WO1999043671A1

WO1999043671A1 - Substituted aminomethyl isoxazoline derivatives useful as antimicrobials

Info

Publication number: WO1999043671A1
Application number: PCT/US1999/004262
Authority: WO
Inventors: Michael R. Barbachyn; Joel Morris; Donn G. Wishka; Richard C. Thomas; David R. Graber
Original assignee: Pharmacia and Upjohn Co; Upjohn Co
Current assignee: Pharmacia and Upjohn Co
Priority date: 1998-02-25
Filing date: 1999-02-10
Publication date: 1999-09-02
Anticipated expiration: 2000-08-25
Also published as: AU3180999A; CA2318762A1; EP1060179A1; JP2002504550A

Abstract

The present invention provides novel substituted aminoheteroaromatic isoxazoline derivatives of formula (I), wherein R1 is H, alkyl, cycloalkyl, alkoxy, amino, or alkylamino; Y is H, F, or CH3; W is O, or S; Ring P is a 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms, wherein the 5-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl, a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene, naphthyl or 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms; Q is a 4-, 5-, 6-, 7-, or 9-membered heterocyclic moiety containing one or more nitrogen, sulfur and/or oxygen. The compounds of the invention have high antimicrobial activity for preventing and treating infectious diseases.

Description

SUBSTITUTED AMINOMETHYL ISOXAZOLINE DERIVATIVES USEFUL AS ANTIMICROBIALS

FIELD OF THE INVENTION The present invention relates to novel substituted aminoheteroaromatic isoxazoline derivatives, to pharmaceutical compositions containing them as active ingredients, and to methods of using them. The compounds of the invention have antimicrobial activity for preventing and treating infectious diseases.

BACKGROUND OF THE INVENTION

Antibacterial agents such as oxazolidinones are a class of known orally- active, synthetic antibacterial agents and there are numerous references in the art disclosing a variety of oxazolidinone derivatives. For example, U.S. Patent Nos. 4,705,799 and 5,523,403 and European Patent Application 0,316,594 disclose substituted phenyl-2-oxazolidinones, including the sulfides, sulfoxides, sulfones, sulfonamides, nitriles, acetamides and a tropane ring. U.S. Patent Nos. 4,948,801; 5,254,577 and 5,130,316 disclose arylbenzene oxazolidinyl compounds, wherein the aryl includes the (un)substituted phenyl and pyridyl groups. European Patent Applications 0,697,412; 0,694,544; 0,694,543 and 0,693,491 disclose 5 to 9-membered heteroaryl-oxazolidinones having one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen.

This invention describes substituted aminoheteroaromatic isoxazoline derivatives useful as antibacterial agents. The compounds of the invention are novel and distinct from antibacterial oxazolidinones in that the usual oxazolidinone rings are replaced by an isoxazoline moiety. These compounds have antibacterial activity comparable to the corresponding oxazolidinones. They are effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci and streptococci, as well as anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium aυium.

INFORMATION DISCLOSURE U.S. Patent No. 4,283,403 discloses 3-aryl-2-isoxazolines useful for the protection of plants from diseases. Danish Patent No. 2,725,763 discloses substituted 2-isoxazolines which is fungicidal against phytophthora infestation on tomatoes. The compounds also show antibacterial activity.

U.S. Patent No. 3,769,295 discloses nitrofuryl derivatives of 5-substituted isoxazolines useful as antimicrobial agents.

WO 95/14680 Al discloses 3-aryl-2-isoxazolines which is useful in inhibiting PDEjy, the treatment of inflammatory diseases and the treatment of AIDs, asthma, arthritis, etc.

S. S. Ghabrial, et al, Acta Chemica Scandinavica, B 41, pp. 426-434 (1987) discloses the synthesis of heteroaromatic compounds via the isoxazoline route.

U.S. Patent No. 5,547,950 discloses oxazolidinones containing a substituted diazine moiety and their use as antimicrobials.

International Publication No. WO 95/07271 discloses substituted oxazine and thiazine oxazolidinone antimicrobials.

International Publication No. WO 9514684 discloses esters of substituted- hydroxyacetyl piperazine phenyl oxazolidinones. International Publication No. WO 95/25106 discloses oxazolidinone derivatives and pharmaceutical compositions containing them.

International Publication No. WO 96/13502 discloses phenyloxazolidinone antimicrobials.

International Publication No. WO 96/23788 discloses hetero-aromatic ring substituted phenyloxazolidinone antimicrobials.

International Publication No. WO 97/21708 discloses 4-pyrimidinyl- or 4- pyrazinyl-piperazinyl-phenyl-oxazolidinone derivatives.

SUMMARY OF THE INVENTION In one aspect, the present invention provides a compound of formula I

Q

\\

-R ι

H N \

I or pharmaceutically acceptable salts thereof wherein: Ri is (a) H,

(b) Cj.₈ alkyl, which may be substituted with one or more halo, -OH,

-2- C₁ alkoxy or C_1-4 acyloxy,

(c) C₃.₆ cycloalkyl,

(d) C₁ alkoxy,

(e) amino, or (f) NHCC^a alkyl), wherein C^ alkyl may be substituted with one or more halo; Y is H, F, or CH₃; W is O, or S; Ring P is (a) a 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms, wherein the 5-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl,

(b) a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein the 6-membered heteroaromatic moiety can additionally have a fused- on benzene, naphthyl or 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms, or

(c) a phenyl ring fused-on with a benzene, naphthyl, 6-membered heteroaromatic moiety having at least one nitrogen atom or a 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms; Q is

(a) a 5-membered heterocyclic moiety having one to four nitrogen atoms selected from structures consisting of i, ii, iii, iv, v, vi, vii, viii, and ix;

n₂ M.

R;

IV

^ €'v AV Λ-N ^N,_N

Rff R ^N. *_%^■"» _R^ _D^N, vi vii viii

(b) a 9-membered heterocyclic moiety having one to four nitrogen atoms selected from structures consisting of x, xi, xii, xiii, xiv, xv, xvi, xvii, and xviii;

-3- V2 D R?

N ^ ₂ F~~W \ xi

R₂ N- N-

\

XII XIII xiv XV

*2 R R₂

& ^N^TN δ N-^cN

XVI XVII xviii

(c) a heterocyclic ring having a nitrogen atom selected from structures consisting of xix, xx, xxi, xxii, and xxiii;

17

(CH₂)_n

R₇- r 9 R« :N^'

R₈ R₇

xxii

- 21

(d) E N —

^R 20

^R25

(e) Z-(CH₂)_q-N^ H— , or

^R26

-4- ⁽f⁾

wherein R₂ is

(a) H,

(b) halo,

(c) -OH,

(d) -OR₃,

(e) -SR₃,

( ) -S(0)_;R₃ ,

(g⁾ -CN,

(h) -0₂CR₃,

(i) -NHC(=0)R₃,

(j) -NHC0₂R₃,

(k) -NHS0₂R₃,

(1) -C0₂R₄,

(m) -C(=0)N(R₃)₂,

(n) -C(=O)R₃,

(o) C_ω alkyl,

(P) C₃.₈ cycloalkyl, wherein groups (o) and (p) may be substituted with one or more of the preceding groups (a)-(n),

(q) phenyl, which may be substituted with one or more of the preceding groups (a)-(p),

(r) -CH=CHCO₂Et, or

(s) -C(=NR₄)R₅;

R is

(a) H, (b) Ci-β alkyl, (c) C₃.₈ cycloalkyl, wherein groups (b) and (c) may be substituted with one or more of halo, -OH, C_M alkoxy, C_w acyl, C₁ acyloxy, or -OC(=O)CH₂N(CH₃)₂, or

(d) phenyl, which may be substituted with one or more of the preceding groups (b) to (c); R₄ is -OH or -OCH₃; R₅ is H, or -CH₃; R₆ is

(a) H,

(b) -OR₁₀, (c) -SR₁₀,

(d) -NR_UR₁₂,

(e) -CN,

(f) C₁ alkoxycarbonyl,

(g) carboxamide, (h) C_1A acyl, which may be substituted with one or more halo, -OH,

C₁ alkoxy or C^ acyloxy,

(i) -N(OH)(C₁.₆ alkyl),

(j) -N(OH)CH₂phenyl,

(k) -NS0₂( C_halky!) wherein C^g alkyl may be substituted with one or more halo, C^g alkoxy or phenyl, or

(1) F; R₇ is

(a) H,

(b) -OH, (c) -OCC^g alkyl),

(d) C_M alkyl,

(e) phenyl, or

( ) F; R₈ is (a) H,

(b) C ₃ alkyl, which may be substituted with halo, -OH, -C0₂ C_w alkyl, C_j.₃ acyloxy, C_w alkyoxy or -N(C_W alkyl)₂,

(c) phenyl, or

(d) pyridyl; R₉ is O, S, -NR₁₃, or -CR₁₄R₁₅;

Rio is

(a) H,

(b) C ._e alkyl, which may be substituted with one or more halo, -CN, -OH, C^g alkoxy, C_x.₈ acyloxy, C_w alkoxycarbonyl, or phenyl, (c) C-_₈ acyl, which may be substituted with one or more -OH,

C_LS alkoxy, C^ acyloxy,

-6- (d) C_{l S} alkoxycarbonyl,

(e) carboxamide, which may be substituted with a C₁ alkyl or phenyl on the carboxamide nitrogen, or

(f) phenyl, which may be substituted with one or more halo, -CN, C_j.₃ alkoxy, C^ alkoxycarbonyl or C₁ alkyl;

R_n and R₁₂ are the same and different and are

(a) H,

(b) Ci.₈ alkyl, which may be substituted with one or more halo, -CN, -OH, C^g alkoxy, C^ acyloxy, C^g alkoxycarbonyl, phenyl, (c) C ₈ acyl, which may be substituted with one or more -OH, amino,

C^g alkoxy, C^ acyloxy, C_1Λ acylamino,

(d) benzoyl, which may be substituted with one or more halo, -OH, amino, C^g alkoxy, C^g acyloxy, Cj.₄ acylamino, C^ alkoxycarbonylamino,

(e) Cj.₈ alkoxycarbonyl, (f) benzyloxycarbonyl,

(g) tertbutoxycarbonyl,

(h) carboxamide, which may be substituted with a C_lA alkyl or phenyl on the carboxamide nitrogen, (i) trifluoracetyl, or (j) C_w acyl;

R₁₃ is H, -OR₁₀, -NHR₁₀, or C^g alkyl, which may be substituted with phenyl; R₁₄ and R₁₅ are the same and different and are

(a) H,

(b) C₁ alkyl, which may be substituted with halo, -OH, C^alkoxy,

Ci.₄ alkoxycarbonyl, or phenyl,

(c) C_LS acyl,

(d) C₁ alkoxycarbonyl,

(e) -CN, or

(f) F;

R₁₆ is 0, or S;

R₁₇ and R_lg are the same and different and are

(a) H,

(b) Cj.₄ alkyl, which may be substituted with halo, -OH or C₁ alkoxy,

(c) -OH, (d) C₁ alkoxy, which may be substituted with -OH or C₁ alkoxy,

(e) NR_nR₁₂, or

-7- (f> Ci.₄ acyloxy;

R₁₉ is H, or -CH₃;

E is

(a) -0-, or

(b) -S(=0)_m-;

R₂₀ is

(a) H,

(b) -CH₃,

(c) -CN,

(d) -CO₂H,

(e) -CO₂R₂₂, or

( ) -(CH^_jR^;

R₂₁ is H, or -CH₃;

R₂₂ is

(a) H,

(b) C_j.g alkyl, which may be substituted with halo, -OH, C_x.4 alkoxy. C₁ acyloxy or -0-CH₂-phenyl,

(c) C₃.₆ cycloalkyl,

(d) amino,

(e) -N(C_M alkyl)₂,

(f) -NHCC^g alkyl), or

(g) C^_β alkoxy;

R₂₃ is

(a) -OH,

(b) -0&22.

(0 -OC(=O)R₂₂,

(d) amino,

(e) -NHC(=0)R₂₂, or

( -N(R₂₄)₂;

R₂₄ is

(a) H,

(b) C₁ alkyl, which may be substituted with halo, -OH, C_w alkoxy, amino, -NCC^g alkyl)₂, or -NHCCm alkyl), or

(c) p-toluenesulfonyl; wherein Z is

(a) H, (b) -C(=0)R₂₇,

(c) C_w alkyl,

(d) benzyl,

(e) phenyl, wherein groups (d) and (e) may be substituted with one or more halo, -OCH₃, -OH, amino or C_w alkyl,

(f) -OR∞ ,

(g) -OC(=0)R₂₉, (h) -S-C-.₆ alkyl, (i) -SOa-C^ alkyl, (j) phenylsulfonyl,

(k) p-toluenesulfonyl,

(1) -SO₂-N(R₃₀)₂,

(m) -C(0)-OR₃₁,

(n) -C(O)-N(R₃₀)₂, (o) -N(R₃₀)₂, or

(p) a 6-membered heterocyclic moiety having one to three nitrogen atoms selected from structures consisting of xxiv, xxv, xxvi, xxvii, xxviii, xxix,

,N,

L- XXIV - xxv i- xxXvi

L^ ar

XXVIII xxix

L is

(a) H, amino, C--₄ alkyl, or halo; R₂₅ and R₂₆ are the same and different and are

(a) H, (b) Ci-_β alkyl, or

(c) C₃.₆ cycloalkyl; R^ is

(a) C^g alkyl,

(b) C^g alkylhydroxyl, (c) phenyl, or

-9- (d) i

Rag is

(a) H,

(b) Cn alkyl,

(c) vinyl, or

(d) phenyl, which may be substituted with one to more halo, C^ alkoxy, -OH, amino or C₁ alkyl;

R₂₉ is C^g < alkyl, or phenyl;

R₃₀ is independently

(a) H,

(b) C₁ alkyl, or

(c) phenyl, which may be substituted with C^ alkyl or C_M alkoxy; R₃₁ is

(a) C_{1 S} alkyl,

(b) phenyl, which may be substituted with C_w alkyl or C_l alkoxy, or

(c) benzyl, which may be substituted with C₁ alkyl or C ₄ alkoxy; wherein R₃₂ and R₃₃ are the same and different and are (a) H,

(b) halo,

(c) C_j.₈ alkyl, which may be substituted with one or more R₄₅,

(d) C₃.₆ cycloalkyl,

(e) -(CH₂)_m-OR₃₆, or (f) -C(=0)-R₃₈;

R₃₄ and R₃₅ are the same and different and are

(a) H,

(b) Cj.₈ alkyl, which may be substituted with one or more R₄₅,

(c) C₁ alkoxy, (d) C .₈ alkylthio,

(e) -(CH₂)_m-OR₃₉,

(f) -0-(CH₂)_m-OR₃₉,

(g) -NR₄₀R₄₁,

(h) -N=CH-NR₄₂R₄₃, (i) -C(=O)-NR₄₀R₄₁, or

0^') -(CH₂)_m-C(=A)-R₃₈, wherein A is O or ethyleneketal,

-10- or R₃₄ and R₃₅ may combine together to form

(k) =0,

(1) =NR₄₄,

(m) =S, or

(n) =CR₄₂R₄₃; R₃₆ and R₃₇ are the same and different and are

(a) H,

(b) C _₈ alkyl, which may be substituted with one or more R₄₅, or

(c) -CH₂OCH₃; R₃₈ is

(a) H,

(b) -(CH₂)_m-OH,

(c) C^g alkyl, which may be substituted with one or more R₄₅,

(d) C^g alkoxy, (e) -0-CH₂-0-C(=0)-R₃₆, or

(f) -(CH₂)_m-C(=0)-OR₃₆; R₃₉ is

(a) H,

(b) C^g alkyl, which may be substituted with one or more R₄₅, (c) C₂.₈ alkenyl,

(d) -(CH₂)_m-OR₃₆,

(e) -(CH₂)_m-C(=0)-R₃₈,

(f) -C(=0)-(CH₂)_m-OR₄₃, or

(g) tosyl; R₄₀ and R₄₁ are the same and different and are

(a) H,

(b) -(CH₂)_m-OR₃₆₎

(c) C^g alkyl, which may be substituted with one or more R₄₅,

(d) -C(=0)-R₃₈, (e) -C(=0)-NR₃₆R₃₇,

(f) -(CH₂)_p-phenyl,

(g) thiazol-2-yl, or R₄₀ and R₄₁ may combine together to form

(h) pyrrolidino, (i) piperidino,

(j) piperazino,

-11- (k) morpholino, or

(1) thiomorpholino, wherein groups (h) to (1) may be substituted with C^g alkyl or -(CH₂)_m-OH; R₄₂ and R₄₃ are the same and different and are

(a) H,

(b) C_j.₈ alkyl, which may be substituted with one or more R₄₅,

(c) -C(=O)-R₃₈, or

(d) -(CH₂)_p-phenyl;

R₄₄ is

(a) H,

(b) -OR₃₉,

(c) Cj.₈ alkyl, which may be substituted with one or more R₄₅,

(d) C₁ alkoxy,

(e) -(CH₂)_p-phenyl,

(f) -NR₄₀R₄₁,

(g) -NH-C(=NH)-NH₂,

(h) [l,2,4]triazol-4-yl, or

(i) -CN;

R₄₅ is

(a) halo,

(b) -OH,

(c) -CN,

(d) C-.₆ alkoxy,

(e) amino,

( ) -N(C₁.₆ alkyl)₂,

(g) -NH(C₁.g alkyl), or

(h) carboxyl;

•_ is a double bond or a single bond; i is 1 or 2; m is 0, 1 or 2; n is 0 or 1; p is 1, 2, 3 or 4; and q is 0, 1, 2, 3 or 4.

In another aspect, the present invention provides compounds of formula II

^x f^→

H

II

-12- or pharmaceutically acceptable salts thereof wherein: R_j and W are the same as defined in claim 1; Ring T is a 6-membered heteroaromatic moiety having one to three nitrogen atoms, wherein the 6-membered heteroaromatic moiety has a fused-on 5-membered heteroaromatic moiety which in turn has one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms; X is

(a) carboxyl,

(b) halo, (c) -CN,

(d) mercapto,

(e) formyl,

(f) -CF₃,

(g) -N0₂, (h) C_M alkoxy,

(i) Ci.g alkoxycarbonyl,

(j) C₁ alkythio,

(k) C^g acyl,

(1) -NR₄₈ R₄₉₎ (m) C_lJβ alkyl which can be substituted with R₅₀

(n) C₂.₈ alkenylphenyl optionally substituted with one or two R₅₁,

(o) phenyl optionally substituted with one or two R₅₁,

(p) -CH=NOH,

(q) -CH=N-(OC₁.₆ alkyl), (r) a 5-, or 6-membered heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R ^v5.1>

(S) or

I I \

(t) ^N-N

H

R₄₈ and R₄₉ are the same and different and are (a) H,

-13- (b) C_w alkyl,

(c) C₅.₆ cycloalkyl, or

(d) R₄₈ and R₄₉ taken together with the nitrogen atom is a 5-, 6- membered heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, C^ alkyl, or C^ acyl;

R₅₀ is

(a) -OH,

(b) C^ alkoxy,

(c) C_1-4 acyl,

(d) -NR₄₈R₄₉,

(e) -NHC(=S)NH₂,

(f) -NHC(=O)NH₂,

(g) -NHC(=O)R₄₉,

(h) -SO₂NR₅₅R₅₆, or

(i) -NRSO₂R₅₅;

R₅₁ is

(a) carboxyl,

(b) halo,

(c) -CN,

(d) mercapto,

(e) for yl,

⁽f⁾ CF₃,

⁽g) -NO₂,

(h) C_x_₆ alkoxy,

(i) Ci.₆ alkoxycarbonyl,

⁽J⁾ C_j.₆ alkythio,

(k) C_M acyl,

(1) C^g alkyl optionally substituted with OH, C-_₅ alkoxy, C^ acyl, or

-NR₄₈R₄₉,

(m) phenyl,

(n) -C(=0)NR₅₂ R₅₃,

(o) -JN _{48 9},

(P) -N(R₅₂)(-SO₂R₅₄),

⁽q) -SO₂-NR₅₂R₅₃, or

(r) -S(=0)_iR₅₄;

-14- R₅₂ and R₅₃ are the same and different and are

(a) H,

(b) C₁ alkyl, or

(c) phenyl; R₅₄ is

(a) C_1A alkyl, or

(b) phenyl optionally substituted with C_M alkyl; R₅₅ and R₅₆ are the same and different and are

(a) H, or (b) C_1-β alkyl; and j is 0 or 1.

These compounds have antimicrobial activity against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply- resistant staphylococci and streptococci, as well as anaerobic organisms such as bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium aυium.

DETAILED DESCRIPTION OF THE INVENTION For the purpose of the present invention, the carbon 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 C^ defines the number of carbon atoms present from the integer "i" to the integer "j", inclusive. Thus, C_j.₄ alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof. The terms "C^ alkyl", "C_w alkyl", "C_u alkyl", and "C^ alkyl" refer to an alkyl group having one to three, one to four, one to six, or one to eight carbon atoms respectively such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and their isomeric forms thereof.

The term "C₂.₈ alkenyl" refers to at least one double bond alkenyl group having two eight carbon atoms such as, for example, ethenyl, propenyl, butenyl, pentenyl, pentdienyl, hexenyl, hexdienyl, heptenyl, heptdienyl, octenyl, octdienyl, octatrienyl, and their isomeric forms thereof.

The terms "C₃.₆ cycloalkyl", and "C₃.₈ cycloalkyl" refer to a cycloalkyl having three to six, or three to eight carbon atoms respectively such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and their isomeric forms thereof.

-15- The terms "C_w alkoxy", "C^ alkoxy", "C_x_₆ alkoxy", and "C^ alkoxy" refer to an alkyl group having one to three, one to four, one to six, or one to eight carbon atoms respectively attached to an oxygen atom such as, for example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy and their isomeric forms thereof.

The terms "C₁₄ acyl", "C_M acyl", and "C_M acyl" refer to a -C(=O)R group, wherein R is an alkyl group of one to four, one to six or one to eight carbon atoms and their isomeric forms thereof.

The terms "C^ alkoxycarbonyl", "C^g alkoxycarbonyl", and "C^g alkoxycarbonyl" refer to a -C0₂R group, wherein R' is an alkyl group of one to three, one to six, or one to eight carbon atoms and their isomeric forms thereof.

The terms "C^ acyloxy", "C₁ acyloxy", and "C^ acyloxy" refer to a -OC(=0)R group, wherein R" is an alkyl group of one to three, one to four, or one to eight carbon atoms and their isomeric forms thereof. The term "C^ acylamino" refers to a -NHC(=0)R group, wherein R is an alkyl group of one to four carbon atoms and their isomeric forms thereof.

The term "C₁₄ alkoxycarbonylamino" refers to -NHC(=0)OR, wherein R is an alkyl group of one to four carbon atoms and their isomeric forms thereof.

The term "C^ hydroxyl" refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof attached to a hydroxy group.

The term "C^g alkylthio" refers to an alkyl group having one to six carbon atoms and isomeric forms thereof attached to a sulfur atom.

The term "halo" refers to fluoro, chloro, bromo, or iodo.

The compounds of the present invention can be converted to their salts, where appropriate, according to conventional methods.

The term "pharmaceutically acceptable salts" refers to acid addition salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate and the like. These salts may be in hydrated form.

The compounds of formula I of this invention contain a chiral center at C5 of the isoxazoline ring, and as such there exist two enantiomers or a racemic mixture of both. This invention relates to both the enantiomers, as well as mixtures containing both the isomers. The preferred enantiomer is the one having (R) - absolute configuration at C-5 of the isoxazoline ring. In addition, depending on the substituents, additional chiral centers and other isomeric forms may be present

-16- in any of the Q or R_x group, and this invention embraces all possible stereoisomers and geometric forms in these groups.

Ring P or Ring T below contained in the compounds formula I or formula II are typical heteroaromatic isoxazolines of this invention. It will be understood that the named heteroaromatic moiety do not limit the scope of the invention, but are named merely to help one skilled in the art to understand the invention. They are 3-isoquinolinyl, 1-isoquinolinyl, 2-quinolinyl, 3-quinolinyl, 3-(5,6,7,8-tetrahydro)- isoquinolinyl, l-(5,6,7,8-tetrahydro)-isoquinolinyl, 2-(5,6,7,8-tetrahydro)-quinolinyl, 3-(5,6,7,8-tetrahydro)-quinolinyl, 3-(5,6-dihydro)-2H-2-pyrindinyl, l-(5,6-dihydro)-2H- 2-pyrindinyl, 2-(5,6-dihydro)-lH-l-pyrindinyl, 3-(5,6-dihydro)-lH-l-pyrindinyl, 5-furo[2,3-c]pyridinyl, 6-furo[3,2-c]pyridinyl, 4-furo[3,2-c]pyridinyl, 7-furo[2,3- c]pyridinyl, 6-furo[2,3-b]pyridinyl, 5-furo[3,2-b]pyridinyl, 5-(2,3-dihydro)-furo[2,3- c]pyridinyl, 6-(2,3-dihydro)-furo[3,2-c]pyridinyl, 4-(2,3-dihydro)-furo[3,2-c]pyridinyl, 7-(2,3-dihydro)-furo[2,3-c]pyridinyl, 6-(2,3-dihydro)-furo[2,3-b]pyridinyl, 5-(2,3- dihydro)-furo[3,2-b]pyridinyl, 6-(l,3-dihydro)-furo[3,4-c]pyridinyl, 4-(l,3-dihydro)- furo[3,4-c]pyridinyl, 2-(5,7-dihydro)-furo[3,4-b]pyridinyl, 6-(3,4-dihydro)-2H- pyrano[2,3-c]pyridinyl, 6-(3,4-dihydro)-lH-pyrano[3,4-c]pyridinyl, 7-(3,4-dihydro)-lH- pyrano[4,3-c]pyridinyl, 7-(3,4-dihydro)-2H-pyrano[3,2-c]pyridinyl, 5-(3,4-dihydro)-2H- pyrano[3,2-c]pyridinyl, 5-(3,4-dihydro)-lH-pyrano[4,3-c]pyridinyl, 8-(3,4-dihydro)-lH- pyrano[3,4-c]pyridinyl, 8-(3,4-dihydro)-2H-pyrano[2,3-c]pyridinyl, 7-(3,4-dihydro)-2H- pyrano[2,3-b]pyridinyl, 2-(5,6-dihydro)-lH-pyrano[3,4-b]pyridinyl, 2-(5,6-dihydro)-2H- pyrano[4,3-b]pyridinyl, 6-(3,4-dihydro)-2H-pyrano[3,2-b]pyridinyl, 5-lH-pyrrolo[2,3- c]pyridinyl, 6-lH-pyrrolo[3,2-c]pyridinyl, 4-lH-pyrrolo[3,2-c]pyridinyl, 7-1H- pyrrolo[2,3-c]pyridinyl, 6-lH-pyrrolo[2,3-b]pyridinyl, 5-lH-pyrrolo[3,2-b]pyridinyl, 5- (2,3-dihydro)-lH-pyrrolo[2,3-c]pyridinyl, 6-(2,3-dihydro)-lH-pyrrolo[3,2-c]pyridinyl, 4- (2,3-dihydro)-lH-pyrrolo[3,2-c]pyridinyl, 7-(2,3-dihydro)-lH-pyrrolo[2,3-c]pyridinyl, 6-(2,3-dihydro)-lH-pyrrolo[2,3-b]pyridinyl, 5-(2,3-dihydro)-lH-pyrrolo[3,2-b]pyridinyl, 6-(l,3-dihydro)-lH-pyrrolo[3,4-c]pyridinyl, 4-(l,3-dihydro)-lH-pyrrolo[3,4-c]pyridinyl, 2-(5,7-dihydro)-lH-pyrrolo[3,4-b]pyridinyl, 6-1,7-naphthyridinyl, 6-2,7naphthyridinyl, 7-2,6-naphthyridinyl, 7-1,6-naphthyridinyl, 5-1,6-naphthyridinyl, 5-2,6- naphthyridinyl, 8-2,7-naphthyridinyl, 8-1,7-naphthyridinyl, 7-1,8-naphthyridinyl, 2- 1,7-naphthyridinyl, 2-1,6-naphthyridinyl, 6-1,5-naphthyridinyl, 6-(l,2,3,4- tetrahydro)-l,7-naphthyridinyl, 6-(l,2,3,4-tetrahydro)-2,7-naphthyridinyl, 7-( 1,2,3,4- tetrahydro)-2,6-naphthyridinyl, 7-( 1,2,3,4- tetrahydro)- 1,6-naphthyridinyl, 5-( 1,2,3,4- tetrahydro)- 1,6-naphthyridinyl, 5-(l,2,3,4-tetrahydro)-2,6-naphthyridinyl, 8-( 1,2,3,4- tetrahydro)-2,7-naphthyridinyl, 8-(l,2,3,4-tetrahydro)-l,7-naphthyridinyl, 7-( 1,2,3,4-

-17- tetrahydro)- 1,8-naphthyridinyl, 2-(5,6,7,8-tetrahydro)-l,7-naphthyridinyl, 2-(5,6,7,8- tetrahydro)-l,6-naphthyridinyl, 6-(l,2,3,4-tetrahydro)-l,5-naphthyridinyl, 1-naphthyl, 2-naphthyl, 5-(l,2,3,4-tetrahydro)-naphthyl, 6-(l,2,3,4-tetrahydro)-naphthyl, 4-(2,3- dihydro)-lH-indenyl, 5-(2,3-dihydro)-lH-indenyl, 5-benzofuranyl, 4-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 5-(2,3-dihydro)-benzofuranyl, 4-(2,3-dihydro)- benzofuranyl, 6-(2,3-dihydro)-benzofuranyl, 7-(2,3-dihydro)-benzofuranyl, 4-(l,3- dihydro)-isobenzofuran, 5-(l,3-dihydro)-isobenzofuran, 4-lH-indolyl, 5-lH-indolyl, 6-lH-indolyl, 7-lH-indolyl, 4-(2,3-dihydro)-lH-indolyl, 5-(2,3-dihydro)-lH-indolyl, 6- (2,3-dihydro)-lH-indolyl, 7-(2,3-dihydro)-lH-indolyl, 4-(l,3-dihydro)-lH-isoindolyl, 5- (l,3-dihydro)-lH-isoindolyl, 5-(3,4-dihydro)-lH-2-benzopyranyl, 6-(3,4-dihydro)-lH-2- benzopyranyl, 7-(3,4-dihydro)-lH-2-benzopyranyl, 8-(3,4-dihydro)-lH-2-benzopyranyl, 5-(3,4-dihydro)-2H-l-benzopyranyl, 6-(3,4-dihydro)-2H-l-benzopyranyl, 7-(3,4- dihydro)-2H-l-benzopyranyl, 8-(3,4-dihydro)-2H-l-benzopyranyl, 5-( 1,2,3,4- tetrahydro)-isoquinolinyl, 6-(l,2,3,4-tetrahydro)-isoquinolinyl, 7-(l,2,3,4-tetrahydro)- isoquinolinyl, 8-(l,2,3,4-tetrahydro)-isoquinolinyl, 5-(l,2,3,4-tetrahydro)-quinolinyl, 6- (l,2,3,4-tetrahydro)-quinolinyl, 7-(l,2,3,4-tetrahydro)-quinolinyl, 8-(l,2,3,4- tetrahydro)-quinolinyl, 4 -quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8- quinolinyl, 1-cyclohexenyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyri.midinyl, 2-imidazolyl, 4-imidazolyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-oxazolyl, 4- oxazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 5-methyl-3-isoxazolyl, 5-phenyl-3- isoxazolyl, 4-thiazolyl, 3-methyl-2-pyrazinyl, 5-methyl-2-pyrazinyl, 6-methyl-2- pyrazinyl, 5-chloro-2-thienyl, 3-furyl, benzofuran-2-yl, benzothien-2-yl, 2H-1- benzopyran-3-yl, 2,3-dihydrobenzopyran-5-yl, 2,3-dihydrobenzofuran-2-yl, 1- methylimidazol-2-yl, quinoxalin-2-yl, isoquinolin-3-yl, piperon-5-yl, 4,7- dichlorobenzoxazol-2-yl, 4,6-dimethylpyrimidin-2-yl, 4-methylpyrimidin-2-yl, 2,4- dimethylpyrimidin-6-yl, 2-methylpyrimidin-4-yl, 4-methylpyrimidin-6-yl, 6- chloropiperon-5-yl, 5-chloroimidazo[l,2-a]pyridin-2-yl, l-H-inden-3-yl, l-H-2-methyl-inden-2-yl, 3,4-dihydronaphth-l-yl, S-4-isopropenylcylcohexen-l-yl, and 4-dihydronaphth-2-yl. The compounds of this invention can be prepared in accordance to one or more of the processes discussed below. In SCHEMES I, II, III, IV and V below, X, Y, Q and R_x are as defined previously; A is a halogen atom or substituent Q.

As shown in SCHEME I, halogenated heteroaromatic aldehyde 1 can be converted to the corresponding nitrile oxide 2 via three steps: formation of the corresponding oxime, halogenation of resultant oxime to generate an intermediate hydroximinoyl halide, and treatment of this intermediate with a suitable base such

-18- as triethylamine to afford nitrile oxide 2. The resultant nitrile oxides 2 undergo a 1,3-dipolar cycloaddition with 3, either allylic amides (wherein R_x is C^ alkyl) or carbamates (R_x is O-alkyl), to generate isoxazolines of structure 4 (wherein W is oxygen atom). SCHEME I

„ ^C ^?κN.+.

^HCOR! 3

^Q-c τ „ F' O w

All these methods are well known to those skilled in the art, and are discussed in further detail in the following references: P. Caramella et al., "1,3- Dipolar Cycloaddition Chemistry", Vol. 1, Chapter 3 of "Nitrile Oxides and Imines", A. Padwa, Ed., John Wiley & Sons, Inc., New York, 1984, pp. 291-392, and references cited therein; C. J. Easton et al., "Advances in Heterocyclic Chemistry", Vol. 60 of "Cycloaddition Reactions of Nitrile Oxides with Alkenes", A. R. Katritzky, Ed., Academic Press, San Diego, 1994, pp. 261-327, and references cited therein; C. Grundmann, et al., J. Org. Chem., 1968, Vol. 33, p. 476; K. C. Liu et al, J. Org. Chem. 1980, Vol. 45, p. 3916; T. Mukaiyama et al., J Am. Chem. Soc , 1960, Vol. 82, p. 5339. If desirable, the corresponding thioamide isoxazolines 4 are readily prepared by treatment of carbonyl amide isoxazolines 4 with Lawesson's Reagent in

^■19- a suitable solvent such as 1,4-dioxane at reflux temperature.

Compounds 4 are either examples of compounds of formula I of the present invention or are the intermediates that can be further elaborated to compounds of formula I of the present invention. For example, when A is a halogen atom (preferably a fluoro atom), treatment of halogenated heteroaromatic isoxazolines 4 with various amines in the presence of a suitable base such as, for example, dipotassium hydrogenphosphate, potassium carbonate, sodium hydride, or excess amines, in a suitable solvent such as, for example, N,N-dimethylformamide, dimethylsulf oxide, tert-butanol, neat amine, etc., at a suitable temperature in the range 40-140 °C and sometimes in a sealed pressure vessel, affords the compound I of the present invention.

As shown in SCHEME II, the nitrile oxide 2 can be reacted with allyl alcohol to generate 5-(hydroxymethyl)isoxazolines 5. Then, the structure 5 is converted to the corresponding alkylsulfonate or arylsulfonate 6. A representative alkylsulfonyl derivative, the mesylate (Re = CH₃), is prepared by reacting 5 with methanesulfonyl chloride in pyridine/dichloromethane or methanesulfonyl chloride and triethylamine in dichloromethane. Utilization of arylsulfonyl chloride reagents, for example, p- toluenesulfonyl chloride in pyridine or 3-nitrobenzenesulfonyl chloride and triethylamine in dichloromethane, affords aryl sulfonates such as tosylate (R_c is p- tolyl) or nosylate (R_c is 3-nitrophenyl), respectively. The mesylate or nosylate derivative 6 is then converted to the corresponding 5-(aminomethyl) isoxazoline 7 by treatment with aqueous ammonia in a suitable solvent system, for example acetonitrile/isopropanol or tetrahydrofuran isopropanol, in a sealed reaction vessel, and at a suitable temperature in the range from 40 to 90 °C. It will be apparent to those skilled in the art that alternative synthetic procedures for the introduction of the requisite aminomethyl side chain are available. For example, the sulfonate 6 can be reacted with an azide source such as sodium or potassium azide in an aprotic solvent such as N,N-dimethylformamide or l-methyl-2-pyrrolidinone optionally in the presence of a catalyst such as 18-crown-6 at a temperature of 50 to 90 °C to generate the corresponding δ-(azidomethyl) isoxazoline. The azide moiety is then reduced by hydrogenation with a palladium or platinum catalyst in a suitable solvent such as ethyl acetate or methanol to give 7. Alternatively, the azidomethyl intermediate can be reduced to the corresponding amine 7 by a two-step process involving treatment with a trivalent phosphorus compound such as triphenylphosphine in a suitable solvent such as tetrahydrofuran followed by hydrolysis of the resultant iminophosphorane with water. See: M.

-20- Vaultier, et al, Tetrahedron Lett, 1983, Vol. 24, p. 763. The amine 7 is then converted to the isoxazoline derivatives 3 by reactions known to those skilled in the art. For example, the amine 7 can be reacted with an acid chloride or anhydride in a basic solvent system such as pyridine or triethylamine/dichloromethane at a temperature ranging from -30 to 30 °C to provide the acylated compound 4 (wherein W is oxygen atom).

SCHEME II

A\₍ f ^{p ■}

^ ₀-

^^OH

^A 5 p ,

OH

^A:e o OS0₂R_c

^A-c7^

Λ

NhL

x3 x w -R 4 ^H

Various methods for acylation reactions are discussed further in J. March, "Advanced Organic Chemistry", 3rd ed., John Wiley & Sons, Inc., New York, 1985, pp. 370-375. The corresponding thioamides phenyl isoxazoline 4 (W is sulfur atom) are readily prepared by treatment of amide phenyl isoxazoline with Lawesson's

-21- Reagent in a suitable solvent such as 1,4-dioxane at reflux temperature. It will be apparent to those skilled in the art that other carbonyl-containing groups within the scope of this invention can be readily appended to the amine 7 by standard acylation techniques to give additional examples of 4. The remaining synthetic steps which lead structure 4 to the compound of formula I are the similar to that described in SCHEME I.

SCHEME III outlines an alternative reaction procedure which permits synthetic access to selected compounds of formula I of the present invention. It will be apparent to one skilled in the art that the exemplified Q substituent, morpholine or thiomorpholine, is merely representative and that other heterocyclic ring systems are possible. A halogenated heteroaromatic ester of structure 8 (wherein halogen is preferably a fluorine atom) is reacted with morpholine (wherein E is oxygen atom) or thiomorpholine (wherein E is sulfur atom), in the presence of a suitable base such as dipotassium hydrogenphosphate, in an appropriate solvent such as dimethylsulfoxide, and at a suitable temperature in the range from 60 to 100 °C, to provide the morpholino adduct 9. The ester moiety of 9 is then reduced to the corresponding heteroaromatic alcohol 10 with an appropriate reducing agent, such as lithium aluminum hydride and the like, in a suitable solvent, for example tetrahydrofuran, and at a suitable temperature in the range from -20 to 0 °C.

SCHEME III

The product alcohol 10 is then oxidized, employing catalytic tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide in dichloromethane, to the corresponding carboxaldehyde 11. The remaining synthetic

-22- steps which lead aldehyde 11 through nitrile oxide 12 to morpholino phenylisoxazoline 13 are similar to the procedures described in SCHEME I. Furthermore, in the case where E is sulfur atom, the sulfur atom can be oxidized to provide the corresponding sulfones and sulfoxides, respectively, in an early synthetic step or at the end of synthetic step if desirable. The detailed procedure for this oxidation is discussed in international publication No. WO 97/09328.

Enantiomerically enriched heteroaromatic isoxazolines of formula I may be obtained through the racemic phenylisoxazolines 3 or 4 by employing high pressure liquid chromatography (HPLC) over a chiral stationary phase. In a typical separation, the mixture of enantiomers is chromatographed with a 5x50 cm

Chiralpak AD column, eluting with heptane/isopropanol chloroform mixtures as the mobile phase, to provide the individual (R)- or (S)-enantiomer. If desired, the separation of enantiomers can be conducted either on the early intermediates 3 or 4 or on the final product. Enantiomerically enriched heteroaromatic isoxazolines may also be prepared according to procedures outlined in SCHEMES IV and V.

SCHEME IV

A\

1©6 OH

-23- As illustrated in SCHEME IV, reaction of nitrile oxides 2 with α,β-unsaturated esters or amides 14 undergoes an asymmetric 1,3-dipolar cycloaddition to provide compound 15. In this reaction, group R_d of compound 14 is a chiral auxiliary used to control the direction of asymmetric induction, and therefore it allows the asymmetric cycloaddition to occur with high steroselectivity. Compound 14 can be prepared from, among the others, Kemp's triacid, Oppolzer's sultam, or cbiro-inositol as described in such references as D. P. Curran et al., J. Am. Chem. Soc, 1989, Vol. Ill, p. 9238; J. A. Stack, et al., Tetrahedron, 1993, Vol. 49, p. 995; D. P. Curran et al., Tetrahedron Lett., 1988, Vol. 29, p. 3555; W. Oppolzer, et al., Tetrahedron Lett., 1991, Vol. 32, p. 4893; T. Akiyama et al., Tetrahedron Lett., 1992, Vol. 33, p. 5763; Y. H. Kim et al, Tetrahedron Lett, 1993, Vol. 34, p. 6063; C. J. Easton et al, "Advances in Heterocyclic Chemistry", Vol. 60 of "Cycloaddition Reactions of Nitrile Oxides with Alkenes", A. R. Katritzky, Ed., Academic Press, San Diego, 1994, pp. 261-327, and references cited therein. Use of appropriate chiral auxiliaries to control the steroselectivity of the asymmetric 1,3- dipolar cycloaddition provides access, ultimately, to both enantiomers of 15. For simplicity, only one enantiomer is presented. Racemic esters of structural formula 15 (wherein R_d is OMe or OEt) may also be resolved by an enzymatic ester hydrolysis procedure described in S. Yang et al., Monatsh. Chem., 1994, Vol. 125, p. 469.

The enantiomeric cycloadducts 15 may be further purified by recrystallization or chromatography. Treatment of the cycloadducts 15 with a suitable reducing agent such as L-selectride (commercially available) in an appropriate solvent such as tetrahydrofuran then provides the enantiomerically enriched δ-(hydroxymethyl) isoxazolines 16. The remaining synthetic steps which lead 16 to enantiomerically enriched heteroaromatic isoxazolines 4A are similar to the procedures outlined in SCHEME II.

Alternatively, compound 16 may prepared by treatment of nitrile oxide 2 with an allyl alcohol via a highly enantioselective 1,3-dipolar cycloaddition as shown in SCHEME V.

The reaction occurs in the presence of diethylzinc and (R,R)- and (S,S)- tartaric acid esters, preferably, diisopropyl esters, in a suitable solvent such as chloroform or dichloromethane and at a temperature in the range of about -20 to 0 °C. See Y. Ukaji et al., Chem. Letters, 1993, p. 1847. The remaining synthetic steps which lead compound 16 to enantiomerically enriched heteroaromatic

-24- isoxazolines of formula 4A are similar to the procedures outlined in SCHEME II.

SCHEME V

,OH

Av

R_e0₂C. C0₂R_θ

HO y OH

Y ?

4A

Following the procedures outlined in SCHEMES I-V, and making non-critical variations but starting with heteroaromatic moiety Ring T, compounds of formula II can be obtained.

The pharmaceutical compositions of this invention may be prepared by combining the compounds of formula I of this invention with a solid or liquid pharmaceutically acceptable carrier, and optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques. Solid form compositions include powders, tablets, dispersible granules, capsules and suppositories. A solid carrier can be at least one substance which may also function as a diluent, flavoring agent, soiubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like. Liquid form compositions include solutions, suspensions and emulsions. For example, there may be provided solutions of the compounds of this invention dissolved in water, water-propylene glycol, and water-polyethylene glycol systems, optionally containing conventional coloring agents, flavoring agents, stabilizers and thickening agents.

The pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula I according to

-25- this invention.

The quantity of active component, that is, the compounds of formula I according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.

In therapeutic use for treating bacterial infections in humans and other animals that have been diagnosed with bacterial infections, the compounds or pharmaceutical compositions thereof will be administered orally, parenterally, transdermally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective. Generally, such antibacterially effective amount of dosage of active component will be in the range of about 0.1 to about 100 mg/kg, more preferably about 3.0 to about 50 mg kg of body weight/day. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the bacterial infection being treated, and the particular compounds being used. Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day. These compounds are useful for the treatment of microbial infections in humans and other warm blooded animals by either oral, parenteral, topical, or transdermal administration. In general, the preferred form of administration is orally. Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compounds according to formula I as a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a suitably buffered isotonic solution having a pH of about 3.5 - 6. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine, to name a few. The compounds according to formula I generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg/ml to about 400 mg/ml. The

-26- resulting liquid pharmaceutical composition will be administered so as to obtain the above mentioned antibacterially effective amount of dosage. The compounds of formula I according to this invention are advantageously administered orally in solid and liquid dosage forms. The compounds of this invention are useful antimicrobial agents, effective against various human and veterinary pathogens, including multiply-resistant staphylococci and streptococci, as well as anaerobic organisms such as bacteroides and clostridia species, and acid-resistant organisms such as Mycobacterium tuberculosis and Mycobacterium aυium. Humans or animals infected with such pathogens are readily diagnosed by a physician or veterinarian of ordinary skill, throughout the specification, it is intended that citations to the literature are expressly incorporated by reference herein.

-27-

Claims

We claim:

1. A compound of formula I

CK

X

I or pharmaceutically acceptable salts thereof wherein: R_x is

(a) H,

(b) C^g alkyl, which may be substituted with one or more halo, -OH, C₁ alkoxy or C acyloxy, (c) C₃.₆ cycloalkyl,

(d) C^g alkoxy,

(e) amino, or

(f) NH(C_1.3 alkyl), wherein C^ alkyl may be substituted with one or more halo; Y is

(a) H,

(b) F, or

(0 CH₃;

W is

(a) 0, or

(b) S;

Ring P is

(a) aa 55--πm:embered heteroaromatic moiety having one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms, wherein the 5-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl,

(b) a 6-membered heteroaromatic moiety having one to three nitrogen atoms, wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene, naphthyl or 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms, or

-28- (c) a phenyl ring fused-on with a benzene, naphthyl, 6-membered heteroaromatic moiety having at least one nitrogen atom or a 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms; Q is

£N

*l xJ, i

N i-N

R .-N. R₉ N F^N

R yN^'

VI VII III

R₂-

N ^R₂

R₂

&:

XII XIII

& ?2

^N^ _N^ N-^N

XVI XVII

-29- f?17

CH₂)_n

V >18 ^ f

^Rιε xx

>21

(d) E N —

¹20

*25

(e) or

Z-(CH₂)_q-N. —

^Λ26

^34

^R35 — Λ

N —

(f)

R ^κ^33 ^~ -(CH₂)_π

wherein Ra is

(a) H,

(b) halo,

(c) -OH,

(d) -OR₃,

(e) -SR₃,

() -SCOjRa,

(g) -CN,

(h) -0₂CR₃,

(i) -NHC(=0)R₃,

-30- (j) -NHC0₂R₃,

(k) -NHS0₂R₃,

(1) -C0₂R₄,

(m) -C(=0)N(R₃)₂,

(n) -C(=0)R₃,

(o) C₁ alkyl,

(P⁾ C₃.₈ cycloalkyl wherein groups (o) and (p) may be substituted with one or more of the preceding groups (a)-(n), (q) phenyl, which may be substituted with one or more of the preceding groups (a)-(p),

(r) -CH=CHC0₂Et, or (s) -C(=NR₄)R₅; R₃ is (a) H,

(b) C_M alkyl,

(c) C₃.₈ cycloalkyl, wherein groups (b) and (c) may be substituted with one or more of halo, -OH, C_x-₄ alkoxy, C₁₄ acyl, C^ acyloxy, or -OC(=O)CH₂N(CH₃)₂, or (d) phenyl, which may be substituted with one or more of the preceding groups (b) to (c); R₄ is

(a) -OH or

(b) -OCH₃; R₅ is

(a) H, or

(b) -CH₃; wherein R₆ is

(a) H, (b) -OR₁₀,

(c) -SR₁₀,

(d) -NR_nR₁₂,

(e) -CN,

(f) C_w alkoxycarbonyl, (g) carboxamide,

(h) Ci-₄ acyl, which may be substituted with one or more halo, -OH,

-31- C_1A alkoxy or C_H acyloxy, (i) -N(OH)(C₁.₆ alkyl), (j) -N(OH)CH₂phenyl, (k) -NS0₂(C₁.₆alkyl) wherein C^g alkyl may be substituted with one or more halo, C^g alkoxy or phenyl, or (1) F;

R₇ is

(a) H, (b) -OH,

(c) -OCCi-β alkyl),

(d) Ci-₄ alkyl,

(e) phenyl, or

(f F;

Ro is

(a) H,

(b) 0^₃ alkyl, which may be substituted with halo, -OH, -C0₂ C₁ alkyl, Ci.₃ acyloxy, C^ alkyoxy or -N(C₁₄ alkyl)₂,

(c) phenyl, or

(d) pyridyl; R₉ is

(a) O,

(b) S,

(c) -NR₁₃, or

(d) -CR₁₄R₁₅; R₁₀ is

(a) H,

(b) C^g alkyl, which may be substituted with one or more halo, -CN, -OH, C _& alkoxy, C^g acyloxy, C_w alkoxycarbonyl, or phenyl,

(c) C^g acyl, which may be substituted with one or more -OH, C^g alkoxy, C^ acyloxy,

(d) Ci-g alkoxycarbonyl,

(e) carboxamide, which may be substituted with a C_:.₄ alkyl or phenyl on the carboxamide nitrogen, or

(f) phenyl, which may be substituted with one or more halo, -CN, Ci.₃ alkoxy, C_u alkoxycarbonyl or C-^ alkyl;

R_n and R₁₂ are the same and different and are

-32- (a) H,

(b) C^g alkyl, which may be substituted with one or more halo, -CN, -OH, C_λ_₈ alkoxy, C₁ acyloxy, C^g alkoxycarbonyl, phenyl,

(c) C^g acyl, which may be substituted with one or more -OH, amino, C^g alkoxy, C^g acyloxy, C_w acylamino,

(d) benzoyl, which may be substituted with one or more halo, -OH, amino, C ₈ alkoxy, C^ acyloxy, C_w acylamino, C₁₄ alkoxycarbonylamino,

(e) C_λ.₈ alkoxycarbonyl,

(f benzyloxycarbonyl, (g) tertbutoxycarbonyl,

(h) carboxamide, which may be substituted with a C₁ alkyl or phenyl on the carboxamide nitrogen, (i) trifluoracetyl, or 0^') Cχ-₈ acyl; R₁₃ is

(a) H,

(b) -OR₁₀,

(c) -NHR₁₀, or

(d) C ₈ alkyl, which may be substituted with phenyl; R₁₄ and R₁₅ are the same and different and are

(a) H,

(b) C₁ alkyl, which may be substituted with halo, -OH, C^alkoxy, C_j.₄ alkoxycarbonyl, or phenyl,

(c) C_LS acyl,

(d) C_M alkoxycarbonyl,

(e) -CN, or

(f) F;

R₁₆ is

(a) 0, or

(b) S;

R₁₇ and R₁₈ are the same and different and are

(a) H,

(b) C-.₄ alkyl, which may be substitu

(c) -OH,

(d) C_w alkoxy, which may be substit

(e) NR_nR₁₂, or

-33- ( ) C₁ acyloxy

R₁₉ is

(a) H, or

(b) -CH₃;

E is

(a) -0-, or

(b) -S(=0)_m-;

Rao is

(a) H,

(b) -CH₃,

(c) -CN,

(d) -CO₂H,

(e) -CO₂R₂₂, or

( ) -(CH^R^;

R₂₁ is

(a) H, or

(b) -CH₃;

Raa is

(a) H, (b) C^g alkyl, which may be substituted with halo, -OH, C₁₄ alkoxy,

C₁ acyloxy or -0-CH₂-phenyl,

(c) C₃.₆ cycloalkyl,

(d) amino,

(e) -N(C_M alkyl)₂,

(f) -NH(C₁.₆ alkyl), or

(g) C^g alkoxy;

R^₃ ^is

(a) -OH,

(b) -OR22>

(c) -OC(=0)R₂₂,

(d) amino,

(e) -NHC(=0)R₂₂, or

(f) -N(Ra₄)₂.

R24 ^is

(a) H,

(b) C^ aallkkyyll,, wwhhiicchh i mr ay be substituted with halo, -OH, C_1A alkoxy,

-34- amino, -N C^ alkyl)₂, or -NH(C₁.₆ alkyl), or (c) p-toluenesulfonyl; wherein Z is

(a) H,

(b) -C(=0)R₂₇,

(c) Ci-g alkyl,

(d) benzyl,

(f) " Rag ,

(g) -OC(=0)R₂₉,

(h) -S-Ci.₆ alkyl,

(i) -SOa-Cw alkyl,

(j) phenylsulfonyl,

(k) p-toluenesulfonyl,

(1) -SO₂-N(R₃₀)₂,

(m) -C(0)-OR₃₁,

(n) -C(O)-N(R₃₀)₂,

(o) -N(R₃₀)₂, or

--N .

_L ^y L^ ^N L^ .^

FT

XXVIII y

L is

(a) H,

(b) amino,

(c) C_w alkyl, or

(d) halo; R₂₅ and Ra₆ are the same and different and are

(a) H,

-35- (b) C^g alkyl, or

(0 C₃.₆ cycloalkyl;

-2₇ IS

(a) Ci.₆ alkyl,

(b) C-.₈ alkylhydroxyl,

(0 phenyl, or

(d)

R₂₈ is :r

(a) H,

(b) C_ω alkyl,

(c) vinyl, or

(d) phenyl, which may be substituted with one to more halo, C_w alkoxy, -OH, amino or C₁ alkyl;

R_jg is

(a) C^g alkyl, or

(b) phenyl; R₃₀ is independently (a) H,

(b) C₁ alkyl, or

(c) phenyl, which may be substituted with C₁ alkyl or C^ alkoxy; R₃₁ is

(a) C-.g alkyl, (b) phenyl, which may be substituted with C₁ alkyl or C₁ alkoxy, or

(c) benzyl, which may be substituted with C₁ alkyl or C_w alkoxy; wherein R₃₂ and R₃₃ are the same and different and are

(a) H,

(b) halo, (c) C^g alkyl, which may be substituted with one or more R₄₅,

(d) C₃.₆ cycloalkyl,

(e) -(CH₂)_m-OR₃₆, or

(f) -C(=0)-R₃₈;

R₃₄ and R₃₅ are the same and different and are (a) H,

(b) C^g alkyl, which may be substituted with one or more R₄₅,

-36- (c) Cn, alkoxy,

(d) Ci-_β alkylthio,

(e) -(CH₂)_m-OR₃₉,

(f -0-(CH₂)_m-OR₃₉, (g) -NR₄₀R₄₁,

(h) -N=CH-NR₄₂R₄₃,

(i) -C(=O)-NR₄₀R₄₁, or

(j) -(CH₂)_m-C(=A)-R₃₈, wherein A is O or ethyleneketal, or R₃₄ and R₃₅ may combine together to form (k) =0,

(1) =NR₄₄,

(m) =S, or

(n) =CR₄₂R₄₃;

R₃₆ and R₃₇ are the same and different and are (a) H,

(b) C_j.₈ alkyl, which may be substituted with one or more R₄₅, or

(c) -CH₂OCH₃; R₃₈ is

(a) H, (b) -(CH₂)_m-0H,

(c) C^g alkyl, which may be substituted with one or more R₄₅,

(d) Cj.₈ alkoxy,

(e) -0-CH₂-O-C(=0)-R₃₆, or

(f) -(CH₂)_m-C(=0)-OR₃₆; R₃₉ is

(a) H,

(b) C^g alkyl, which may be substituted with one or more R₄₅,

(c) C₂.₈ alkenyl,

(d) -(CH₂)_m-OR₃₆, (e) -(CH₂)_m-C(=0)-R₃₈,

(£) -C(=0)-(CH₂)_m-OR₄₃, or

(g) tosyl;

R₄₀ and R₄₁ are the same and different and are

(a) H, (b) -(CH₂)_m-OR₃₆,

(c) C-.₈ alkyl, which may be substituted with one or more R₄₅,

-37- (d) -C(=0)-R₃₈,

(e) -C(=0)-NR₃₆R₃₇,

(f) -(CH₂)_p-phenyl,

(g) thiazol-2-yl, or R₄₀ and R₄₁ may combine together to form

(h) pyrrolidino,

(i) piperidino,

(j) piperazino,

(k) morpholino, or (1) thiomorpholino, wherein groups (h) to (1) may be substituted with C^g alkyl or -(CH₂)_m-OH; R₄₂ and R₄₃ are the same and different and are

(a) H,

(b) C_LS alkyl, which may be substituted with one or more R₄₅, (c) -C(=0)-R₃₈, or

(d) -(CH₂)_p-phenyl; R₄₄ is

(a) H,

(b) -0R₃₉, (c) C^g alkyl, which may be substituted with one or more R₄₅,

(d) Cχ.₈ alkoxy,

(e) -(CH₂)_p-phenyl,

(f) -NR₄₀R₄₁,

(g) -NH-C(=NH)-NH₂, (h) [l,2,4]triazol-4-yl, or

(i) -CN; R₄₅ is

(a) halo,

(b) -OH, (c) -CN,

(d) C-.g alkoxy,

(e) amino,

(f) -N(C_M alkyl)₂,

(g) -NH(C₁_₆ alkyl), or (h) carboxyl;

- is a double bond or a single bond;

-38- i is 1 or 2; m is 0, 1 or 2; n is 0 or 1; p is 1, 2, 3 or 4; and q is 0, 1, 2, 3 or 4.

2. A compound of formula I according to claim 1 wherein R_x is

(a) Cχ-₃ alkyl,

(b) Ci-g alkoxy, or (c) -NIKCi-j alkyl).

3. A compound of formula I according to claim 1 wherein R_x is CH₃.

4. A compound of formula I according to claim I wherein Y is H, or F.

5. A compound of formula I according to claim 1 wherein W is O.

6. A compound of formula I according to claim 1 wherein W is S.

7. A compound of formula I according to claim 1 wherein Ring P is pyridyl.

8. A compound of formula I according to claim 1 wherein Q is a 5-membered heterocyclic moiety having one to four nitrogen atoms selected from structures consisting of i, ii, iii, and vi

r\ Π₂ _R2X Xil. X^N _R2J . i ii iii vi wherein ^ is as defined in claim 1.

9. A compound of formula I according to claim 8 wherein R^ is

(a) H,

(b) -CN,

(c) -C(=0)H,

(d) -C(=NH)-OH, or

(e) C^a alkyl hydroxyl;

-39-

10. A compound of formula I according to claim 1 wherein Q is

(a) O \

(b) o-

(c) N — or

^(d) z- ^^ - ^;

wherein E is as defined in claim 1.

11. A compound of formula I according to claim 10 wherein Z is

(a) H,

(b) -C(=0)R₂₇, (c) pyridinyl,

(d) 2-pyrimidinyl,

(e) 4-pyrimidinyl, or

(f) pyridazinyl; wherein groups (c) to (f) may be substituted with amino, methyl, F, or CI; wherein R₂₇ is as defined in claim 1.

12. A compound of formula I according to claim 11 wherein R^ is

(a) C_M alkyl,

(b) C^a alkylhydroxyl, or

^(c) :

-40-

13. A compound of formula II

,X VP \ C— R

N

H

II or pharmaceutically acceptable salts thereof wherein:

R_x and W are the same as defined in claim 1; Ring T is a 6-membered heteroaromatic moiety having one to three nitrogen atoms, wherein the 6-membered heteroaromatic moiety has a fused-on 5-membered heteroaromatic moiety which in turn has one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms;

X is (a) carboxyl,

(b) halo,

(c) -CN,

(d) mercapto,

(e) formyl, (f) -CF₃,

(g) -N0₂,

(h) C^g alkoxy,

(i) C ₆ alkoxycarbonyl,

0^') Cj.₆ alkythio, (k) C_w acyl,

(1) -NR₄₈ R₄₉,

(m) Cj.₆ alkyl which can be substituted with R₅₀

(n) C₂.₈ alkenylphenyl optionally substituted with one or two R₅₁,

(o) phenyl optionally substituted with one or two R₅₁, (p) -CH=NOH,

(q) -CH=N-(OC₁.₆alkyl),

(r) a 5-, or 6-membered heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R ',51>

-41- (s) , or

(t) N'

H

R₄₈ and R₄₉ are the same and different and are

(a) H,

(b) C_w alkyl, (c) C₅.₆ cycloalkyl, or

(d) R₄₈ and R₄₉ taken together with the nitrogen atom is a 5-, 6- membered heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, C_u alkyl, or C_w acyl; R₅₀ is

(a) -OH,

(b) C^ alkoxy,

(c) C_1Λ acyl,

(d) -NR₄₈R₄₉, (e) -NHC(=S)NH₂,

(f) -NHC(=0)NH₂,

(g) -NHC(=0)R₄₉, (h) -S0₂NR₅₅R₅₆, or (i) -NRS0₂R₅₅; R₅₁ is

(a) carboxyl,

(b) halo, (0 -CN,

(d) mercapto, (e) formyl,

( ) CF₃,

(g) -N0₂,

(h) C^g alkoxy,

(i) C_j.₆ alkoxycarbonyl, (j) 0^ alkythio,

(k) C^g acyl,

-42- (1) C^g alkyl optionally substituted with OH, Cj.g alkoxy, C^_s acyl, or

-NR₄₈R₄₉,

(m) phenyl,

(n) -C(=0)NR₅₂ R₅₃, (o) -NR₄₈R₄₉,

(p) -N(R₅₂)(-S0₂R₅₄),

(q) -S0₂-NR₅₂R₅₃, or

(r) -S(=0)_;R₅₄; R₅₂ and R₅₃ are the same and different and are (a) H,

(b) C^e alkyl, or

(c) phenyl; R₅₄ is

(a) C_L4 alkyl, or (b) phenyl optionally substituted with C-.₄ alkyl;

R₅₅ and R₅₆ are the same and different and are

(a) H, or

(b) C_M alkyl; and j is 0 or 1.

14. A compound of formula II according to claim 14 wherein Ring T is

*yyy

15. A compound of formula II according to claim 14 wherein X is

(a) Cj.₄ alkyl which can be substituted with R₅₀

(b) phenyl optionally substituted with one or two R₅₁, (c) -CH=NOR,

(d) pyridyl optionally substituted with one or two R₅₁,

(e) thienyl optionally substituted with one or two R₅₁; R₅₀ and R₅₁ are the same as defined in claim 14.

16. A compound of formula II according claim 14 wherein R₄₈ and R₄₉ are the same and different and are

-43- a) H, b) Ci-₃ alkyl, or c) R₄₈ and R₄₉ taken together with the nitrogen atom are morpholinyl, pyrrolidinyl, piperazinyl or piperidyl ring;

17. A method for treating microbial infections in patients comprising: administering to a patient in need thereof an effective amount of a compound of formula I as shown in claim 1 or formula II as shown in claim 13.

18 The method of claim 17 wherein said compound of formula I or formula II is administered orally, parenterally, topically or transdermally in a pharmaceutical composition.

19. The method of claim 17 wherein said compound of formula I or formula II is administered orally in a pharmaceutical composition.

20. The method of claim 17 wherein said compound of formula I or formula II is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day.

21. A pharmaceutical composition comprising a compound of claim 1 or claim 13 and a pharmaceutically acceptable carrier.

22. The compounds of claim 1 having the following provisos:

(a) where R_x is -CH₃, W is O, ring P is 3-pyridinyl, Y is H, then Q is not 6-pyrazol-l-yl, 6-1,2,4-triazol-l-yl, 6-(4-iodo-pyrazol-l-yl),

6-(4-acetyl-pyrazol-l-yl) or 6-(4-phenyl-pyrazol-l-yl);

(b) where Rj is -CH₃, W is O, Y is H, then ring P is not benzofuran-5-yl.

-44-