationaJ search report is 
restricted to the invention first mentioned in the claims; it is covered by claims Nosj 



Remark on Protest TTie additional search fees were accompanied by the appUcanfs protest 

I j No protest accompanied the payment of additional search fees. 



Form PCr/ISA/310 (continuation of first sheet (1)) (July 1992) 



INTERNATIONAL SEARCH REPORT 


Intf .onal Application No 

PCT/CA 94/00669 


Palcnl documcnl 
cited in search rcpcri 


Publicaiion 
date 


* Patent family 
mcmbcr(s) 


Publication 
date 



WO-A-9 104977 



18-04-91 



AU-A- 


6513190 


28- 


-04- 


-91 


CA-A- 


2067803 


07- 


-04- 


■91 


EP-A- 


0494914 


22- 


-07- 


-92 


JP-T- 


5503290 


03- 


-06- 


-93 


US-A- 


5264430 


23- 


■11- 


-93 


US-A- 


5264429 


23- 


-11- 


-93 



WO-A-9217482 15-10-92 



US-A- 


5258377 


02-11-93 


AU-A- 


1556092 


02-11-92 


CA-A- 


2107892 


09-10-92 


EP-A- 


0580650 


02-02-94 


HU-A- 


66046 


28-09-94 


JP-T- 


6506207 


14-07-94 



WO-A-9218474 29-10-92 



US-A- 


5264430 


23-11-93 


US-A- 


5264429 


23-11-93 


AU-A- 


1561292 


17-11-92 


CA-A- 


2107891 


09-10-92 


EP-A- 


0581789 


09-02-94 


HU-A- 


66140 


28-09-94 



JP-A-7676285 


NONE 


JP-A-7680890 


NONE 



Form PCT.1SA'310 (pateni family innev) (July 1993} 



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