AU3180999A

AU3180999A - Substituted aminomethyl isoxazoline derivatives useful as antimicrobials

Info

Publication number: AU3180999A
Application number: AU31809/99A
Authority: AU
Inventors: Michael R. Barbachyn; David R. Graber; Joel Morris; Richard C. Thomas; Donn G Wishka
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: 1999-09-15
Also published as: CA2318762A1; EP1060179A1; JP2002504550A; WO1999043671A1

Description

WO 99/43671 PCT/US99/04262 SUBSTITUTED AMINOMETHYL ISOXAZOLINE DERIVATIVES USEFUL AS ANTIMICROBIALS FIELD OF THE INVENTION 5 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. 10 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 15 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 20 heteroaryl-oxazolidinones having one to three atoms selected from the group consist ing 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 25 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 30 organisms such as Mycobacterium tuberculosis and Mycobacterium avium. INFORMATION DISCLOSURE U.S. Patent No. 4,283,403 discloses 3-aryl-2-isoxazolines useful for the protection of plants from diseases. 35 Danish Patent No. 2,725,763 discloses substituted 2-isoxazolines which is fungicidal against phytophthora infestation on tomatoes. The compounds also show -1- WO 99/43671 PCT/US99/04262 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 5 PDEv, 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 10 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. 15 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 20 substituted phenyloxazolidinone antimicrobials. International Publication No. WO 97/21708 discloses 4-pyrimidinyl- or 4 pyrazinyl-piperazinyl-phenyl-oxazolidinone derivatives. SUMMARY OF THE INVENTION 25 In one aspect, the present invention provides a compound of formula I R PW H / 30 H I or pharmaceutically acceptable salts thereof wherein:

R

1 is 35 (a) H, (b) C 1 ., alkyl, which may be substituted with one or more halo, -OH, -2- WO 99/43671 PCT/US99/04262 C14 alkoxy or C1 4 acyloxy, (c) C 3 6 cycloalkyl, (d) C 1 .8 alkoxy, (e) amino, or 5 (f) NH(C 1 3 alkyl), wherein C 1 3 alkyl may be substituted with one or more halo; Y is H, F, or CH 3 ; W is 0, orS; Ring P is 10 (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 15 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 20 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; 25 NNN iii iii iv 30 R R2N N N N N:N 2 , N R 2 NR2 R 2 N ,, R 2 V vi vii viii ix (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; 35 -3- WO 99/43671 PCT/US99/04262 R R2 R N R x XI 5 R2 2 R2 N- R2 N R2 N xii xiii xiv xv

RR

2 R2

R

2 10N N N N N 10 \ Xvi Xvii Xviii (c) a heterocyclic ring having a nitrogen atom selected from structures consisting of xix, xx, xxi, xxii, and xxiii; 15 R6 R 17 R R C H 2 ) R R 9 8 R j / .

H

N

16

R

8 N

R

8 RN R R xix xx xxi 20 R6 R R\ R8 (CH 2 )n

R

7 R8 R 8 NN R7 N\ R7 -'-R7 R8 7 R8 N

R

8

R

7 25 xxii xxiii (d) E N R20 30 R25 (e) , or Z-(C H 2 )q_N _ 35 R26 -4- WO 99/43671 PCT/US99/04262

R

34

R

32 (f)

R

35 N

(CH

2 ) R33 ' 2(C , 5 wherein R 2 is (a) H, (b) halo, (c) -OH, (d) -OR 3 , 10 (e) -SR 3 , (f) -S(O)iR3 , (g) -CN, (h) -0 2

CR

3 , (i) -NHC(=O)R 3 , 15 (j) -NHCO 2

R

3 , (k) -NHSO 2

R

3 , (1) -CO 2

R

4 , (m) -C(=O)N(R 3

)

2 , (n) -C(=O)R 3 , 20 (o) C 1

-

s alkyl, (p) C.

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 25 groups (a)-(p), (r) -CH=CHCO 2 Et, or (s) -C(=NR 4 )R5;

R

3 is (a) H, 30 (b) C 1

.

6 alkyl, (c) C 3 s cycloalkyl, wherein groups (b) and (c) may be substituted with one or more of halo, -OH, C14 alkoxy, C 14 acyl, C 1

.

4 acyloxy, or -OC(=O)CH 2

N(CH

3

)

2 , or (d) phenyl, which may be substituted with one or more of the preceding 35 groups (b) to (c);

R

4 is -OH or -OCH 3 ; -5- WO 99/43671 PCT/US99/04262

R

5 is H, or -CH 3 ;

R

6 is (a) H, (b) -OR 1 0 o, 5 (c) -SR 1 0 , (d) -NR 11

R

1 2 , (e) -CN, (f) C 1

-

4 alkoxycarbonyl, (g) carboxamide, 10 (h) C 14 acyl, which may be substituted with one or more halo, -OH,

C

14 alkoxy or C 1

-

4 acyloxy, (i) -N(OH)(C1.6 alkyl), (j) -N(OH)CH 2 phenyl, (k) -NSO 2

(C

1 6 alkyl) wherein C 1

,

6 alkyl may be substituted with one or 15 more halo, C 1 6 alkoxy or phenyl, or (1) F;

R

7 is (a) H, (b) -OH, 20 (c) -O(C 1 6 alkyl), (d) C 1 4 alkyl, (e) phenyl, or (f) F; R. is 25 (a) H, (b) C 1 3 alkyl, which may be substituted with halo, -OH, -CO 2

C

1

.

4 alkyl,

C

1 3 acyloxy, C 1

.

3 alkyoxy or -N(C 1

.-

4 alkyl) 2 , (c) phenyl, or (d) pyridyl; 30 R 9 is O, S, -NR 13 , or -CR 1 4

R

1 5 ;

R

1 0 is (a) H, (b) C 1 , alkyl, which may be substituted with one or more halo, -CN, -OH,

C,

a alkoxy, C 1 .s acyloxy, C1- 4 alkoxycarbonyl, or phenyl, 35 (c) C, 8 acyl, which may be substituted with one or more -OH,

CI-.

8 alkoxy, C 1 ., acyloxy, -6- WO 99/43671 PCT/US99/04262 (d) Cis 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, 5 C 13 - alkoxy, C- 3 alkoxycarbonyl or C 4 alkyl;

R

1 , and R 12 are the same and different and are (a) H, (b) C 1 , alkyl, which may be substituted with one or more halo, -CN, -OH,

C

1 8 alkoxy, C 1

.

8 acyloxy, C 1

.

s alkoxycarbonyl, phenyl, 10 (c) CI- 8 acyl, which may be substituted with one or more -OH, amino,

C

1 j- alkoxy, C 1

.

8 acyloxy, C 1

.

4 acylamino, (d) benzoyl, which may be substituted with one or more halo, -OH, amino, C1-s alkoxy, C 1

.

8 acyloxy, C.

4 acylamino, C 1

.

4 alkoxycarbonylamino, (e) C1.8 alkoxycarbonyl, 15 (f) benzyloxycarbonyl, (g) tertbutoxycarbonyl, (h) carboxamide, which may be substituted with a C 1

.

4 alkyl or phenyl on the carboxamide nitrogen, (i) trifluoracetyl, or 20 (j) C 1

.

6 acyl;

R

1 3 is H, -ORo 10 , -NHR 0 , or C 1

.

8 alkyl, which may be substituted with phenyl;

R

14 and R 1 5 are the same and different and are (a) H, (b) C 1 4 alkyl, which may be substituted with halo, -OH, C 1

.-

4 alkoxy, 25 C 1

.

4 alkoxycarbonyl, or phenyl, (c) C 1 .- acyl, (d) C1-4 alkoxycarbonyl, (e) -CN, or (f) F; 30 R 1 6 is O, or S;

R

17 and Rs 18 are the same and different and are (a) H, (b) C 1

.

4 alkyl, which may be substituted with halo, -OH or C 1

_

4 alkoxy, (c) -OH, 35 (d) C 1 -4 alkoxy, which may be substituted with -OH or C 1 - alkoxy, (e) NR 1

R

1 2 , or -7- WO 99/43671 PCT/US99/04262 (f) C 1

.

4 acyloxy;

R

19 is H, or -CH3 E is (a) -0-, or 5 (b) -S(=O)m-;

R

20 is (a) H, (b) -CH 3 , (c) -CN, 10 (d) -CO 2 H, (e) -CO 2

R

22 , or (f) -(CH 2 )ARi 3 ;

R

21 is H, or -CH 3 ;

R

22 is 15 (a) H, (b) C 1 s 6 alkyl, which may be substituted with halo, -OH, C1-4 alkoxy, C14 acyloxy or -O-CH 2 -phenyl, (c) C36 cycloalkyl, (d) amino, 20 (e) -N(Cl 6 alkyl) 2 , (f) -NH(C 1 .6 alkyl), or (g) C 1

.

6 alkoxy;

R

23 is (a) -OH, 25 (b) -OR 22 , (c) -OC(=0)R 22 , (d) amino, (e) -NHC(=O)R2 2 , or (f) -N(R24)2; 30 R 2 4 is (a) H, (b) C-4 alkyl, which may be substituted with halo, -OH, C,- 4 alkoxy, amino, -N(C 1 6 alkyl) 2 , or -NH(C 1 6 alkyl), or (c) p-toluenesulfonyl; 35 wherein Z is (a) H, -8- WO 99/43671 PCT/US99/04262 (b) -C(=O)R 27 , (c) C1-6 alkyl, (d) benzyl, (e) phenyl, wherein groups (d) and (e) may be substituted with one or 5 more halo, -OCH 3 , -OH, amino or C 14 alkyl, (f) -OR28 , (g) -OC(=O)R 29 , (h) -S-C 1 6 alkyl, (i) -SO 2

-C

1

.

6 alkyl, 10 (j) phenylsulfonyl, (k) p-toluenesulfonyl, (1) -SO 2

-N(R

3 0

)

2 , (m) -C(O)-OR 3, (n) -C(O)-N(Ro) 2 , 15 (o) -N(R 3 0

)

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, 20 LLY L L xxiv xxv xxvi L N N L N -L -- N , , NL -" xxvii xxviii xxix 25 L is (a) H, amino, C1.4 alkyl, or halo;

R

2 5 and R 26 are the same and different and are (a) H, 30 (b) C 1

.

6 alkyl, or (c) C 36 cycloalkyl; R, is (a) C 1

.

6 alkyl, (b) Cs alkylhydroxyl, 35 (c) phenyl, or -9- WO 99/43671 PCT/US99/04262 (d)

R

28 is 5 (a) H, (b) C 1

-

6 alkyl, (c) vinyl, or (d) phenyl, which may be substituted with one to more halo, C 1

.

4 alkoxy, -OH, amino or C 14 alkyl; 10 R 29 is C 1

.

6 alkyl, or phenyl;

R

30 o is independently (a) H, (b) C 1

_

4 alkyl, or (c) phenyl, which may be substituted with C 1

.

4 alkyl or C 1

-.

4 alkoxy; 15 R.

1 is (a) C 1

.

6 alkyl, (b) phenyl, which may be substituted with C1- 4 alkyl or C 14 alkoxy, or (c) benzyl, which may be substituted with C 1

.

4 alkyl or C 1

.

4 alkoxy; wherein R 32 and R 33 are the same and different and are 20 (a) H, (b) halo, (c) C 1

.

8 alkyl, which may be substituted with one or more R 45 , (d) Cs.

6 cycloalkyl, (e) -(CH 2 )m-OR 3 6 , or 25 (f) -C(=O)-Res;

R

4 and R 35 are the same and different and are (a) H, (b) C 1

.

s alkyl, which may be substituted with one or more R45, (c) C 1

.

s alkoxy, 30 (d) C 1

-

s alkylthio, (e) -(CH 2 )m-OR9, (f) -O-(CH 2 )m-OR 3 9, (g) -NR 40

R

41 , (h) -N=CH-NR 4 2

R

4 3 , 35 (i) -C(=O)-NR 4 0

R

41 , or (j) -(CH 2 )m-C(=A)-R 3 s, wherein A is O or ethyleneketal, -10- WO 99/43671 PCT/US99/04262 or R 3 4 and R 35 may combine together to form (k) =0, (1) =NR 44 , (m) =S, or 5 (n) =CR 42

R

43 ;

R

36 and R 3 7 are the same and different and are (a) H, (b) C 1 . alkyl, which may be substituted with one or more R 4 5 , or (c) -CH 2

OCH

3 ; 10 R 3 8 is (a) H, (b) -(CH 2 )m-OH, (c) C 1 , alkyl, which may be substituted with one or more R 4 5 , (d) Cl, alkoxy, 15 (e) -O-CH 2 -O-C(=0)-R36, or (f) -(CH 2 )m-C(=0)-OR 36 ;

R

39 is (a) H, (b) CI 8 alkyl, which may be substituted with one or more R45, 20 (c) C 2 -8 alkenyl, (d) -(CH 2 )m-OR 36 , (e) -(CH 2 )m-C(=0)-R 3 8 , (f) -C(=O)-(CH 2 )m-OR 43 , or (g) tosyl; 25 R 40 and R 41 are the same and different and are (a) H, (b) -(CH 2 )m-OR 86 , (c) Cls alkyl, which may be substituted with one or more R4., (d) -C(=O)-R 3 8 , 30 (e) -C(=0)-NR 36

R

37 , (f) -(CH 2 )p-phenyl, (g) thiazol-2-yl, or R 40 and R 41 may combine together to form (h) pyrrolidino, 35 (i) piperidino, (j) piperazino, -11- WO 99/43671 PCT/US99/04262 (k) morpholino, or (1) thiomorpholino, wherein groups (h) to (1) may be substituted with C 1 , alkyl or -(CH 2 )m-OH;

R

42 and R 4 3 are the same and different and are 5 (a) H, (b) C 1 - alkyl, which may be substituted with one or more R45, (c) -C(=O)-R 38 , or (d) -(CH 2 )p-phenyl;

R

4 4 is 10 (a) H, (b) -OR 3 9 , (c) C 1 ,- alkyl, which may be substituted with one or more R 45 , (d) Cs, alkoxy, (e) -(CH 2 )p-phenyl, 15 (f) -NR 40

R

41 , (g) -NH-C(=NH)-NH 2 , (h) [1,2,4]triazol-4-yl, or (i) -CN;

R

45 is 20 (a) halo, (b) -OH, (c) -CN, (d) C 1 6 alkoxy, (e) amino, 25 (f) -N(C 1 6 alkyl) 2 , (g) -NH(C 1 6 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. 30 In another aspect, the present invention provides compounds of formula II X / C-R, r N/ H N\ H 35 II -12- WO 99/43671 PCT/US99/04262 or pharmaceutically acceptable salts thereof wherein:

R

1 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 5 turn has one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms; X is (a) carboxyl, (b) halo, 10 (c) -CN, (d) mercapto, (e) formyl, (f) -CF3, (g) -NO 2 , 15 (h) C 1 6 alkoxy, (i) C 1 6 alkoxycarbonyl, (j) C 1 6 alkythio, (k) C 1

.

6 acyl, (1) -NR 48

R

49 , 20 (m) C1- 6 alkyl which can be substituted with R 5 0 so (n) C 2 -8 alkenylphenyl optionally substituted with one or two R 51 , (o) phenyl optionally substituted with one or two R.

1 , (p) -CH=NOH, (q) -CH=N-(OC 1

.

6 alkyl), 25 (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 , 0 30 (SH) , or 30 -N (t) N-N H 35 R 4 . and R 4 9 are the same and different and are (a) H, -13- WO 99/43671 PCT/US99/04262 (b) C1-4 alkyl, (c) C5 6 cycloalkyl, or (d) R 48 and R 4 9 taken together with the nitrogen atom is a 5-, 6 membered heterocyclic moiety which optionally has a further hetero atom selected 5 from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, C 1 -3 alkyl, or C 1 3 acyl; Rso 50 is (a) -OH, (b) C, 1 alkoxy, 10 (c) CI 4 acyl, (d) -NR 48

R

49 , (e) -NHC(=S)NH 2 , (f) -NHC(=O)NH 2 , (g) -NHC(=O)R 49 , 15 (h) -SO 2

NR

55

R

56 , or (i) -NRSO 2

R

55 ;

R

51 is (a) carboxyl, (b) halo, 20 (c) -CN, (d) mercapto, (e) formyl, (f) CF 3 , (g) -NO 2 , 25 (h) C 16 alkoxy, (i) C 1

.

6 alkoxycarbonyl, (j) C 16 alkythio, (k) C 1

-

6 acyl, (1) C 1 6 alkyl optionally substituted with OH, C1-5 alkoxy, C 15 acyl, or 30 -NR48R49, (m) phenyl, (n) -C(=O)NR 5 2 R53, (0) -NR 48

R

49 , (p) -N(R 52 )(-SO2R 54 ), 35 (q) -S0 2

-NR

52

R

53 , or (r) -S(=O)iR 54 ; -14- WO 99/43671 PCT/US99/04262

R

52 and R 53 are the same and different and are (a) H, (b) C 1

.

6 alkyl, or (c) phenyl; 5 R 54 is (a) C,4 alkyl, or (b) phenyl optionally substituted with C 1

.

4 alkyl;

R

5 , and R 56 are the same and different and are (a) H, or 10 (b) C 1

.

6 alkyl; andj 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 15 bacteroides and clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium. DETAILED DESCRIPTION OF THE INVENTION For the purpose of the present invention, the carbon content of various 20 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 defines the number of carbon atoms present from the integer 'T"i" to the integer "j", inclusive. Thus, C 1

.

4 alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof. 25 The terms "C 1

.

3 alkyl", "Cl-.

4 alkyl", "C- 1

.

6 alkyl", and "C- 8 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 "C 2

.

8 alkenyl" refers to at least one double bond alkenyl group 30 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 "C 3

.

6 cycloalkyl", and "C 3

.

8 cycloalkyl" refer to a cycloalkyl having three to six, or three to eight carbon atoms respectively such as, for example, 35 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and their isomeric forms thereof. -15- WO 99/43671 PCT/US99/04262 The terms "C 1

.

3 , alkoxy", "C- 1

.

4 alkoxy", "Cl- 6 alkoxy", and "C- 1

.

s 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 5 isomeric forms thereof. The terms "C 1

.

4 acyl", "C 1

.

6 acyl", and "Cl., 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 1

.

3 alkoxycarbonyl", "C 1

.

6 alkoxycarbonyl", and "C1-8 10 alkoxycarbonyl" refer to a -CO 2 R 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 1

.

3 acyloxy", "C 1 4 acyloxy", and "C 1

.

s acyloxy" refer to a -OC(=O)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. 15 The term "C 1

.

4 acylamino" refers to a -NHC(=O)R group, wherein R is an alkyl group of one to four carbon atoms and their isomeric forms thereof. The term "C 1

.

4 alkoxycarbonylamino" refers to -NHC(=O)OR, wherein R is an alkyl group of one to four carbon atoms and their isomeric forms thereof. The term "C 1

.

8 hydroxyl" refers to an alkyl group having one to eight carbon 20 atoms and isomeric forms thereof attached to a hydroxy group. The term "C 1

.

8 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, 25 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, 30 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 35 (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- WO 99/43671 PCT/US99/04262 in any of the Q or R 1 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 5 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, 1-(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, 1-(5,6-dihydro)-2H 10 2-pyrindinyl, 2-(5,6-dihydro)-l1H-1-pyrindinyl, 3-(5,6-dihydro)-l1H-1-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 15 dihydro)-furo[3,2-b]pyridinyl, 6-(1,3-dihydro)-furo[3,4-c]pyridinyl, 4-(1,3-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)- 1H-pyrano[3,4-c]pyridinyl, 7-(3,4-dihydro)- 1H 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)- 1H-pyranol[4,3-c]pyridinyl, 8-(3,4-dihydro)- 1H 20 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)-l1H-pyrano[3,4-b]pyridinyl, 2-(5,6-dihydro)-2H pyranol[4,3-b]pyridinyl, 6-(3,4-dihydro)-2H-pyranol[3,2-b]pyridinyl, 5-1H-pyrrolo[2,3 c]pyridinyl, 6-1H-pyrrolo[3,2-c]pyridinyl, 4-1H-pyrrolo[3,2-c]pyridinyl, 7-1H pyrrolo[2,3-c]pyridinyl, 6-1H-pyrrolol[2,3-b]pyridinyl, 5-1H-pyrrolo[3,2-b]pyridinyl, 5 25 (2,3-dihydro)-l1H-pyrrolo[2,3-c]pyridinyl, 6-(2,3-dihydro)-1H-pyrrolo[3,2-c]pyridinyl, 4 (2,3-dihydro)- 1H-pyrrolo[3,2-c]pyridinyl, 7-(2,3-dihydro)- 1H-pyrrolo[2,3-c]pyridinyl, 6-(2,3-dihydro)- 1H-pyrrolo[2,3-b]pyridinyl, 5-(2,3-dihydro)- 1H-pyrrolo[3,2-b]pyridinyl, 6-(1,3-dihydro)- 1H-pyrrolo[3,4-c]pyridinyl, 4-(1,3-dihydro)- 1H-pyrrolo[3,4-c]pyridinyl, 2-(5,7-dihydro)-l1H-pyrrolo[3,4-b]pyridinyl, 6-1,7-naphthyridinyl, 6-2,7naphthyridinyl, 30 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-(1,2,3,4 tetrahydro)-1,7-naphthyridinyl, 6-(1,2,3,4-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 35 tetrahydro)-1,6-naphthyridinyl, 5-(1,2,3,4-tetrahydro)-2,6-naphthyridinyl, 8-(1,2,3,4 tetrahydro)-2,7-naphthyridinyl, 8-(1,2,3,4-tetrahydro)-1,7-naphthyridinyl, 7-(1,2,3,4 -17- WO 99/43671 PCT/US99/04262 tetrahydro)-1,8-naphthyridinyl, 2-(5,6,7,8-tetrahydro)-1,7-naphthyridinyl, 2-(5,6,7,8 tetrahydro)-1,6-naphthyridinyl, 6-(1,2,3,4-tetrahydro)-1,5-naphthyridinyl, 1-naphthyl, 2-naphthyl, 5-(1,2,3,4-tetrahydro)-naphthyl, 6-(1,2,3,4-tetrahydro)-naphthyl, 4-(2,3 dihydro)-l1H-indenyl, 5-(2,3-dihydro)-1H-indenyl, 5-benzofuranyl, 4-benzofuranyl, 5 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-(1,3 dihydro)-isobenzofuran, 5-(1,3-dihydro)-isobenzofuran, 4-1H-indolyl, 5-1H-indolyl, 6-1H-indolyl, 7-1H-indolyl, 4-(2,3-dihydro)-l1H-indolyl, 5-(2,3-dihydro)-l1H-indolyl, 6 (2,3-dihydro)-l1H-indolyl, 7-(2,3-dihydro)-l1H-indolyl, 4-(1,3-dihydro)-l1H-isoindolyl, 5 10 (1,3-dihydro)-l1H-isoindolyl, 5-(3,4-dihydro)-1H-2-benzopyranyl, 6-(3,4-dihydro)- 1H-2 benzopyranyl, 7-(3,4-dihydro)-l1H-2-benzopyranyl, 8-(3,4-dihydro)-l1H-2-benzopyranyl, 5-(3,4-dihydro)-2H-1-benzopyranyl, 6-(3,4-dihydro)-2H-1-benzopyranyl, 7-(3,4 dihydro)-2H-1-benzopyranyl, 8-(3,4-dihydro)-2H-1-benzopyranyl, 5-(1,2,3,4 tetrahydro)-isoquinolinyl, 6-(1,2,3,4-tetrahydro)-isoquinolinyl, 7-(1,2,3,4-tetrahydro) 15 isoquinolinyl, 8-(1,2,3,4-tetrahydro)-isoquinolinyl, 5-(1,2,3,4-tetrahydro)-quinolinyl, 6 (1,2,3,4-tetrahydro)-quinolinyl, 7-(1,2,3,4-tetrahydro)-quinolinyl, 8-(1,2,3,4 tetrahydro)-quinolinyl, 4 -quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8 quinolinyl, 1-cyclohexenyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-imidazolyl, 4-imidazolyl, 2-benzothiazolyl, 2-benzoxazolyl, 2-benzimidazolyl, 2-oxazolyl, 4 20 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 25 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[1,2-a]pyridin-2-yl, 1-H-inden-3-yl, 1-H-2-methyl-inden-2-yl, 3,4-dihydronaphth-1l-yl, S-4-isopropenylcylcohexen-1l-yl, and 4-dihydronaphth-2-yl. 30 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, 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 35 corresponding oxime, halogenation of resultant oxime to generate an intermediate hydroximinoyl halide, and treatment of this intermediate with a suitable base such -18- WO 99/43671 PCT/US99/04262 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 1 is C,-, alkyl) or carbamates (R, is O-alkyl), to generate isoxazolines of structure 4 (wherein W is oxygen atom). 5 SCHEME I A CHO 101 10~ A l\O " 2 15 ]p NHCOR, -o 3 A--~ N NR 1 4 H 20 N JR I H 25 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 30 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., JAm. Chem. Soc., 1960, Vol. 82, 35 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- WO 99/43671 PCT/US99/04262 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 5 (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, dimethylsulfoxide, tert-butanol, neat amine, etc., at a suitable temperature in the 10 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 15 derivative, the mesylate (Rc = CH.), 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, is p 20 tolyl) or nosylate (R, 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 oC. 25 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 1-methyl-2-pyrrolidinone optionally in the presence of a catalyst such as 18-crown-6 30 at a temperature of 50 to 90 oC to generate the corresponding 5-(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 35 compound such as triphenylphosphine in a suitable solvent such as tetrahydrofuran followed by hydrolysis of the resultant iminophosphorane with water. See: M. -20- WO 99/43671 PCT/US99/04262 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 5 temperature ranging from -30 to 30 'C to provide the acylated compound 4 (wherein W is oxygen atom). SCHEME II 10 L -c y 0-o 2 15 ¥><-J" ,N ' .5 OH A C 15 OH 5 20 A "P 64 OS0 2 R, 25 AN

-NH

2 7 30 A ),,. N W , 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, 35 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- WO 99/43671 PCT/US99/04262 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 5 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 10 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 15 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. 20 SCHEME III ENE halo,, E NH N\C, N\C 25 Y CCO 2 R Y- 'CO 2 R y ' CO2H 8 9 10 E E E 3 0 N ' c , cc y _ N 'CHO C N 6 y N W , Y I+ ' 11 12 13 N' H The product alcohol 10 is then oxidized, employing catalytic 35 tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide in dichloromethane, to the corresponding carboxaldehyde 11. The remaining synthetic -22- WO 99/43671 PCT/US99/04262 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 5 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 10 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. 15 Enantiomerically enriched heteroaromatic isoxazolines may also be prepared according to procedures outlined in SCHEMES IV and V. SCHEME IV 20 ; Rd 14 25 Y c D 0 15 HO Rd H O 30 16 OH I H ANN 35 4A H -23- WO 99/43671 PCT/US99/04262 As illustrated in SCHEME IV, reaction of nitrile oxides 2 with af-unsaturated esters or amides 14 undergoes an asymmetric 1,3-dipolar cycloaddition to provide compound 15. In this reaction, group Rd of compound 14 is a chiral auxiliary used to control the direction of asymmetric induction, and 5 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 chiro-inositol as described in such references as D. P. Curran et al., J. Am. Chem. Soc., 1989, Vol. 111, 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; 10 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 15 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 Rd 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. 20 469. 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 5-(hydroxymethyl) 25 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 30 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 oC. See Y. Ukaji et al., Chem. Letters, 1993, p. 1847. The remaining synthetic 35 steps which lead compound 16 to enantiomerically enriched heteroaromatic -24- WO 99/43671 PCT/US99/04262 isoxazolines of formula 4A are similar to the procedures outlined in SCHEME II. SCHEME V 5 ,- AOH A A C' c N . ReO2C ,CO2Re OH Y 1N, .O 2 0 HO OH 16 H 10 Y 'C N R, 4A H H 15 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 20 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 25 also function as a diluent, flavoring agent, solubilizer, 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 30 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 35 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- WO 99/43671 PCT/US99/04262 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 5 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 10 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 15 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 20 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 25 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 30 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 35 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- WO 99/43671 PCT/US99/04262 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. 5 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 avium. Humans or animals infected with such 10 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

1. A compound of formula I 5 %- N H N H I 10 or pharmaceutically acceptable salts thereof wherein: R, is (a) H, (b) Cl., alkyl, which may be substituted with one or more halo, -OH, C14 alkoxy or C 1 4 acyloxy, 15 (c) C 3 . 6 cycloalkyl, (d) Cl., alkoxy, (e) amino, or (f) NH(C 1 3 alkyl), wherein C 1 - 3 alkyl may be substituted with one or more halo; 20 Y is (a) H, (b) F, or (c) CH 3 ; W is 25 (a) O, or (b) 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 30 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 35 three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms, or -28- WO 99/43671 PCT/US99/04262 (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; 5 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; 10 R2ZN R 2 N R N R 2 2 R 2 N4R2 'R i ii 2 R2 iv N. NN N 15 v vi vii viii ix 15 (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; 20 1 20 R2 X Xi x xl 25R 2 R 2 N- R N 25 N xii xiii xiv xv R2 R 2 R R N N xvi xvii xviii 30 (c) a heterocyclic ring having a nitrogen atom selected from structures consisting of xix, xx, xxi, xxii, and xxiii; 35 -29- WO99/43671 PCT/US99/04262 R 7 R R7

2- n R 8 R R 8 R18 N 1 N R1 N R 8 R 8R 1 9 5 xix xx xxi R R 6 R RR8 R8 R7 R • ( C H 2 ) n R8 R R7 N RR R7 R 8 7 R 8 10 R 8 R 7 xxii xxiii (d) E N 15 R 2 0 R25 (e) , or Z--(CH 2 )q-N N 20 R 2 6 R34 32 25 N 25 (f) R33 (H 2 )n wherein R 2 is (a) H, (b) halo, 30 (c) -OH, (d) -OR 8 , (e) -SR 3 , (f) -S(O) i R3, (g) -CN, 35 (h) -O 2 CR 3 , (i) -NHC(=O)R 3 , -30- WO 99/43671 PCT/US99/04262 (j) -NHCO 2 R 3 , (k) -NHSO 2 R 3 , (1) -C0 2 R 4 , (m) -C(=O)N(R 3 ) 2 , 5 (n) -C(=O)R 3 , (o) C,, alkyl, (p) CM. cycloalkyl, wherein groups (o) and (p) may be substituted with one or more of the preceding groups (a)-(n), 10 (q) phenyl, which may be substituted with one or more of the preceding groups (a)-(p), (r) -CH=CHCO 2 Et, or (s) -C(=NR 4 )R; R 3 is 15 (a) H, (b) C1.6 alkyl, (c) C 3 . 8 cycloalkyl, wherein groups (b) and (c) may be substituted with one or more of halo, -OH, C 14 alkoxy, C 14 acyl, C 1 . 4 acyloxy, or -OC(=O)CH 2 N(CH) 2 , or 20 (d) phenyl, which may be substituted with one or more of the preceding groups (b) to (c); R 4 is (a) -OH or (b) -OCH 3 ; 25 R 5 is (a) H, or (b) -CH 3 ; wherein R 6 is (a) H, 30 (b) -OR 1 0 o, (c) -SR 1 0 , (d) -NR 11 R 1 2 , (e) -CN, (f) C 1 4 alkoxycarbonyl, 35 (g) carboxamide, (h) C 1 , acyl, which may be substituted with one or more halo, -OH, -31- WO 99/43671 PCT/US99/04262 C14 alkoxy or C,- 4 acyloxy, (i) -N(OH)(C 1 .6 alkyl), (j) -N(OH)CH 2 phenyl, (k) -NSO 2 (C 1 - 6 alkyl) wherein C 1 . 6 alkyl may be substituted with one or 5 more halo, C 1 6 alkoxy or phenyl, or (1) F; R 7 is (a) H, (b) -OH, 10 (c) -O(C 1 - 6 alkyl), (d) C1-4 alkyl, (e) phenyl, or (f) F; Rs is 15 (a) H, (b) C- 3 alkyl, which may be substituted with halo, -OH, -CO 2 C1- 4 alkyl, C 1 . 3 acyloxy, C 1 3 alkyoxy or -N(C-4 alkyl) 2 , (c) phenyl, or (d) pyridyl; 20 R 9 is (a) O, (b) S, (c) -NR 13 , or (d) -CR 1 4 R 1 5 ; 25 R 10 is (a) H, (b) C 1 - 8 alkyl, which may be substituted with one or more halo, -CN, -OH, C,., alkoxy, C- 8 acyloxy, C 1 . 4 alkoxycarbonyl, or phenyl, (c) C 1 .s acyl, which may be substituted with one or more -OH, 30 C- 8 alkoxy, C 1 .s acyloxy, (d) C 1 . 8 alkoxycarbonyl, (e) carboxamide, which may be substituted with a C 1 . 4 alkyl or phenyl on the carboxamide nitrogen, or (f) phenyl, which may be substituted with one or more halo, -CN, 35 C1- 3 alkoxy, C 1 . 3 alkoxycarbonyl or C 1 . 4 alkyl; R 1 , and R 12 are the same and different and are -32- WO 99/43671 PCT/US99/04262 (a) H, (b) C 1 - 8 alkyl, which may be substituted with one or more halo, -CN, -OH, Ci- 8 alkoxy, C, 8 acyloxy, C,, alkoxycarbonyl, phenyl, (c) Ci s - acyl, which may be substituted with one or more -OH, amino, 5 C 1 _ 8 alkoxy, C 1 ., acyloxy, C 1 . 4 acylamino, (d) benzoyl, which may be substituted with one or more halo, -OH, amino, C 1 - s alkoxy, C 1 , s acyloxy, Ci4 acylamino, C 1 . 4 alkoxycarbonylamino, (e) Ci.s alkoxycarbonyl, (f) benzyloxycarbonyl, 10 (g) tertbutoxycarbonyl, (h) carboxamide, which may be substituted with a C 1 . 4 alkyl or phenyl on the carboxamide nitrogen, (i) trifluoracetyl, or (j) C 1 . 6 acyl; 15 R 13 is (a) H, (b) -OR 10 io, (c) -NHRi 0 , or (d) Cis 8 alkyl, which may be substituted with phenyl; 20 R 14 and R 15 are the same and different and are (a) H, (b) C 1 . 4 alkyl, which may be substituted with halo, -OH, C 1 -alkoxy, C14 alkoxycarbonyl, or phenyl, (c) C 1 . 8 acyl, 25 (d) C14 alkoxycarbonyl, (e) -CN, or (f) F; R 16 is (a) O, or 30 (b) S; R 7 and R 1 s are the same and different and are (a) H, (b) C 14 alkyl, which may be substituted with halo, -OH or C 1 .- 4 alkoxy, (c) -OH, 35 (d) C 14 alkoxy, which may be substituted with -OH or C1- 4 alkoxy, (e) NR 11 R 1 2 , or -33- WO 99/43671 PCT/US99/04262 (f) C 1 4 acyloxy; R 1 9 is (a) H, or (b) -CH 3 ; 5 E is (a) -0-, or (b) -S(=O)m-; R 20 is (a) H, 10 (b) -CH 3 , (c) -CN, (d) -CO 2 H, (e) -CO2R 22 , or (f) -(CH 2 )iR 2 3 ; 15 R 21 is (a) H, or (b) -CH 3 ; R2 2 is (a) H, 20 (b) C 1 . 6 alkyl, which may be substituted with halo, -OH, C 1 4 alkoxy, C 1 . 4 acyloxy or -O-CH 2 -phenyl, (c) C3- 6 cycloalkyl, (d) amino, (e) -N(C 1 6 alkyl)2, 25 (f) -NH(C 1 .6 alkyl), or (g) C 1 . 6 alkoxy; R 23 is (a) -OH, (b) -OR 22 , 30 (c) -OC(=O)R 2 2 , (d) amino, (e) -NHC(=O)R 22 , or (f) -N(R 2 4 ) 2 ; R 24 is 35 (a) H, (b) C 14 alkyl, which may be substituted with halo, -OH, C 14 alkoxy, -34- WO 99/43671 PCT/US99/04262 amino, -N(C 1 . 6 alkyl) 2 , or -NH(C 1 6 alkyl), or (c) p-toluenesulfonyl; wherein Z is (a) H, 5 (b) -C(=O)R 27 , (c) C1.6 alkyl, (d) benzyl, (e) phenyl, wherein groups (d) and (e) may be substituted with one or more halo, -OCH3, -OH, amino or C 1 4 alkyl, 10 (f) -OR 28 1, (g) -OC(=O)R2 9 , (h) -S-C 1 6 alkyl, (i) -S0 2 -C 1 . 6 alkyl, (j) phenylsulfonyl, 15 (k) p-toluenesulfonyl, (1) -S0 2 -N(R 30 ) 2 , (m) -C(O)-OR 1 , (n) -C(O)-N(R3 0 ) 2 , (o) -N(R 30 ) 2 , or 20 (p) a 6-membered heterocyclic moiety having one to three nitrogen atoms selected from structures consisting of xxiv, xxv, xxvi, xxvii, xxviii, xxix, r- N N N -N LL L 25 xxiv xxv xxvi X25 L i xxvii xxviii xxix 30 L is (a) H, (b) amino, (c) C 1 4 alkyl, or (d) halo; 35 R 25 and R 2 6 are the same and different and are (a) H, -35- WO 99/43671 PCT/US99/04262 (b) C 1 6 alkyl, or (c) C 3 . 6 cycloalkyl; R 2 7 is (a) C1.6 alkyl, 5 (b) C1.8 alkylhydroxyl, (c) phenyl, or (d) 10 R 28 is (a) H, (b) C 1 . 6 alkyl, (c) vinyl, or (d) phenyl, which may be substituted with one to more halo, C1-4 alkoxy, 15 -OH, amino or C 1 4 alkyl; R 29 is (a) C1.6 alkyl, or (b) phenyl; R 30 is independently 20 (a) H, (b) C 1 -4 alkyl, or (c) phenyl, which may be substituted with C 14 alkyl or C 1 . 4 alkoxy; R 31 is (a) C 1 _ 6 alkyl, 25 (b) phenyl, which may be substituted with C 14 alkyl or C 1 - 4 alkoxy, or (c) benzyl, which may be substituted with C 1 4 alkyl or C 14 alkoxy; wherein R8 2 and R 33 are the same and different and are (a) H, (b) halo, 30 (c) Cj., alkyl, which may be substituted with one or more R4s, (d) C 3 . 6 cycloalkyl, (e) -(CH 2 )m-OR 3 6 , or (f) -C(=O)-R 3 8 s; R 34 and R 3 5 are the same and different and are 35 (a) H, (b) C, 8 alkyl, which may be substituted with one or more R 45 , -36- WO 99/43671 PCT/US99/04262 (c) C 1 , 8 alkoxy, (d) Cl, alkylthio, (e) -(CH 2 )m-OR 9 , (f) -O-(CH 2 )m-OR 39 , 5 (g) -NR 40 R 41 , (h) -N=CH-NR 42 R 4 3 , (i) -C(=O)-NR 4 0 R 41 , or (j) -(CH 2 ) m-C(=A)-Rs, wherein A is O or ethyleneketal, or R 34 and R 3 5 may combine together to form 10 (k) =O, (1) =NR 44 , (m) =S, or (n) =CR 42 R 43 ; R 36 and R 37 are the same and different and are 15 (a) H, (b) C 1 s alkyl, which may be substituted with one or more R 45 , or (c) -CH 2 OCH 3 ; R 38 is (a) H, 20 (b) -(CH 2 )m-OH, (c) C 1 - 8 alkyl, which may be substituted with one or more R45, (d) Cl-s alkoxy, (e) -O-CH 2 -O-C(=0)-R 3 6 , or (f) -(CH 2 )m-C(=O)-OR 36 ; 25 R 39 is (a) H, (b) C 1 - s alkyl, which may be substituted with one or more R 45 , (c) C 2 . 8 alkenyl, (d) -(CH 2 )m-OR 6 , 30 (e) -(CH 2 ) m-C(=O)-R 38 , (f) -C(=0)-(CH 2 )m-OR 4 3 , or (g) tosyl; R 40 and R 41 are the same and different and are (a) H, 35 (b) -(CH 2 )-OR 36 , (c) Cl- s alkyl, which may be substituted with one or more R 4 5 , -37- WO 99/43671 PCT/US99/04262 (d) -C(=O)-R 8 s, (e) -C(=O)-NR 3 6 R 3 7 , (f) -(CH 2 )p-phenyl, (g) thiazol-2-yl, 5 or R 40 and R 41 may combine together to form (h) pyrrolidino, (i) piperidino, (j) piperazino, (k) morpholino, or 10 (1) thiomorpholino, wherein groups (h) to (1) may be substituted with C 18 alkyl or -(CH 2 )m-OH; R 42 and R 43 are the same and different and are (a) H, (b) C 1 s alkyl, which may be substituted with one or more R45, 15 (c) -C(=O)-R 8 s, or (d) -(CH 2 )p-phenyl; R 4 4 is (a) H, (b) -OR 3 9 , 20 (c) C,- alkyl, which may be substituted with one or more R4., (d) C 1 8 alkoxy, (e) -(CH 2 )p-phenyl, (f) -NR 40 R 41 , (g) -NH-C(=NH)-NH 2 , 25 (h) [1,2,4]triazol-4-yl, or (i) -CN; R 45 is (a) halo, (b) -OH, 30 (c) -CN, (d) C 1 . 6 alkoxy, (e) amino, (f) -N(C 16 - alkyl) 2 , (g) -NH(C 1 6 alkyl), or 35 (h) carboxyl; -. is a double bond or a single bond; -38- WO 99/43671 PCT/US99/04262 i is 1 or 2; mis 0, 1 or 2; n is 0 or 1; pis 1, 2, 3 or4;and 5 qis 0, 1,2, 3 or4. 2. A compound of formula I according to claim 1 wherein R 1 is (a) C1.3 alkyl, (b) C 1 , alkoxy, or 10 (c) -NH(C 1 . 3 alkyl).

3. A compound of formula I according to claim 1 wherein Rx is CH 3 .

4. A compound of formula I according to claim I wherein Y is H, or F. 15

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. 20

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 25 R2 ' R 2 C R 2 ' R 2 Z i ii iii vi wherein R 2 is as defined in claim 1. 30

9. A compound of formula I according to claim 8 wherein R 2 is (a) H, (b) -CN, (c) -C(=O)H, 35 (d) -C(=NH)-OH, or (e) C 1 . 3 alkyl hydroxyl; -39- WO 99/43671 PCT/US99/04262

10. A compound of formula I according to claim 1 wherein Q is (a) N 5 (b) CN 10 (c) E N or (d) Z-N N 15 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(=O)R 27 , 20 (c) pyridinyl, (d) 2-pyrimidinyl, (e) 4-pyrimidinyl, or (f) pyridazinyl; wherein groups (c) to (f) may be substituted with amino, methyl, F, or Cl; wherein 25 R 27 is as defined in claim 1.

12. A compound of formula I according to claim 11 wherein R 27 is (a) C 1 - 3 alkyl, (b) C 1 - 2 alkylhydroxyl, or 30 (c)0 35 -40- WO 99/43671 PCT/US99/04262

13. A compound of formula II 5 X N /C R , H \ H II or pharmaceutically acceptable salts thereof wherein: R 1 and W are the same as defined in claim 1; 10 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 15 (a) carboxyl, (b) halo, (c) -CN, (d) mercapto, (e) formyl, 20 (f) -CF 3 , (g) -NO 2 , (h) C 1 - 6 alkoxy, (i) C 1 6 alkoxycarbonyl, (j) CI6 alkythio, 25 (k) C 1 6 acyl, (1) -NR 48 R 49 , (m) C 1 6 alkyl which can be substituted with R 50 (n) C 2 -8 alkenylphenyl optionally substituted with one or two R5 1 , (o) phenyl optionally substituted with one or two Rs 1 , 30 (p) -CH=NOH, (q) -CH=N-(OC 1 - 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 5 1 , 35 -41- WO 99/43671 PCT/US99/04262 0 (s) (CH 2 )i , or 5 (t) N-N H R 48 and R 49 are the same and different and are (a) H, (b) C 1 4 alkyl, 10 (c) C 5 6 cycloalkyl, or (d) R 48 and R 49 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 0, and can in turn be optionally substituted with, including on the further nitrogen atom, C 1 . 3 alkyl, or C 1 . 3 acyl; 15 R 50 is (a) -OH, (b) C 14 alkoxy, (c) C 14 acyl, (d) -NR 4 8 R 4 9 , 20 (e) -NHC(=S)NH 2 , (f) -NHC(=O)NH 2 , (g) -NHC(=O)R 49 , (h) -S0 2 NR55R 56 , or (i) -NRSO 2 R 55 ; 25 R 51 is (a) carboxyl, (b) halo, (c) -CN, (d) mercapto, 30 (e) formyl, (f) CF 3 , (g) -NO 2 , (h) C,- 6 alkoxy, (i) C 1 -6 alkoxycarbonyl, 35 (j) C 1 .6 alkythio, (k) C 16 acyl, -42- WO 99/43671 PCT/US99/04262 (1) C 1 6 alkyl optionally substituted with OH, C 1 ., alkoxy, C 1 . 5 acyl, or -NR 48 R 49 , (m) phenyl, (n) -C(=O)NR 52 R 53 , 5 (0) -NR 48 R 49 , (p) -N(R 52 )(-SO 2 R 54 ), (q) -S0 2 -NR 52 R 53 , or (r) -S(=O)iR 5 4 ; R 52 and R, 3 are the same and different and are 10 (a) H, (b) C 1 . 6 alkyl, or (c) phenyl; R 5 4 is (a) C14 alkyl, or 15 (b) phenyl optionally substituted with C 1 . 4 alkyl; R 55 and R56 are the same and different and are (a) H, or (b) C 1 . 6 alkyl; andj is 0 or 1. 20

14. A compound of formula II according to claim 14 wherein Ring T is x 25

15. A compound of formula II according to claim 14 wherein X is (a) C 1 . 4 alkyl which can be substituted with R 5 0 (b) phenyl optionally substituted with one or two Re, 30 (c) -CH=NOR, (d) pyridyl optionally substituted with one or two R 5 1 , (e) thienyl optionally substituted with one or two R 5 ,; Ro 50 and R 5 , are the same as defined in claim 14. 35

16. A compound of formula II according claim 14 wherein R 4 , and R 4 9 are the same and different and are -43- WO 99/43671 PCT/US99/04262 a) H, b) C,- 3 alkyl, or c) R 4 . and R 49 taken together with the nitrogen atom are morpholinyl, pyrrolidinyl, piperazinyl or piperidyl ring; 5

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. 10

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 15 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. 20

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 1 is -CH 3 , W is O, ring P is 3-pyridinyl, Y is H, then Q is not 25 6-pyrazol-1-yl, 6-1,2,4-triazol-1-yl, 6-(4-iodo-pyrazol-1-yl), 6-(4-acetyl-pyrazol-1-yl) or 6-(4-phenyl-pyrazol-1-yl); (b) where R 1 is -CH 3 , W is O, Y is H, then ring P is not benzofuran-5-yl. -44-