W0 97/10223
`
`PCT/US96/14135
`
`0
`g)
`
`h)
`
`H30-C(OHCH2)2-C(O)-.
`R9-S02-,
`
`O
`
`A (EM VIII
`
`, or
`
`i)
`
`R12-NH-C(O)-;
`
`wherein R9 is
`
`a)
`
`b)
`
`c)
`
`d)
`
`-CH3,
`
`-CHQCI
`
`-CH2CH=CI-I2,
`
`aryl, or
`
`-CH2CN;
`e)
`wherein R10 and RH are independently
`
`a)
`
`H-.
`
`CH3—; or
`b)
`R10 and R11 taken together are -CH2-CH2-;
`wherein R12 is -(CH2)p-aryl;
`wherein R13 is
`
`20
`
`a)
`b)
`
`c)
`
`d)
`e)
`
`R20-C(R10XRn)-C(0)-.
`R30-C(O)-,
`
`R4-0(0)-,
`
`119-502-, or
`R12-NH-C(O)-;
`
`25
`
`wherein m is zero (0) or one (1);
`
`wherein n is one (1) to three (3), inclusive;
`
`wherein p is zero (0) or one (1);
`
`wherein aryl is phenyl substituted with zero (0) or one (1) of the following:
`
`30
`
`35
`
`3°3,:9£E:&€E°,
`
`.1?’
`
`-Cl,
`
`-OCH3,
`
`-OH,
`
`-Nn2,
`
`401-C4)aJkyl,
`
`-0-C(O)-OCH3,
`
`-N02, or
`
`MYLAN - EXHIBIT 1006 - Part 6 of 14
`
`1384
`
`1384
`
`MYLAN - EXHIBIT 1006 - Part 6 of 14
`
`

`
`W0 97/10223
`
`PCT/US96/14135
`
`i)
`
`-CN;
`
`with the following provisos:
`1)
`in the moiety of formula II, z1 is -CH(R5)-CH2- wherein R5 is (cl-
`C3)alkyl, only when n is one (1), A1 is H and A2 is R20-CH2-C(O)-NH-, R3O-C(0)-
`NH-, or R4—(-3(0)-NH-; and
`
`5
`
`in the moiety of formula II, when Z1 is —CH2-, n is one ( 1).
`2)
`The present invention more particularly provides:
`
`The compound of claim 1 wherein Q1 is the moiety of formula II;
`The compound of claim 1 wherein Q1 is the moiety of formula III;
`The compound of claim 1 wherein Q1 is the moiety of formula IV;
`The compound of claim 1 wherein Q1 is the moiety of formula V;
`The compound of claim 1 wherein one of X1 and X2 is -H and the other is -F
`or wherein X1 is -F and X2 is -F; and
`
`The compound of claim 1 wherein R1 is acetyl.
`
`The compounds of the present invention are named according to the IUPAC
`
`or CAS nomenclature system.
`
`The carbon atom content of various hydrocarbon-containing moieties is
`
`indicated by a prefix designating the minimum and maximum number of carbon
`
`atoms in the moiety, i.e., the prefix Ci-Cj indicates a moiety of the integer "i" to the
`integer "j" carbon atoms, inclusive. Thus, for example, (C1-C3)alkyl refers to alkyl of
`one to three carbon atoms, inclusive, or methyl, ethyl, propyl and isopropyl, straight
`and branched forms thereof.
`
`10
`
`15
`
`20
`
`Throughout this application, abbreviations which are well known to one of
`
`ordinary skill in the art may be used, such as "Ph" for phenyl, "Me" for methyl, and
`"Et" for ethyl.
`
`25
`
`The following Charts I-IX describe the preparation of the parent amine
`
`compounds, which are the starting compounds from which the N-oxide compounds of
`
`the present invention are prepared. All of the starting compounds are prepared by
`
`procedures described in these charts or by procedures analogous thereto, which
`
`would be well known to one of ordinary skill in organic chemistry. The following
`
`applications and publications which further describe and exemplify these procedures
`
`are hereby incorporated by reference herein: WO 95/07271, published 16 March
`
`1995; W096/15130, published 23 May 1996; WO 95/25106, published 21 September
`
`1995; W096/13502, published 9 May 1996; WO 93/23384, published 25 November
`
`1993; W0 95/4684, published 1 June 1995; and PCT/US96/05202, filed 18 April
`1996.
`
`30
`
`35
`
`1385
`
`1385
`
`

`
`W0 97/10223
`
`PCT/US96/14135
`
`In the text below corresponding to these charts, the formula at the lefl:
`margin corresponds to a specific Q2 moiety in the charts and the other variables are
`as defined with X1 and X2 most often being hydrogen or fluorine and R1 most ofien
`
`being -COCI-I3, for purposes of example only.
`’
`CHART 1
`
`10
`
`15
`
`I-A
`
`Using the procedures from WO 95/07271, published 16 March 1995, page
`
`21, line 33, thru page 23, line 32 for preparation of the intermediate sulfide
`
`and then oxidation to the sulfone using the general procedures from WO
`
`95/07271, published 16 March 1995, page 15, line 32 thru page 16, line 14.
`
`I-B
`
`Using the procedures described in WO 95/07271, published 16 March 1995,
`
`page 21, line 33, thru page 23, line 32, but substituting oxazolidine for
`thiazolidine.
`
`CHART II
`
`II-A
`
`Using the general procedures from WO 95/07271, published 16 March 1995,
`
`page 12, line 31, thru page 16, line 14.
`
`II-B
`
`Using the general procedures from WO 95/07271, published 16 March 1995,
`
`page 12, line 31 thru page 16, line 14, but substituting 2-
`
`methylthiomorpholine for thiomorpholine. 2-Methylthiomorpholine is
`
`prepared according to the procedure of Gallego, et al, J. Org. Chem, 1993,
`
`20
`
`58, 3905-11.
`
`II-C
`
`Using the general procedures from W096/15130, published 23 May 1996,
`
`Examples 2 and 3 at page 14, line 24, thru page 17, line 21.
`
`CHART III
`
`III-A
`
`Using the general procedures from WO 95/07271, published 16 March 1995,
`
`page 19, line 6, thru page 21, line 13; and page 23, line 33, thru page 24,
`line 35.
`
`III-B
`
`Using the general procedures from W096/15130, published 23 May 1996,
`
`Example 1 at page 12, line 1, thru page 14, line 22.
`
`CHART IV
`
`IV-A
`
`Using the general procedures from WO 95/25106, published 21 September
`
`1995, page 20, line 27 thru page 22, line 5 but substituting azetidine for
`
`piperidine.
`
`IV-B
`
`Using the general procedures of W096/13502, published 9 May 1996,
`
`Example 11 at page 53, line 32 through page 56, line 3, but substituting 1-
`
`(diphenylmethyl)—3-azetidinone in place of 1-benzyl-3-pyrrolidinone. 1-
`
`(Diphenylmethyl)-3-azetidinone can be prepared by the procedure of
`
`25
`
`30
`
`35
`
`-3-
`
`1386
`
`1386
`
`

`
`W0 97/10223
`
`PCT/US96/14135
`
`Chatterjee, et al, Synthesis, 1973, 153-4.
`
`From IV-B using the general procedure from W096/13502, published 9 May
`
`1996, page 66, line 4 through line 17.
`
`From IV-C using the general procedure from WO 95/25106, published 21
`September 1995, page 28, line 26 through page 29, line 5.
`
`Using the general procedures from W096/13502, published 9 May 1996,
`
`Example 2 at page 33, line 4, thru page 36, line 22.
`
`Starting with IV-E, and using procedures well known for acetylation; e.g.,
`acetic anhydride and triethylamine in a suitable solvent.
`
`10
`
`Using the general procedures from W096/13502, published 9 May 1996,
`
`Example 7 at page 43, line 36, thru page 47, line 28.
`
`Using the general procedures from W096/13502, published 9 May 1996,
`
`Example 6 at page 40, line 31, thru page 43, line 34.
`
`Using the procedures of W096/13502, published 9 May 1996, Example 1 at
`page 29, line 25 thru page 33, line 2.
`Wherein R2 is H; using the procedure described in W096/13502, published
`9 May 1996, Examples 12 and 13 at page 56, line 19 thru page 59, line 4,
`
`but substituting 3-acetylaminoazetidine hydrochloride in place of 3-
`
`(trifluoroacetylamino)pyrrolidine hydrochloride. 3-Acetylaminoazetidine
`
`hydrochloride is prepared by the procedure of Nisato, et al., J. Heterocycl.
`Chem. 1985, 22, 961-3.
`Wherein'R2 is methyl; using the procedure described in W096/13502,
`published 9 May 1996, Examples 12. 13 and 14 at page 56 line 19 thru page
`59 line 27, but substituting 3-acetylaminoazetidine hydrochloride in place of
`3-(trifluoroacetylamino)pyrrolidine hydrochloride and substituting
`
`methoxyacetyl chloride in place of benzyloxyacetyl chloride.
`Wherein R2 is benzyl; using the procedure described in W096/13502,
`published 9 May 1996, Examples 12, 13 and 14 at page 56 line 19 thru page
`59 line 27, but substituting 3-acetylaminoazetidine hydrochloride in place of
`3-(trifluoroacetylarnino)pyrrolidine hydrochloride.
`Wherein R2 is acetyl; using the procedure described in W096/13502,
`published 9 May 1996. Examples 12, 13 and 14 at page 56 line 19 thru page
`59 line 27, but substituting 3-acetylaminoazetidine hydrochloride in place of
`
`15
`
`IV-J
`
`20
`
`25
`
`IV-J
`
`IV-J
`
`30
`
`IV-J
`
`35
`
`3-(trifluoroacetylamino)pyrrolidine hydrochloride and substituting
`
`acetoxyacetyl chloride in place of benzyloxyacetyl chloride.-
`Wherein R3 is methyl, ethyl, propyl, or phenyl; using the procedure
`
`-9-
`
`1387
`
`1387
`
`

`
`W0 97/10223
`
`PCT/US96/14135
`
`described in W096/13502, published 9 May 1996, Examples 12, 13 and 14
`
`at page 56 line 19 thru page 59 line 27, but substituting 3-
`
`acetylaminoazetidine hydrochloride in place of 3-(triiluoroacetyl-
`
`amino)pyrrolidine hydrochloride and substituting methyl, ethyl, propyl, or
`
`IV-L
`
`phenyl chloroformate in place of benzyloxyacetyl chloride.
`Wherein R4 is hydrogen; using the procedure described in W096/13502,
`
`10
`
`15
`
`20
`
`published 9 May 1996, Examples 12, 13 and 14 at page 56 line 19 thru page
`
`59 line 27, but substituting 3—acetylan1inoazetidine hydrochloride in place of
`
`3—(trifluoroacetylamino)pyrrolidine hydrochloride and substituting methyl
`
`formate in place of benzyloxyacetyl chloride.
`
`Wherein R4 is all others listed; using the procedure described in
`
`W096/13502, published 9 May 1996, Examples 12, 13 and 14 at page 56
`
`line 19 thru page 59 line 27, but substituting 3-acetylaminoazetidine
`
`hydrochloride in place of 3-(trifluoroacetylaminwpyrrolidine hydrochloride
`
`and substituting the appropriate acid chloride in place of benzyloxyacetyl
`chloride.
`1
`
`IV-M
`
`Using the general procedures of W096/13502, published 9 May 1996,
`
`Example 1, Steps 2 thru 7, at page 30, line 14 thru page 33, line 2, but
`
`substituting methyl N-benzylazetidine-3-carboxylate in place of 1-(diphenyl-
`
`methyl)-3-methoxyazetidine. Methyl N-benzylazetidine-3-carboxylate can be
`
`prepared by the procedure of Mason, et al, EP 169602 A1.
`
`Starting with IV-M and using the general procedures of WO 95/25106,
`
`published 21 September 1995, page 22, line 11 through line 20.
`
`CHART V
`
`25
`
`V—A
`
`V-B
`
`Using the procedure from WO 95/25106, published 21 September 1995, page
`
`20, Example 1, but using pyrrolidine instead of piperidine.
`
`Using the procedures of W096/13502, published 9 May 1996, Example 11 at
`
`30
`
`35
`
`page 53, line 32, thru page 56, line 3.
`
`From V-B, following the procedure of W096/13502, published 9 May 1996,
`
`page 56, lines 4 through 17.
`
`From V-C. using the general procedure of WO 95/25106, published 21
`
`September 1995, page 28. line 26, thru page 29, line 5.
`Using the procedures described in W096/13502, published 9 May 1996.
`
`Example 10 at page 50. line 25, thru page 53. line 30. Or, from V-C by
`
`reduction using methods well known in the art such as sodium borohydride
`
`in methanol.
`
`1388
`
`1388
`
`

`
`W0 97/10223
`
`PCTIUS96/14135
`
`V-F
`
`V-G
`
`10
`
`15
`
`20
`
`V-J
`
`V-J
`
`From V-E using standard acetylation procedures; e.g., acetic anhydride in
`
`pyridine.
`
`As described in W096/13502, published 9 May 1996, Example 7 at page 43,
`
`line 36. thru page 47, line 28 but substituting 1-benzyl-3-methyl-3-
`
`pyrrolidinol hydrochloride for 1-(diphenylmethyl)-3-methyl-3-azetidinol
`
`hydrochloride. 1-Benzyl-3-methyl-3-pyrrolidinol hydrochloride can be
`
`prepared from 1-benzyl-3-pyrrolidinone by methods known in the art, eg,
`
`reaction with methylmagnesium bromide and treatment of the product with
`
`one equivalent of hydrochloric acid. 1-Benzyl-3-pyrrolidinone is
`
`commercially available.
`
`Using the general procedures of W096/13502, published 9 May 1996,
`
`Example 6 at page 40, line 31 through page 43, line 34, but substituting 1-
`
`benzyl-3-methyl-3-pyrrolidinol hydrochloride (prepared as described above)
`
`in place of 1—(diphenylmethyl)-3-methyl-3-azetidinol hydrochloride.
`
`As described in W096/13502, published 9 May 1996, Example 1 at page 29,
`
`line 25, thru page 33, line 2, but substituting commercially available 1-
`
`benzyl-3-pyrrolidinol for 1-(diphenylmethyl)-3-azetidinol.
`Wherein R2 is H and R5 is H; using the procedure described in
`
`W096/13502, published 9 May 1996, Examples 12 and 13 at page 56, line
`
`19, thru page 59, line 4;
`Wherein R2 is methyl and R5 is H; using the procedure described in
`
`W096/13502, published 9 May 1996, Example 12 at page 56, line 19 thru
`
`page 58, line 27 but substituting methoxyacetyl chloride for benzyloxyacetyl
`chloride.
`
`25
`
`V-J
`
`Wherein R2 is benzyl and R5 is H; using the procedure described in
`
`W096/13502, published 9 May 1996, Example 12 at page 56, line 19 thru
`
`page 58, line 27.
`
`VJ
`
`Wherein R2 is acetyl and R5 is H; using the procedure described in
`
`30
`
`35'
`
`V-J
`
`V-J
`
`W096/13502, published 9 May 1996, Example 12 at page 56, line 19 thru
`
`page 58, line 27 but substituting acetoxyacetyl chloride for benzyloxyacetyl
`chloride.
`
`Where R2 is H and R5 is methyl; using the procedures described in
`
`W096/13502, published 9 May 1996, Example 15 at page 62, lines 5-28.
`Wherein R2 is benzyl and R5 is methyl; using the procedures described in
`
`W096/13502, published 9 May 1996, Example 15, Step 1, at page 62, lines
`5-19.
`’
`
`-11-
`
`1389
`
`1389
`
`

`
`W0 97/] 0223
`
`PCI'lUS96Il4l3S
`
`V-J
`
`Wherein R2 is methyl or acetyl and R5 is methyl; using the procedures
`
`V-J
`
`V-K
`
`described in W096/13502, published 9 May 1996, Example 15, Step 1, at
`
`page 62, lines 5-19, but substituting methoxyacetyl chloride or acetoxyaoetyl
`
`chloride for benzyloxyacetyl chloride.
`Wherein R5 is other alkyl; using the general procedures described above but
`
`subsituting other 4-alkyl-3-aminopyrrolidines in place of 3-amino-4-
`
`methylpyrrolidine.
`Wherein R5 is methyl, ethyl, propyl or phenyl and R5 is H; using the
`
`procedure described in W096/13502, published 9 May 1996, Example 12 at
`
`page 56, line 19 thru page 58, line 27 but substituting methyl chlorofor-
`
`mate, ethyl choroformate, propylchloroformate, or phenylchloroformate for
`
`V-K
`
`benzyloxyacetyl chloride.
`Wherein R5 is methyl, ethyl, propyl, or phenyl and R5 is methyl; by
`
`reaction of (S)-(N)-[[[3-fluoro-4-(3-aminoaz-methylpyrrolidinyl)phenyl]-2-oxo-
`
`5-oxazolidinyllmethyllacetamide with the appropriate chloroformate. The
`
`above amine is prepared according to the procedures of W096/13502,
`
`published 9 May 1996, Example 14, Steps 1-8, at page 59, line 6 through
`
`page 61, line 29.
`
`Wherein R5 is other alkyl; From the appropriate amine and chloroformate.
`
`The amine is prepared according to the procedures of W096/13502,
`
`published 9 May 1996, Example 14, Steps 1-8, at page 59, line 6 through
`
`page 61, line 29, but starting with other 3-alkyl-4-aminopyrrolidines in
`
`place of 4-amino-3-rnethylpyrrolidine.
`Where R4 is H and R5 is H; using the procedure described in W096/13502,
`
`published 9 May 1996, Example 12 at page 56, line 19 thru page 58, line 27
`
`but substituting methyl formate in place of benzyloxyacetyl chloride.
`Where R4 is all others listed and R5 is H; using the procedure described in
`
`W096/13502, published 9 May 1996, Example 12 at page 56, line 19 thru
`
`page 58, line 27 but substituting the appropriate acid chloride in place of
`
`benzyloxyacetyl chloride.
`
`Where R4 is H and R5 is methyl; by reaction of formic acid and
`
`dicyclohexylcarbodiimide. The required amine is prepared according to the
`
`procedures of W096/13502, published 9 May 1996, Example 14, Steps 1-8,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`V-L
`
`at page 59, line 6 through page 61, line 29.
`Where R4 is all others and R5 is methyl; by reaction of (S)-(N)~[[[3-fluoro-4-
`
`(3-amino-4~methylpyrrolidinyl)phenyl]-2-oxo-5-
`
`.12-
`
`1390
`
`1390
`
`

`
`WO 97/10223
`
`PCT/US96ll 4135
`
`oxazolidinyllmethyllacetamide with the appropriate acid chloride. The
`
`required amine is prepared according to the procedures of W096/13502,
`
`published 9 May 1996, Example 14, Steps 1-8, at page 59, line 6 through
`
`page 61, line 29.
`Where R5 is other alkyl; Using the above procedures, but starting with
`
`other 3-alkyl-4-aminopyrrolidines in place of 4-amino-3-methylpyrrolidine.
`Using the general procedure from WO 95/25106, published 21 September
`1995, page 22, lines 6 through 12, 5, but using pyrrolidine-3-carboxylic acid
`
`methyl ester instead of piperidine-4-carboxylic acid ethyl ester. Pyrro1idine-
`
`3-carboxylic acid methyl ester is prepared by the procedure of Morgans, et
`
`al, Tetrahedron Lett., 1979, 1959.
`
`From V-M, using the general procedure of WO 95/25106, published 21
`
`September 1995, page 22, lines12 through 20.
`
`CHART VI
`
`Using the general procedures from WO 95/25106, published 21 September
`
`1995, page 20, line 27, thru page 22, line 5.
`
`Using the procedure of WO 95/25106, published 21 September 1995, WO
`
`95/25106, published 21 September 1995, page 22, line 21 thru line 26.
`
`From VI-B, using the procedure from WO 95/25106, published 21
`
`September 1995, page 22, lines 27 through 35.
`
`From VI-C, using the procedure from WO 95/25106, published 21
`
`September 1995, page 28, line 26 thru page 29, line 5.
`
`Prepared from VI-C by reduction via standard procedures known in the art;
`
`eg, sodium borohydride in methanol.
`
`Prepared from VI-E by procedures known in the art; eg, acetic anhydride
`
`and triethylamine.
`
`Using the procedures from W096/13502, published 9 May 1996, Example 7,
`
`page 43, line 36 thru page 47, line 28 but substituting commercially
`
`available 4-hydroxy-4-methylpiperidine for 3-hydroxy-3-methylazetidine.
`
`Using the procedures from WO 95/25106, published 21 September 1995,
`
`page 20, line 27 thru page 22, line 5, but substituting 4-methoxy—4-
`
`methylpiperidine in place of piperidine. 4-Methoxy-4-methylpiperidine can
`
`be prepared according to the procedure of McManus, et al, J. Med. Chem.,
`
`1965, 8, 766-776.
`
`Using the procedures from WO 95/25106, published 21 September 1995,
`
`page 20 line 27 thru page 22, line 5, but substituting 4-methoxypiperidine
`
`.13-
`
`10
`
`V-N
`
`20
`
`25
`
`30
`
`35
`
`1391
`
`1391
`
`

`
`WO 97110223
`
`PCT/US96/M135
`
`for piperidine. 4-Methoxypiperidine can be made by the procedure of
`
`VI-J
`
`McManus, et al, J. Med. Chem., 1965, 8, 766-776.
`Wherein R2 = H; Prepared by reaction of (S)-N-[[3-[4-(4-aminopiperidinyl)-3
`
`iluoropheny1]-2-oxo-5-oxazolidinyl]methyllacetamide (prepared according to
`the procedures of WO 95/25106, published 21 September 1995, page 22,
`
`1ine36 thru page 23, line 24) with acetoxyacetyl chloride and triethylamine
`
`followed by hydrolysis of the acetoxy group with methanolic potassium
`carbonate.
`
`Wherein R2 = methyl; prepared by reaction of the starting material of VI-J
`(R2 = H) with methoxyacetyl chloride and triethylamine.
`Wherein R2 is benzyl; prepared by reaction of the starting material of VI-J
`(R2 = H) with benzyloxyacetyl chloride and triethylamine.
`Wherein R2 is acetyl; prepared by reaction of the starting material of VIJ
`(R2 = H) with acetoxyacetyl chloride and triethylamine.
`Wherein R3 is methyl, ethyl, propyl, or phenyl; prepared by reaction of the
`starting material of VI-J (R2 = H) with methyl-, ethyl-, propyl-, or
`
`phenylchloroformate.
`
`Wherein R4=H; By reaction of the starting material of VI-J (R2 = H) with
`
`methylformate.
`
`Wherein R4 = all others listed; By reaction of the starting material of VI-J
`(R2 = H) with the appropriate acid chloride.
`
`Using the procedure from WO 95/25106, published 21 September 1995, page
`
`22, line 6 thru line 12.
`
`Using the procedure from WO 95/25106, published 21 September 1995, page
`
`22, lines 12 through 20.
`
`CHART VII
`
`Using the general procedures of WO 95/25106, published 21 September
`
`1995, page 20, line 27 through page 22, line 5, but substituting
`
`commercially available azepine in place of piperidine.
`
`10
`
`15
`
`20
`
`25
`
`VI-J
`
`VIJ
`
`VI-J
`
`VI-N
`
`VII-A
`
`30
`
`VII-B
`
`Using the procedure of WO 95/25106, published 21 September 1995, page
`
`22, line 21 thru line 26 but substituting 1,4-dioxo-8-aza-spiro[4.6]undecane
`
`for 1,4-dioxo-8-aza-spiro[4.5]decane. 1,4-Dioxo-8-aza-spiro[4.6]undecane can
`
`be prepared by the procedure of R. A. Johnson, et al, J. Org. Chem., 1968.
`
`33, 3187-3195.
`
`35
`
`VII-C
`
`From VII-B. following the procedure of W096/13502, published 9 May 1996,
`
`page 56, lines 4 through 17.
`
`-14-
`
`1392
`
`1392
`
`

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`
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`
`VII-D
`
`VII-E
`
`VII-F
`
`VII-G
`
`VII-H
`
`10
`
`15
`
`VII-I
`
`20
`
`VII-J
`
`25
`
`30
`
`35
`
`VII-J
`
`From VII-C using the general procedure of WO 95/25106, published 21
`September 1995, page 28, line 26. thru page 29, line 5.
`
`Prepared from VH-C by reduction via standard procedures known in the
`
`art; eg, sodium borohydride in methanol.
`
`Prepared from VII-E by procedures known in the art; eg, acetic anhydride
`and triethylamine.
`
`Using the procedures from W096/13502, published 9 May 1996, Example 7,
`page 43, line 36 thru page 47, line 28 but substituting 4-hydroxy-4-methyl-
`azepine for 3-hydroxy-3-methylazetidine. 4-Hydroxy-4-methylazepine can
`be prepared by the procedure pf Grob, et al, Helv. Chim.Acta. 1962, 45,
`1823-1830.
`
`Using the general procedures of WO96/13502, published 9 May 1996,
`Example 6, page 40, line 31 through page 43, line 34, but substituting 1-
`benzyl-4-methyl-4-azepinol in place of 1-(diphenylmethyl)-3-methyl-3-
`azetidinol hydrochloride. 1-Benzyl-4-methyl-4-azepinol can be prepared by
`the reaction of methyl magnesium bromide with 1-benzyl-4-azepinone. 1-
`Benzyl-4-azepinone can be prepared by the procedure of Casy, et al, J.
`Chem. Soc. 1964, 5130-5132.
`
`As described in W096/13502, published 9 May 1996, Example 1, at page 29,
`line 25, thru page 33, line 2, but substituting 1-benzyl-4-azepinol for
`1-(diphenylmethyl)-3-azetidinol. 1-Benzyl-4-azepinol can be prepared by the
`procedure of S. Sakanoue, et al, Chem. Pharm. Bull., 1990 38, 2981-2985.
`Wherein R2 is H; using the procedure described in W096/13502, published
`9 May 1996, Examples 12 and 13, page 56, line 19, thru page 59, line 4 but
`substituting 4—(trifluoroacetylamino)azepine in place of 3-
`(trifluoroacety1amino)pyrrolidine. 4—('I‘rifluoroacetylamino)azepine can be
`prepared by reaction of 1-benzyl-4-azepinamine with trifluoroacetic
`
`anhydride in a suitable solvent such as chloroform, followed by removal of
`the benzyl protecting group via hydrogenolysis using palladium on carbon
`
`as a catalyst in a solvent such as ethyl acetate. 1—Benzyl-4-azepinamine can
`be prepared by the procedure of Morosawa, et al, Bull. Chem. Soc. Jpn.,
`1958, 31, 418-422.
`Wherein R2 is methyl; using the procedure described in W096/13502,
`published 9 May 1996, Example 12, page 56, line 19 through page 58, line
`27, but substituting 4—(trifluoroacetylamino)azepine for 4-
`(trifluoroacetylarnino)pyrrolidine and substituting methoxyacetyl chloride in
`
`-15.
`
`1393
`
`1393
`
`

`
`W0 97/10223
`
`PCTIUS96/N135
`
`VII-J
`
`place of benzyloxyacetyl chloride.
`Wherein R2 is benzyl; using the procedure described in WO96/13502,
`
`published 9 May 1996, Example 12, page 56, line 19 through page 58, line
`
`27, but substituting 4-(triiluoroacetylaminohzepine for 4-(trifluoroacetyl-
`
`amino)pyrrolidine.
`
`VIIJ
`
`Wherein R2 is acetyl; using the procedure described in W096/13502,
`
`published 9 May 1996, Example 12, page 56, line 19 through page 58, line
`
`27, but substituting 4-(trifluoroacetylaminohzepine for 4—(trifluoroacetyl-
`
`amino)pyrrolidine and substituting acetoxyacetyl chloride in place of
`
`10
`
`benzyloxyacetyl chloride.
`
`VII-K
`
`Wherein R3 is methyl, ethyl, propyl, or phenyl; prepared by reaction of (S)-
`
`N-[[3-[4—(4-aminoazepinyl)-3—fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]-
`
`acetarnide (prepared as an intermediate in the synthesis of VII—J) with the
`
`appropriate chloroformate and triethylamine in chloroform.
`
`15
`
`VII-L
`
`Wherein R4 is H; Prepared by reaction of (S)-N-[[3-[4-(4-aminoazepinyl)-3-
`
`fluorophenyl]-2—oxo-5-oxazolidinyflmethyllacetamide (prepared as an
`
`intermediate in the synthesis of VII-J) with formic acid according to the
`general procedure of WO 93/23384, published 25 November 1993, page 23,
`lines 4-17.
`
`20
`
`VII-L
`
`Wherein R4 is all others; Prepared by reaction of (S)-N-[[3-[4-(«L
`
`aminoazepinyl)-3-fluorophenyl]-2-oxo-5-oxazolidinyllmethyl]acetamide
`
`(prepared as an intermediate in the synthesis of VII~J) with the appropriate
`
`acid chloride and triethylamine.
`
`VII-M
`
`Using the procedure from WO 95/25106, published 21 September 1995, page
`
`22, line 6 thru line 12, but substituting azepine-4-carboxylic acid ethyl ester
`
`in place of piperidine-4-carboxylic acid ethyl ester. Azepine-4-carboxylic
`
`acid ethyl ester can be prepared from azepine-4-carboxylic acid by normal
`
`procedures known in the art, eg, reaction with ethanol and hydrochloric
`
`acid. Azepine-4-carboxylic acid can be prepared by the procedure of
`
`Krogsgaard—Larsen, et al, Eur. J. Med. Chem. Chim. Ther., 1979, 14, 157-
`
`164.
`
`25
`
`30
`
`VII—N
`
`From VII-M, using the general procedure of WO 95/25106, published 21
`
`September 1995, page 22, lines12 through 20.
`
`CHART VIII
`
`35
`
`VIII-A
`
`Wherein R2 = H; According to the procedure of WO 95/14684, published 1
`
`‘June 1995, page 9, lines 1-28.
`
`- 15-
`
`1394
`
`1394
`
`

`
`WO 97110223
`
`PCT/US96/I 4135
`
`VIII-A
`
`Wherein R2 = methyl; Awarding to the general procedures of W0 93/23384,
`
`VIII-A
`
`5 VHI-A
`
`VIII-B
`
`published 25 November 1993, page 19, lines 26- 33.
`Wherein R2 = benzyl; According to the procedure of W0 95/14684, published
`1 June 1995, page 9, lines 1-14.
`Wherein R2 = acetyl; According to the procedure of WO 95/14684, published
`1 June 1995, page 28, lines 24-35.
`Wherein R3 = Me, Et, Pr, or Ph; Using the general procedure from W0
`
`93/23384, published 25 November 1993, page 23, lines 19-28 and
`
`10 VIII-C
`
`substituting methyl-, ethyl, propyl, or phenylchloroformate as appropriate.
`Wherein R4 = H; Using the general procedures from W0 93/23384,
`
`VIII-C
`
`published 25 November 1993, page 23, lines 4-17.
`Wherein R4 = all others; Using the general procedures from WO 93/23384,
`published 25 November 1993, page 23, lines 19-28, and substituting the
`
`15 VIII-D
`
`VIII-E
`
`VIII-F
`
`VIII-G
`
`20
`
`25
`
`appropriate acid chloride for methylchloroformate.
`
`Prepared according to the general procedure found in W0 93/23384,
`
`published 25 November 1993, page 25, lines 13-25.
`
`Prepared according to the general procedure from W0 93/23384, published
`
`25 November 1993, page 25, lines 13-25, but substituting commercially
`
`available 5-oxo-2-tetrahydrofurancarboxylic acid in place of (R)-2-
`
`tetrahydrofuranoic acid.
`
`Prepared according to the procedure of WO 93/23384, published 25
`
`November 1993, page 18, lines 10-17.
`
`Prepared from N-[[3-[4-[3-fluoro-4-(1—piperaziny1)]phenyl]-2-oxo-5-
`
`oxazolidinyllmethyll-acetamide and the appropriate sulfonyl chloride using
`the general procedure from WO 93/23384, published 25 November 1993,
`
`page 23, lines 19-28. Methyl, chloromethyl, allyl, and substituted
`
`arylsulfonyl chlorides are commercially available. Cyanomethylsulfonyl
`chloride can be prepared according to the procedure of M. P. Sammes, et al,
`
`J. Chem. Soc. (C)., 1971, 2151-2155.
`
`30 VIII-H
`
`Prepared from N-[[3-[4-[3-fluoro-4-(1-piperazinyl)]phenyl]-2-oxo-5-
`
`oxazolidinyl]methyl]-acetamide and piperonyl chloride using the general
`
`procedure from WO 93/23384, published 25 November 1993, page 23, lines
`
`19-28. Piperonyl chloride is commercially available.
`
`.
`
`Prepared from N-[[3-[4-[3~fluoro—4-(1-piperazinyl)]pheny1]-2-oxo-5-
`
`oxazolidinyllmethyll-acetamide and the appropriate carboxylic acid using
`the general procedure of W0 95/14684, published 1 June 1995, page 10,
`
`VIII-I
`
`35
`
`-17-
`
`1395
`
`1395
`
`

`
`W0 97/10123
`
`PCT/US96/l4l35
`
`lines 4-17. The acids are commercially available.
`
`VIII-J
`
`Prepared from N-[[3-[4-[3-fluoro-4-( 1-piperazinyl)lphenyl]-2-oxo-5-
`
`oxazolidinyl]methyl}—acetamide and the appropriate isocyanate. The
`
`required isocyanates are commercially available.
`
`'
`
`CHART D(
`
`Wherein R2 is H; Prepared according to the procedures of PCT/US96/05202,
`
`filed 18 April 1996, Examples 1, 2 and 3, page 12, line 11 through page 15,
`
`line 7.
`
`IX-A
`
`Wherein R2 is methyl; Prepared according to the general procedures of A
`
`10
`
`15
`
`IX-A
`
`IX-A
`
`IX-B
`
`PCT/US96/05202, filed 13 April 1996, Example 2, page 14, lines 1e32, but
`
`substituting methoxyacetyl chloride for benzyloxyacetyl chloride.
`Wherein R2 is benzyl; Prepared accroding to the procedures of
`
`PCT/US96/05202, filed 18 April 1996. Example 2, page 14, lines 16-32.
`Wherein R2 is acetyl; Prepared according to the general procedures of
`
`PCT/US96/05202, filed 18 April 1996, Example 2, page 14, lines 16-32, but
`
`substituting acetoxyacetyl chloride for benzyloxyacetyl chloride.
`
`Using the general procedure of PCT/US96/05202, filed 18 April 1996,
`
`Example 2, page 14, lines 16-32, but substituting the appropriate
`
`chloroformate for benzyloxyacetyl chloride.
`
`20
`
`Wherein R4 is H; Prepared from (S)-N-[[3-[4-[cis-3,7-diazabicyclo[3.3.0]-
`
`octan-7-yl]-3-fluorophenyl]—2-oxo-5-oxazolidinyl]methyl]acetamide
`
`(PCT/US96/05202, filed 18 April 1996, page 14, lines 21-24) using the
`
`general procedures from WO 93/23384, published 25 November 1993, page
`
`23, lines 4-16.
`
`25
`
`Wherein R4 is all others listed; Using the general procedure of
`
`PCT/US96/05202, filed 18 April 1996, Example 2, page 14, lines 16-32, but
`
`substituting the appropriate acid chloride in place of benzyloxyacetyl
`
`chloride.
`
`’
`
`Using the general procedure of PCT/US96/05202, filed 18 April 1996,
`
`Example 2, page 14, lines 16-32, but substituting the appropriate sulfonyl
`
`chloride in place of benzyloxyacetyl chloride. The sulfonyl chlorides can be
`
`obtained as described for VIII-G.
`
`Prepared from (S)-N-[[3-[4—[cis-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-
`
`fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (PCT/US96/05202, filed
`
`18 April 1996, page 14, lines 21-24) and the appropriate carboxylic acid
`
`using the general procedures of WO 93/23384, published 25 November 1993,
`
`.18-
`
`30
`
`35
`
`1396
`
`1396
`
`

`
`W0 97/10223
`
`PCT/US96/M135
`
`page 18, lines 10-17. The appropriate carboxylic acids are commercially
`available.
`
`Prepared by combining (S)-N-[[3-[4-[cis-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-
`
`fluorophenyl]-2-oxo-5-oxazolidinyllmethyllacetamide (PCT/US96/05202, filed
`
`18 April 1996, page 14, lines 21-24) and the appropriate isocyanate. The
`
`required isocyanates are commercially available.
`
`GENERAL PROCEDURE:
`
`The compounds of this invention are prepared by oxidation of a suitable
`
`precursor amine with any of a variety of oxidizing agents. Suitable oxidants include
`
`pertrifluomacetic acid, meta-chloroperbenzoic acid (MCPBA), and magnesium
`
`monoperoxyphthalate (MMPP). For example, the synthesis is shown below for the
`case wherein Q1 is morpholine and the oxidant is MMPP.
`'
`
`©$..,...°”°“
`0
`=
`
`
`o
`
`/ x‘
`
`0
`
`o’fi
`x‘
`“ISL °
`H
`X2
`\_k’N‘R1
`
`CH3OH,0°C
`
`X2
`
`10
`
`15
`
`20
`
`Oxidation of any of the oxazolidinones of Charts I-IX in which Q2 is any of
`
`the other groups previously described is carried out similarly.
`
`Charts X-XVIII show the final N-oxide compounds of the present invention
`
`which are prepared from the parent amines of Charts I-Di, respectively, by using the
`above General Procedures.
`
`25
`
`It will be apparent to those skilled in the art that the described synthetic
`
`procedures are merely representative in nature and that alternative synthetic
`
`processes are known to one of ordinary skill in organic chemistry.
`
`The compounds of the present invention have an advantage over the parent
`
`30
`
`amines in being exceedingly water soluble (see Table 1 below). For example, the
`
`compound of Example No. 2 has a solubility of 409 mg/ml. The parent amine has a
`
`water solubility of only 3.7 mg/ml. The N-oxide compounds of the present invention
`
`also retain all the in uitro and in viva activities of the parent amines. The enhanced
`
`water solubility makes the N-oxide compounds of the present invention ideal for
`
`35
`
`intravenous or injectable formulations.
`
`49
`
`1397
`
`1397
`
`

`
`W0 97110223
`
`PCI‘/US96ll4l3S
`
`Table 1. Solubility Data for the N-oxides and parent amines.
`
`Parent Amine
`
`
`
`Example Number
`
`'
`
`Solubility (mg/mL)
`
`
`
`
`
`(mymL)
`
`N-Oxide Solubility
`
`Pmcedure for Measuring Solubility:
`
`In all solubility studies, an excess of compound is added to 0.5 to 1 ml of
`
`10
`
`pH 7. 50 mM phosphate bufl'er or other vehicle of interest. The samples are
`
`capped and stirred via magnetic stir bars for 24 to 48 hours at room
`
`temperature. Samples are filter centrifuged (800 x g) for 5-10 minutes
`
`through Millipore Ultrafree-MC 0.22 micron filter units. The supernate is
`
`analyzed by either UV or HPLC to quantitate the drug concentration. Results of the
`
`15
`
`solubility testing of the compounds of the present invention are given above in Table
`1.
`
`The oxazolidinone compounds of the present invention have useful activity
`
`against a variety of microorganisms. The in vitro activity of compounds of the
`
`present invention are assessed by standard testing procedures such as the
`
`20
`
`determination of minimum inhibitory concentration (MIC) by agar dilution as
`
`described in "Methods for Dilution Antimicrobial Susceptiblity Tests for Bacteria
`
`That Grow Aerobically" (MFT) published January 1993 by the National Committee
`
`for Clinical Laboratory Standards (NCCLS), 771 East Lancaster Avenue, Villanova,
`
`Pennsylvania 19084, USA. The activity of selected compounds of the present
`
`25
`
`invention against Staphylococcus aureus and Streptococcus pneumoniae are shown in
`
`Table 2.
`
`-20.
`
`I398
`
`1398
`
`

`
`W0 97/10223
`
`PCT/US96/I 4135
`
`Table 2. Activity of the N-oxides against S. Aureus and S. Pneumoniae.
`
`Example
`
`
`
`As such, the compounds of the present invention are useful for treating
`
`microbial infections in humans or other warm-blooded animals by administering to a
`
`patient in need thereof an eflective amount of a compound of Formula I. The
`
`compound is administered in a pharmaceutical composition o