JP2002504550A - Substituted aminomethyl isoxazoline derivatives useful as antimicrobial agents - Google Patents

Abstract

(57) The present invention relates to a compound of the formula (I) Wherein R ₁ is H, alkyl, cycloalkyl, alkoxy, amino or alkylamino; Y is H, F or CH ₃ ; W is O or S; A 5-membered heteroaromatic group having 1 to 3 atoms selected from the group consisting of atoms, wherein the 5-membered heteroaromatic group may further have benzene or naphthyl fused thereto, at least A 6-membered heteroaromatic group having one nitrogen atom, wherein the 6-membered heteroaromatic group is benzene, naphthyl, or 1 to 4 selected from the group consisting of sulfur, nitrogen and oxygen atoms fused thereto. Q may further have a 5-membered heteroaromatic group having 3 atoms); Q is 4-, 5-, 6-, 7- or containing one or more nitrogen, sulfur and / or oxygen. 9- Provides the new substituted Aminohetero aromatic isoxazoline derivative represented by a heterocyclic group. The compounds of the present invention have high antimicrobial activity for preventing and treating infectious diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to novel substituted aminoheteroaromatic isoxazoline derivatives, pharmaceutical compositions containing it as an active ingredient, and methods of using the same. The compounds of the present invention have antimicrobial activity for preventing and treating infectious diseases.

BACKGROUND OF THE INVENTION [0002] Antibacterial agents, such as oxazolidinone, belong to the class of known orally active synthetic antibacterial agents, and there is an enormous reference in the art disclosing various oxazolidinone derivatives. For example, U.S. Patent Nos. 4,705,799 and 5,523,4.
03 and European Patent Application 0,316,594 disclose substituted phenyl-2-oxazolidinones containing sulfide, sulfoxide, sulfone, sulfonamide, nitrile, acetamide and tropane rings. U.S. Patent No. 4,948,
No. 801; No. 5,254,577; No. 5,130,316 is an aryl group (non)
Disclosed are arylbenzene oxazolidinyl compounds containing substituted phenyl and pyridyl groups. European Patent Application 0,697,412; 0,694,544;
Nos. 0,694,543 and 0,693,491 disclose 5- to 9-membered heteroaryl-oxazolidinones having 1 to 3 atoms selected from the group consisting of sulfur, nitrogen and oxygen. I have.

[0003] The present invention describes substituted aminoheteroaromatic isoxazoline derivatives useful as antibacterial agents. The compounds of the present invention are novel in that the normal oxazolidinone ring is replaced by an isoxazoline group and differ from antibacterial oxazolidinone. These compounds have antibacterial activity comparable to the corresponding oxazolidine. They are Gram-positive aerobic bacteria such as multidrug resistant staphylococci and streptococci, and anaerobic organisms such as Bacteroides and Clostridia species,
And Mycobacterium tuberculos
It is effective against a large number of human and veterinary pathogens, including acid-fast organisms such as is) and Mycobacterium avium.

Information Disclosure US Pat. No. 4,283,403 discloses 3-aryl-2-isoxazolines useful for protecting plants from disease. Danish Patent No. 2,725,763 discloses substituted 2-isoxazolines that are bactericidal against the spread of phytofutra on tomato. The compounds also show antibacterial activity. U.S. Pat. No. 3,769,295 discloses nitrofuryl derivatives of 5-substituted isoxazolines useful as antimicrobial agents. WO 95/14680 A1 discloses 3-aryl-2-isoxazolines that are useful for inhibiting PDE _IV , treating inflammatory diseases and treating AIDs, asthma, arthritis and others. S. S. Ghabrial et al., Acta Chemica Scandinavica, B41, pp. 426-434 (1987) disclose the synthesis of heteroaromatic compounds via the isoxazoline pathway. U.S. Pat. No. 5,547,950 discloses oxazolidinones containing a substituted diazine group and their use as antimicrobial agents. International Publication No. WO 95/07271 discloses substituted oxazine and thiazine oxazolidinone antimicrobial agents. International Publication No. WO 95/14684 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 antimicrobial agents. International Publication No. WO 96/23788 discloses hetero-aromatic ring substituted phenyloxazolidinone antimicrobial agents. 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

Embedded image Wherein R ₁ is (a) H, (b) one or more halo, —OH, C _1-8 alkyl optionally substituted by C _1-4 alkoxy or C _1-4 acyloxy, c) C _3-6 cycloalkyl, (d) C _1-8 alkoxy, (e) amino, or (f) NH (C _1-3 alkyl), wherein C _1-3 alkyl is 1 or Y is H, F or CH ₃ ; W is O or S; Ring P is (a) 1 to 4 selected from the group consisting of sulfur, nitrogen and oxygen atoms A 5-membered heteroaromatic group having 3 atoms, wherein the 5-membered heteroaromatic group may further have benzene or naphthyl fused thereto, and (b) having at least one nitrogen atom A 6-membered heteroaromatic group, wherein the 6-membered heteroaromatic group is The combined benzene, naphthyl, or sulfur, to 1 is selected from the group consisting of nitrogen and oxygen atoms 5 having three atoms
(C) benzene, naphthyl, a 6-membered heteroaromatic group having at least one nitrogen atom, or selected from the group consisting of sulfur, nitrogen and oxygen atoms Q is phenyl fused with a 5-membered heteroaromatic group having 1 to 3 atoms; Q is (a) i, ii, iii, iv, v, vi, vii, viii and ix below;

Embedded image A 5-membered heterocyclic group having 1 to 4 nitrogen atoms selected from the structure consisting of: (b) the following x, xi, xii, xiii, xiv, xv, xvi, xvi
i and xviii;

Embedded image A 9-membered heterocyclic group having 1 to 4 nitrogen atoms selected from the structure consisting of: (c) the following xix, xx, xxi, xxii and xxiii;

Embedded image A heterocycle having a nitrogen atom selected from the structure consisting of: (d)

Embedded image (E)

Embedded image Or

Embedded imageWhere R_TwoAre (a) H, (b) halo, (c) -OH, (d) -OR_Three, (E) -SR_Three, (F) -S (O)_iR_Three, (G) -CN, (h) -O_TwoCR_Three, (I) -NHC (= O) R_Three, (J) -NHCO_TwoR_Three, (K) -NHSO_TwoR_Three, (L) -CO_TwoR_Four, (M) -C (= O) N (R_Three)_Two, (N) -C (= O) R_Three, (O) C_1-8Alkyl, (p) C_3-8Cycloalkyl, wherein the groups (o) and (p) are one or more of the groups (a)-(n
(Q) may be substituted with one or more of the aforementioned groups (a) to (p)
Good phenyl, (r) -CH = CHCO_TwoEt, or (s) -C (= NR_Four) R_FiveR_ThreeIs (a) H, (b) C_1-6Alkyl, (c) C_3-8Cycloalkyl, wherein groups (b) and (c) are one or more halo, -OH, C_1-4 Alkoxy, C_1-4Acyl, C_1-4Acyloxy or -OC (= O) CH_TwoN (C
H_Three)_TwoOr (d) substituted with one or more of the above groups (b) to (c)
R may be phenyl;_FourIs -OH or -OCH_ThreeR_FiveIs H or -CH_ThreeR₆Are (a) -H, (b) -OR_Ten, (C) -SR_Ten, (D) -NR₁₁R₁₂, (E) -CN, (f) C_1-4(G) carboxamide, (h) one or more halo, -OH, C_1-4Alkoxy or C_1-4 C optionally substituted with acyloxy_1-4Acyl, (i) -N (OH) (C_1-6Alkyl), (j) -N (OH) CH_TwoPhenyl, (k) -NSO_Two(C_1-6Alkyl), where C_1-6Alkyl is one or more halo, C_1-6Optionally substituted with alkoxy or phenyl, or (l) F;₇Are (a) H, (b) -OH, (c) -O (C_1-6Alkyl), (d) C_1-4Alkyl, (e) phenyl, or (f) F; R₈Is (a) H, (b) halo, -OH, -CO_Two C_1-4Alkyl, C_1-3Acyloxy, C_{1- Three} Alkyloxy or -N (C_1-4Alkyl)_TwoC optionally substituted with_1-3Al
R, (c) phenyl, or (d) pyridyl;₉Is O, S, -NR₁₃Or -CR₁₄R_FifteenR_TenAre (a) H, (b) one or more halo, -CN, -OH, C_1-8Alkoxy, C_1-8Acyloxy, C_1-4Substituted with alkoxycarbonyl or phenyl
May be C_1-8Alkyl, (c) one or more —OH, C_1-8Alkoxy, C_1-8Acyloxy
C optionally substituted with_1-8Acyl, (d) C_1-8Alkoxycarbonyl, (e) C on the nitrogen of the carboxamide_1-4A carboxamide optionally substituted with alkyl or phenyl, or (f) one or more halo, -CN, C_1-3Alkoxy, C_1-3Al
Coxycarbonyl or C_1-4R which is phenyl optionally substituted with alkyl;₁₁And R₁₂Are the same or different; (a) H, (b) one or more halo, -CN, -OH, C_1-8Alkoxy, C_1-8Acyloxy, C_1-8Even if substituted with alkoxycarbonyl or phenyl
Good C_1-8Alkyl, (c) one or more —OH, amino, C_1-8Alkoxy, C_1-8A
Siloxy, C_1-4C optionally substituted with acylamino_1-8Acyl, (d) one or more halo, -OH, amino, C_1-8Alkoxy, C_1-8Acyloxy, C_1-4Acylamino, C_1-4Benzoyl optionally substituted with alkoxycarbonylamino, (e) C_1-8(F) benzyloxycarbonyl, (g) tert-butoxycarbonyl, (h) C on the nitrogen of the carboxamide._1-4A carboxamide optionally substituted with alkyl or phenyl, (i) trifluoroacetyl, or (j) C_1-6R is acyl₁₃Is H, -OR_Ten, -NHR_TenOr C which may be substituted with phenyl _1-8 R is alkyl;₁₄And R_FifteenAre the same or different; (a) H, (b) halo, -OH, C_1-4Alkoxy, C_1-4Alkoxycarbonyl or
Is C which may be substituted by phenyl_1-4Alkyl, (c) C_1-8Acyl, (d) C_1-4R is alkoxycarbonyl, (e) -CN, or (f) F;₁₆Is O or S; R₁₇And R₁₈Are the same or different; (a) H, (b) halo, -OH or C_1-4C optionally substituted with alkoxy_1-4 Alkyl, (c) -OH, (d) -OH or C_1-4C optionally substituted with alkoxy_1-4Arco
Kishi, (e) NR₁₁R₁₂Or (f) C_1-4R is acyloxy;₁₉Is H or -CH_ThreeE is (a) -O- or (b) -S (= O)_m-Is R₂₀Are (a) H, (b) -CH_Three, (C) -CN, (d) -CO_TwoH, (e) -CO_TwoR_{twenty two}Or (f)-(CH_Two)_iR_{twenty three}R_{twenty one}Is H or -CH_ThreeR_{twenty two}Is (a) H, (b) halo, -OH, C_1-4Alkoxy, C_1-4Acyloxy or -O-
CH_Two-C optionally substituted with phenyl_1-6Alkyl, (c) C_3-6Cycloalkyl, (d) amino, (e) -N (C_1-6Alkyl)_Two, (F) -NH (C_1-6Alkyl) or (g) C_1-6R is alkoxy;_{twenty three}Are (a) -OH, (b) -OR_{twenty two}, (C) -OC (= O) R_{twenty two}, (D) amino, (e) -NHC (= O) R_{twenty two}Or (f) -N (R_{twenty four})_TwoR_{twenty four}Is (a) H, (b) halo, -OH, C_1-4Alkoxy, amino, -N (C_1-6Alkyl)_Two , Or -NH (C_1-6Alkyl)_1-4Alkyl or (c) p-toluenesulfonyl; Z is (a) H, (b) -C (= O) R₂₇, (C) C_1-6Alkyl, (d) benzyl, (e) phenyl, wherein the groups (d) and (e) are one or more
B, -OCH_Three, -OH, amino or C_1-4(F) -OR₂₈, (G) -OC (= O) R₂₉, (H) -SC_1-6Alkyl, (i) -SO_Two-C_1-6Alkyl, (j) phenylsulfonyl, (k) p-toluenesulfonyl, (l) -SO_Two−N (R₃₀)_Two, (M) -C (O) -OR₃₁, (N) -C (O) -N (R₃₀)_Two, (O) -N (R₃₀)_TwoOr (p) the following xxiv, xxv, xxvi, xxvii, xxviii,
xxix;

Embedded image A 6-membered heterocyclic group having 1 to 3 nitrogen atoms selected from the structure consisting of: (a) H, amino, C _1-4 alkyl or halo; R ₂₅ and R ₂₆ are The same or different, (a) H, (b) C _1-6 alkyl, or (c) C _3-6 cycloalkyl; R ₂₇ is (a) C _1-6 alkyl, (b) C _1-8 Alkyl hydroxyl, (c) phenyl, or (d)

Embedded image R ₂₈ is (a) H, (b) C _1-6 alkyl, (c) vinyl, or (d) one or more halo, C _1-4 alkoxy, —OH, amino or C substituted with _1-4 alkyl be phenyl optionally; R ₂₉ is an C _1-6 alkyl or phenyl; R ₃₀ is independently, (a) H, (b ) C 1-4 alkyl or, (C) phenyl optionally substituted with C _1-4 alkyl or C _1-4 alkoxy; R ₃₁ is (a) C _1-6 alkyl, (b) C _1-4 alkyl or C _1-4 Phenyl optionally substituted with alkoxy, or (c) benzyl optionally substituted with C _1-4 alkyl or C _1-4 alkoxy; wherein R ₃₂ and R ₃₃ are the same or different; a) H, (b) halo, (c) C optionally substituted with one or more R _{45 1-8} alkyl, (d) C _{3-6 cycloalkyl, (e) - (CH 2} ) be _m -OR ₃₆ or (f) -C (= O) -R 38,; R 34 and R ₃₅ The same or different, (a) H, (b) C _1-8 alkyl optionally substituted with one or more R ₄₅ , (c) C _1-8 alkoxy, (d) C _1-8 alkylthio, _{(e) - (CH 2)} m -OR 39, (f) -O- (CH 2) m -OR 39, (g) -NR 40 R 41, (h) -N = CH-NR 42 R 43, (I) —C (＝ O) —NR ₄₀ R ₄₁ , or (j) — (CH ₂ ) _m —C (） A) —R ₃₈ , wherein A is O or ethylene ketal, or R ₃₄ And R ₃₅ are joined together to form (k) = O, (l) = NR ₄₄ , (m) = S, or (n) = CR ₄₂ R ₄₃ ; R ₃₆ and R ₃₇ are the same Or differently, (a) , (B) 1 or more than optionally substituted with R ₄₅ C _1-8 alkyl, or (c) be a -CH ₂ OCH _3; the _{R 38 (a) H, (} b) - (CH _{2) m -OH, (c)} 1 or more than optionally substituted with R ₄₅ C _1-8 alkyl, (d) C _{1-8 alkoxy, (e) -O-CH 2} -O-C (= O) -R _{36 or, (f) - (CH 2} ) be _{m -C (= O) -OR 36} ; R 39 is substituted with (a) H, (b) 1 or R ₄₅ beyond that _Optionally , C _1-8 alkyl, (c) C _2-8 alkenyl, (d) — (CH ₂ ) _m —OR ₃₆ , (e) — (CH ₂ ) _m —C (＝ O) —R ₃₈ , (f) —C (＝ O) — (CH ₂ ) _m —OR ₄₃ , or (g) tosyl; R ₄₀ and R ₄₁ are the same or different, and (a) H, (b) — (CH _{2) m} -OR _36, 1 or it (c) ultra That R ₄₅ in the optionally substituted C _1-8 alkyl, (d) -C (= O ) -R 38, (e) -C (= O) -NR 36 R 37, (f) - (CH ₂ ) _p -phenyl, (g) thiazol-2-yl, or R ₄₀ and R ₄₁ are bonded together to form (h) pyrrolidino, (i) piperidino, (j) piperazino, (k) morpholino, or (l) forming a thiomorpholino, here, to group (h) no (l) is C _1-8 alkyl or - (CH _{2) m} -OH in well be substitution; R ₄₂ and R ₄₃ (A) H, (b) C _1-8 alkyl optionally substituted with one or more R ₄₅ , (c) —C (＝ O) —R ₃₈ , or (d) - (CH _{2) p} - phenyl; R ₄₄ is (a) H, (b) -OR 39, optionally substituted with (c) 1 or R ₄₅ beyond that There C _1-8 alkyl, (d) C _{1-8 alkoxy, (e) - (CH 2} ) p - _{phenyl, (f) -NR 40 R 41} , (g) -NH-C (= NH) -NH ₂ , (h) [1,2,4] triazol-4-yl or (i) —CN; R ₄₅ is (a) halo, (b) —OH, (c) —CN, (d) C _1-6 alkoxy, (e) amino, (f) -N (C _1-6 alkyl) _2, be a (g) -NH (C _1-6 alkyl), or (h) carboxyl; ... double I is 1 or 2; m is 0, 1 or 2; n is 0 or 1;
p is 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4] or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of formula II

Embedded image Wherein R ₁ and W are the same as defined in claim 1; ring T is a 6-membered heteroaromatic group having 1 to 3 nitrogen atoms, wherein the 6-membered heteroaromatic group The aromatic group has a 5-membered heteroaromatic group fused to it, which in turn has one to three atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms; , (b) halo, (c) -CN, (d ) mercapto, (e) _{formyl, (f) -CF 3, (} g) -NO 2, (h) C 1-6 alkoxy, (i) C _{1 -6} alkoxycarbonyl, (j) C _1-6 alkylthio, (k) C _{1-6 acyl, (l) -NR 48 R 49} , (m) optionally substituted with R ₅₀ C _1-6 alkyl, (n) optionally one or two R ₅₁ in the optionally substituted C _2-8 alkenyl Nirufeniru, 1 optionally (o) Others may be substituted with two R ₅₁ phenyl, (p) -CH = NOH, (q) -CH = N- (OC 1-6 alkyl), optionally one or two (r) A 5- or 6-membered heterocyclic group having 1 to 3 atoms selected from the group consisting of S, N and O, which may be substituted by R ₅₁ , (s)

Embedded image Or (t)

Embedded image R ₄₈ and R ₄₉ are the same or different, and (a) H, (b) C _1-4 alkyl, (c) C _5-6 cycloalkyl, or (d) R ₄₈ and R ₄₉ are nitrogen atoms Together with S, N and O
5-, 6 which may optionally have further heteroatoms selected from the group consisting of and optionally substituted on further nitrogen atoms, optionally with C _1-3 alkyl or C _1-3 acyl. R ₅₀ is (a) —OH, (b) C _1-4 alkoxy, (c) C _1-4 acyl, (d) —NR ₄₈ R ₄₉ , (e) —NHC ( _{= S) NH 2, (f} ) -NHC (= O) NH 2, (g) -NHC (= O) R 49, (h) -SO 2 NR 55 R 56 or (i) -NRSO ₂ R _55, R ₅₁ is (a) carboxyl, (b) halo, (c) —CN, (d) mercapto, (e) formyl, (f) CF ₃ , (g) —NO ₂ , (h) C _{1 -6} alkoxy, (i) C _1-6 alkoxycarbonyl, (j) C _1-6 alkylthio, (k) C _1-6 acyl, optionally (l) H, C _1-5 alkoxy, C _1-5 acyl or -NR ₄₈ may be substituted with R ₄₉ C _1-6 alkyl, (m) phenyl, (n) -C (= O ) NR 52 R 53 _{, (o) -NR 48 R 49} , (p) -N (R 52) (- SO 2 R 54), (q) -SO 2 -NR 52 R 53 or, (r) -S (= O ) i It is R _54; R ₅₂ and R ₅₃ are the same or different, (a) H, be a (b) C _1-6 alkyl or (c) phenyl,; R ₅₄ is (a) C _1-4 alkyl or, (B) phenyl optionally substituted with C _1-4 alkyl; R ₅₅ and R ₅₆ are the same or different; (a) H, or (b) C _1-6 alkyl; and j Is 0 or 1.] or a pharmaceutically acceptable salt thereof.

[0007] These compounds are gram-positive aerobic bacteria, such as multidrug-resistant staphylococci and streptococci, and anaerobic organisms, such as Bacteroides and Clostridia species, and Mycobacterium tubercosis.
ulosis) and has antimicrobial activity against a vast array of human and veterinary pathogens, including acid-fast organisms such as Mycobacterium avium.

DETAILED DESCRIPTION OF THE INVENTION For the purposes of the present invention, the carbon content of various hydrocarbon-containing groups is indicated by a prefix indicating the minimum and maximum number of carbon atoms in the group, ie, the prefix The term C _ij defines the number of carbon atoms present in the integers "i" to "j". Thus, C _1-4 alkyl refers to alkyl of 1-4 carbon atoms, or methyl, ethyl, propyl, butyl and isomeric forms thereof.

The terms “C _1-3 alkyl”, “C _1-4 alkyl”, “C _1-6 alkyl” and “C _1-8 alkyl” each refer to 1 to 3, 1 to 4 Of 1 to 6
Or an alkyl group having 1 to 8 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric forms thereof. The term “C _2-8 alkenyl” refers to at least one double-bonded alkenyl group having 2 to 8 carbon atoms, such as ethenyl, propenyl, butenyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, Heptadienyl, octenyl, octadienyl, octatrienyl and their isomeric forms.

The terms “C _3-6 cycloalkyl” and “C _3-8 cycloalkyl” are each 3
Refers to cycloalkyl having from 6 to 6 or 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and isomeric forms thereof. The _terms "C _1-3 alkoxy", "C _1-4 alkoxy", "C _1-6 alkoxy", and "C _1-8 alkoxy" are each independently one to three, Refers to an alkyl group having 1 to 4, 1 to 6, or 1 to 8 carbon atoms, such as methoxy, ethoxy, propyloxy, butyloxy,
Refers to pentyloxy, hexyloxy, heptyloxy or octyloxy and their isomeric forms.

“C_1-4Acyl), "C_1-6Acyl), and "C_1-8The term "acyl" is represented by -C (
＝ O) R groups, wherein R is an alkyl group of 1 to 4, 1 to 6, or 1 to 8 carbon atoms and isomeric forms thereof. "C_1-3Alkoxycarbonyl "," C_1-6Alkoxycarbonyl "and" C _1-8 The term "alkoxycarbonyl" means that R 'is one to three, one to six,
Or an alkyl group of 1 to 8 carbon atoms and their isomeric forms -C
O_TwoRefers to an R group. "C_1-3Acyloxy ”,“ C_1-4Acyloxy ”and“ C_1-8The term acyloxy "denotes that R" "is one to three, one to four, or one to eight.
Refers to alkyl groups of carbon atoms and their isomeric forms, -OC (= O) R groups.

The term “C _1-4 acylamino” refers to alkyl groups where R is 1 to 4 carbon atoms and the isomeric forms thereof —NHC (＝ O) R groups. The term " _C1-4 alkoxycarbonylamino" refers to an alkyl group of 1 to 4 carbon atoms where R is and its isomeric form -NHC (= O) OR. The term "C _1-8 hydroxyl" refers to alkyl groups having one to eight carbon atoms attached to a hydroxy group and isomeric forms thereof. The term “C _1-8 alkylthio” refers to alkyl groups having one to six carbon atoms attached to a sulfur atom and isomeric forms thereof. The term "halo" refers to fluoro, chloro, bromo or iodo. The compounds of the invention may, where appropriate, be converted into their salts according to conventional methods. The term "pharmaceutically acceptable salts" refers to acid addition salts useful for administering the compounds of the present invention, including hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates , Acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citrate, 2-hydroxyethylsulfonate, fumarate and the like. These salts can exist in hydrated form.

The compounds of the formula I according to the invention contain a chiral center at C5 of the isoxazoline ring and as such there are two enantiomers or a racemic mixture of both. The present invention relates to both enantiomers, as well as mixtures comprising both isomers.
Preferred enantiomers are those having the (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 on any of the Q or R ₁ groups, and the present invention contemplates all possible stereoisomers and geometric forms in these groups. Is included.

The following ring P or T included in compound I or II is a typical heteroaromatic isoxazoline of the present invention. It will be appreciated that the listed heteroaromatic groups are not limiting of the scope of the invention, but are provided merely to assist those skilled in the art in understanding 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-2-pyrindinyl, 2- (5,6-dihydro) -1H-
1-pyrindinyl, 3- (5,6-dihydro) -1H-1-pyrindinyl, 5-fluoro [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) -Flo [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- (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-pyrano [4,3-c] pyridinyl, 8- (3,4-dihydro) -1H-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) -1H-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 -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-pyrrolo [2,3-b] pyridinyl, 5-1H-pyrrolo [3,2-b] pyridinyl, 5- (2,3-dihydro) -1H-pyrrolo [2, 3-c] pyridi Le, 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) -1H-pyrrolo [3,4
-B] pyridinyl, 6-1,7-naphthyridinyl, 6-2,7-naphthyridinyl, 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-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-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) -1H-indenyl, 5- (2,3-dihydro) -1H-
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- (1,3-dihydro) -isobenzofuran, 5- (1,3-dihydro) -isobenzofuran, 4-1H-indolyl, 5-1H-indolyl, 6-1H-indolyl, 7-1H- In drill, 4- (2,3
-Dihydro) -1H-indolyl, 5- (2,3-dihydro) -1H-indolyl,
6- (2,3-dihydro) -1H-indolyl, 7- (2,3-dihydro) -1H-indolyl, 4- (1,3-dihydro) -1H-isoindolyl, 5- (1,3-dihydryl) (Dro) -1H-isoindolyl, 5- (3,4-dihydro) -1H-2-benzopyranyl, 6- (3,4-dihydro) -1H-2-benzopyranyl, 7- (3,4-dihydro)- 1H-2-benzopyranyl, 8- (3,4-dihydro) -1H-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) -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-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, quinoxaline- 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-chloropiperone -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-1-yl, S- 4-isopropenylcyclohexen-1-yl and 4-dihydronaphth-2-yl.

The compounds of the present invention may be prepared according to one or more of the processes discussed below. In Reaction Schemes I, II, III, IV and V described below, X, Y, Q
And R ₁ is the same as previously defined; A is a halogen atom or a substituent Q. As shown in Scheme I, the halogenated heteroaromatic aldehyde 1 can be converted to the corresponding nitrile oxide 2 via three steps: formation of the corresponding oxime, halogenation of the resulting oxime to intermediate halogenation Hydroxyiminoyl is formed, and this intermediate is treated with a suitable base such as triethylamine to give nitrile oxide 2. The resulting nitrile oxide 2 undergoes 1,3-dipolar cycloaddition with either an allylic amide (wherein R ₁ is C _1-3 alkyl) or a carbamate (R ₁ is O-alkyl). To form an isoxazoline of structure 4 (where W is an oxygen atom).

[0016]

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All these methods are well known to those skilled in the art and are discussed in further detail in the following references: “Nitrile Oxides and Imines”, edited by A. Padwa, John Wiley & Sons, Inc. , New York, 1984, Vol. 1, Chapter 3, pp. 291-392, p. Caram
ella et al., “1,3-Dipolar Cycloaddition Chemistry”, and references cited therein; “Cycloaddition Reactions of Nitrile Oxides with Alkenes” AR Katr.
itzky, CJEas, Academic Press, San Diego, Vol. 60, 1994, pp. 261-327.
Ton et al., "Advances in Heterocyclic Chemistry" and references cited therein; C. Grundmann et al. Org. Chem. , 1968, Vol. 33, p. 476; KCLiu et al., JO
rg. Chem. 1980, Vol. 45, p. 3916; Mukaiyama et al., J. Am. Chem. Soc., 1960, Vol.
82, p.5339. If desired, the corresponding thioamide isoxazoline 4 is readily prepared by treating the carbonylamide isoxazoline 4 with a Loessson's reagent in a suitable solvent such as 1,4-dioxane at reflux temperature.

Compound 4 is either an example of a compound of Formula I of the present invention or an intermediate that can be further synthesized to a compound of Formula I of the present invention. For example, A
Is a halogen atom (preferably a fluorine atom), the halogenated heteroaromatic isoxazoline 4 can be converted to a suitable solvent such as N, N-dimethylformamide, dimethylsulfoxide, tert-butanol, neat amine and the like. Medium, at a suitable temperature in the range of 40-140 ° C., sometimes in a closed pressure vessel, with various amines in the presence of a suitable base such as dipotassium hydrogen phosphate, potassium carbonate, sodium hydride. Treatment or treatment with an excess of an amine gives compound I of the present invention.

As shown in Reaction Scheme II, nitrile oxide 2 can be reacted with allyl alcohol to produce 5- (hydroxymethyl) isoxazoline 5. The structure 5 is then converted to the corresponding alkylsulfonate or arylsulfonate 6.
A representative alkylsulfonyl derivative, mesylate (R _c = CH ₃ ), is prepared by reacting 5 with methanesulfonyl chloride in pyridine / dichloromethane or methanesulfonyl chloride in dichloromethane and triethylamine. By utilizing an arylsulfonyl chloride reagent in pyridine, such as p-toluenesulfonyl chloride or 3-nitrobenzenesulfonyl chloride and triethylamine in dichloromethane, tosylate (R _c is p-tolyl) or nosylate (R _c is 3- Arylsulfonates such as nitrophenyl). The mesylate or nosylate derivative 6 is then reacted in a closed reaction vessel at a suitable temperature of 40 to 90 ° C. with a suitable solvent system, for example aqueous ammonia in acetonitrile / isopropanol or tetrahydrofuran / isopropanol, To 5- (aminomethyl) isoxazoline 7.

It will be apparent to those skilled in the art that alternative synthetic methods are available that introduce the essential aminomethyl side chains. For example, sulfonate 6 can optionally be 18-crown-
Azide source such as sodium azide or potassium azide in an aprotic solvent such as N, N-dimethylformamide or 1-methyl-2-pyrrolidinone in the presence of a catalyst such as To produce the corresponding 5- (azidomethyl) isoxazoline. The azide group is then reduced by hydrogenation using a palladium or platinum catalyst in a suitable solvent such as ethyl acetate or methanol to give 7. Alternatively, the azidomethyl intermediate is a two-step process comprising treating with a trivalent phosphorus compound such as triphenylphosphine in a suitable solvent such as tetrahydrofuran, followed by hydrolyzing the resulting iminophosphorane with water. Can be reduced to the corresponding amine 7. M. See Vaultier et al., Tetrahedron Lett., 1983, Vol. 24, p. 763. The amine 7 is then converted to the isoxazoline derivative 3 by a reaction known to those skilled in the art.
Convert to For example, 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 in the range of -30 to 30 ° C. to give the acylated compound 4 (W Is an oxygen atom).

[0021]

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Various methods for the acylation reaction are described in March, “Advanced Organic Chemistry”
, Third Edition, John Wiley & Sons, Inc., New York, 1985, pp. 370-375. The corresponding thioamido phenyl isoxazoline 4 (W is a sulfur atom) is readily prepared by treating amido phenyl isoxazoline with a Roessson's reagent at reflux temperature in a suitable solvent such as 1,4-dioxane. It will be apparent to those skilled in the art that other carbonyl-containing groups within the scope of the present invention can be readily added to amine 7 by standard acylation techniques to provide further examples of 4. The remaining synthetic steps that lead to Structure 4 to compounds of Formula I
As described in Reaction Scheme I.

Reaction Scheme III outlines another reaction scheme that allows 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 substituents, morpholine or thiomorpholine, are merely representative, and that other heterocyclic systems are possible. The halogenated heteroaromatic ester of structure 8 (wherein halogen is preferably a fluorine atom) is prepared in a suitable solvent such as dimethylsulfoxide in the presence of a suitable base such as dipotassium hydrogen phosphate and morpholine (wherein E is an oxygen atom or thiomorpholine (where E is a sulfur atom) and 60
The morpholino adduct 9 is obtained by reacting at a suitable temperature in the range from -100 ° C to 100 ° C. The ester group of 9 is then converted to the corresponding heteroaromatic alcohol 10 at a suitable temperature of -20 to 0 ° C using a suitable reducing agent such as lithium aluminum hydride in a suitable solvent such as tetrahydrofuran. To be reduced to

[0024]

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The product alcohol 10 is then oxidized to the corresponding carboxaldehyde 11 using catalytic tetrapropylammonium perruthenate and N-methylmorpholine-N-oxide in dichloromethane. The remaining synthetic steps leading the aldehyde 11 to the morpholino phenylisoxazoline 13 via the nitrile oxide 12 are similar to the procedure described in Scheme I. Further, if E is a sulfur atom, the sulfur atom can be oxidized, if desired, at an earlier synthesis step or at the end of the synthesis step to give the corresponding sulfone and sulfoxide, respectively. The detailed procedure of this oxidation is discussed in International Publication No. WO 97/09328.

The enantiomeric-rich heteroaromatic isoxazolines of the formula I can be obtained via racemic phenylisoxazolines 3 or 4 by using high-performance liquid chromatography (HPLC) on a chiral stationary phase. In a typical separation, a mixture of enantiomers is eluted with a heptane / isopropanol / chloroform mixture as mobile phase, 5 × 50 cm Chiralpak A.
Chromatography using a D column gives the individual (R)-or (S) -enantiomers. If desired, separation of the enantiomers can be performed on either the early intermediates 3 or 4 or the final product.

Enantiomeric rich heteroaromatic isoxazolines can also be prepared according to the procedures outlined in Schemes IV and V.

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As illustrated in Reaction Scheme IV, nitrile oxide 2 is reacted with an α, β-unsaturated ester or amide 14 to undergo asymmetric 1,3-dipolar cycloaddition to give compound 1
Get 5. In this reaction, group R _d of compound 14 is a chiral auxiliary used in order to control the orientation of the asymmetric introduction, therefore, it allows the asymmetric cycloaddition with high stereoselectivity. Compound 14, among others, DPCurran et al., J. Am. Chem. Soc., 1989, Vol. 111, p. 9238; JAStack et al., Tetrahedron, 1993, Vol. 49, p. 995; DPCurran et al., T.
etrahedron 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; YHKim et al., Tetrahedron Lett., 1993, Vol. 34, p. 6063; "Cycloadditio
n Reactions of Nitrile Oxides with Alkenes ”, edited by AR Katritzky et al., Acade
MIC Press, San Diego, 1994, pp. 261-327, CJ Easton et al., "Advanced in H
eterocyclic Chemistry ", Vol. 60 and the references cited therein, which may be prepared from Kemp's triacid, Oppolzer's sultam or chiro-inositol. The use of a suitable chiral auxiliary to control the stereoselectivity of the asymmetric 1,3-dipolar cycloaddition ultimately provides access to both 15 enantiomers. The racemic ester of formula 15 wherein R _d is OMe or OEt is shown in S. Yang et al., Monatsh. Chem., 1994, V
ol, p. 469, p. 469.

The enantiomeric cycloaddition product 15 can be further purified by recrystallization or chromatography. The cycloaddition product 15 is then treated with a suitable reducing agent such as L-selectride (commercially available) in a suitable solvent such as tetrahydrofuran to give the enantiomer-rich 5- (hydroxymethyl) isoxazoline 1
Get 6. The remaining synthetic steps leading to 16 enantiomer-rich heteroaromatic isoxazoline 4A are similar to the procedure outlined in Scheme II. Alternatively, compound 16 is a highly enantioselective 1 as shown in Scheme V.
It can also be prepared by treating nitrile oxide 2 with allyl alcohol via a 2,3-dipolar cycloaddition. The reaction is carried out in a suitable solvent such as chloroform or dichloromethane in the presence of diethylzinc and (R, R)-and (S, S) -tartaric acid esters, preferably diisopropyl ester, in the range of about -20 to 0 ° C. Happens at temperature. See Y. Ukaji et al., Chem. Letters, 1993, p. The remaining synthetic steps leading to compound 16 to enantiomerically rich heteroaromatic isoxazolines of formula 4A are similar to the procedure outlined in Scheme II.

[0030]

Embedded image With minor modifications except starting at the heteroaromatic ring T, the reaction schemes IV
The compounds of formula II can be obtained according to the procedures outlined in

The pharmaceutical compositions of the present invention can be prepared, using standard and conventional techniques, by combining a compound of Formula I of the present invention with a solid or liquid pharmaceutically acceptable carrier, if desired. It can be prepared by combining with adjuvants and excipients which may be used. Solid form compositions include powders, tablets, dispersible granules, capsules and suppositories. The solid carrier can be at least one substance that can also function as a diluent, flavoring agent, solubilizer, wetting agent, suspending agent, binder, tablet disintegrant, and encapsulating agent.
Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic substances, low melting waxes, cocoa butter and the like. Compositions in liquid form include:
Solutions, suspensions, and emulsions are included. For example, compounds of the present invention dissolved in water, water-propylene glycol, and water-polyethylene glycol systems, which may optionally contain conventional coloring, flavoring, stabilizing and thickening agents. Can be provided.

The pharmaceutical composition is provided by using conventional techniques. Preferably, the compounds are present in unit dosage form containing an effective amount of the active ingredient, ie, a compound of Formula I according to the present invention. The amount of the active ingredient in the pharmaceutical composition and its unit dosage form, i.e. the compound of formula I according to the invention, can vary widely depending on the particular application, the potency and the desired concentration of the particular compound, Or you can adjust. Generally, the amount of active ingredient will range from 0.5% to 90% by weight of the composition. In therapeutic applications for treating bacterial infections in humans and other animals diagnosed as having a bacterial infection, the compound or pharmaceutical composition thereof may be administered at a concentration, i.e., an antibacterial efficacy. It will be administered orally, parenterally, dermally and / or topically at dosages to obtain and maintain the amount or blood level of the active ingredient in the animal to be treated. Generally, dosages of such antibacterially effective amounts of active ingredients will be within the range of from about 0.1 to about 100 mg / kg, more preferably from about 3.0 to about 50 mg / kg body weight / day. Would. It is to be understood that the dosage may vary depending on the requirements of the patient, the severity of the bacterial infection to be treated, and the particular compound used. Also, the initial dose to be administered may be increased above the upper limit to rapidly achieve the desired blood level, or the initial dose may be less than optimal, and the daily dose may be adjusted according to the particular situation. It should also be understood that the process can be gradually increased. If desired, the daily dose can be divided into multiple doses for administration, for example 2 to 4 times per day.

These compounds are useful for the treatment of microbial infections in humans and other homeothermic animals by either oral, parenteral, topical or transdermal administration. Generally, the preferred form of administration is oral. Pharmaceutical compositions for parenteral administration are generally 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. Soluble salts (acid addition salts or basic salts)
As a pharmaceutically acceptable amount of a compound according to Formula I. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+)-lysine and L (+)-arginine, to name a few. It is. Compounds of formula I are generally present at about 1 mg /
The carrier will be dissolved in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of ml to about 400 mg / ml. The resulting liquid pharmaceutical composition will be administered so as to provide an antibacterial effective amount of the dosage described above. The compounds of the formula I according to the invention are advantageously administered in solid and liquid dosage forms.

The compounds of the present invention include anaerobic organisms, such as multidrug resistant staphylococci and streptococci, and Bacteroides and Clostridia species, and Mycobacterium tuberculosis and Mycobacterium avium. ) Is effective against various human and veterinary pathogens, including acid-fast organisms. Humans or animals affected by such pathogens are readily diagnosed by a physician or veterinarian of ordinary skill. Throughout the specification, citations to publications are intended to be incorporated by reference as part of the specification.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/496 A61K 31/496 31/5377 31/5377 31/55 31/55 A61P 31/04 A61P 31 / 04 C07D 413/04 C07D 413/04 413/14 413/14 471/04 101 471/04 101 102 102 491/048 491/048 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM ), L, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM , HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72 Inventor Don J. Wishka 49906 Northampton Road, 1431 Northampton Road, Kalamazoo, Michigan United States Richard Sea Thomas United States 49009 Wild Cherry Lane No. 2166, Kalamazoo, Michigan, USA (72) Inventor David Earl Grabber 49008 Kalamazoo, Michigan, Woodcliff Drive 3604 F-term (reference) 4C056 AA01 AB01 AC01 AD01 AE02 BA03 BA11 4C063 AA01 BB01 CC51 CC52 CC62 CC75 CC76 CC79 CC81 CC92 DD06 DD07 DD12 DD14 DD15 DD25 DD26 DD29 DD34 DD51 EE01 4C065 AA04 AA05 BB04 BB06 BB09 BB10 DD02 DD03 EE02 HH01 JJ01 PP09 4C086 AA01 AA02 AA03 BC67 BC69 BC70 BC82 BC84 CB05 CB09 CB22 GA02 GA04 GA07 GA08 GA09 GA10 MA01 MA04 MA52 MA55 MA63 NA

Claims (22)

[Claims] 1. A compound of the formula I Wherein R ₁ is (a) H, (b) one or more halo, —OH, C _1-8 alkyl optionally substituted by C _1-4 alkoxy or C _1-4 acyloxy, c) C _3-6 cycloalkyl, (d) C _1-8 alkoxy, (e) amino, or (f) NH (C _1-3 alkyl), wherein C _1-3 alkyl is 1 or Y is (a) H, (b) F, or (c) CH ₃ ; W is (a) O, or (b) S; and ring P is ( a) a 5-membered heteroaromatic group having 1 to 3 atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms, wherein the 5-membered heteroaromatic group is benzene or naphthyl fused thereto. (B) a 6-membered heteroaromatic group having 1 to 3 nitrogen atoms, Koni該 6-membered heteroaromatic radical benzene fused thereto, naphthyl or sulfur,
May further have a 5-membered heteroaromatic group having 1 to 3 atoms selected from the group consisting of nitrogen and oxygen atoms, or (c) benzene, naphthyl, 6-membered having at least one nitrogen atom Or a phenyl fused thereto with a 5-membered heteroaromatic group having 1 to 3 atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms; and Q is (a) i, ii, iii, iv, v, vi, vii, viii and ix; A 5-membered heterocyclic group having 1 to 4 nitrogen atoms selected from the structure consisting of: (b) the following x, xi, xii, xiii, xiv, xv, xvi, xvi
i and xviii; A 9-membered heterocyclic group having 1 to 4 nitrogen atoms selected from the structure consisting of: (c) the following xix, xx, xxi, xxii and xxiii; A heterocycle having a nitrogen atom selected from the structure consisting of: (d) (E) Or (f) Wherein R ₂ is (a) H, (b) halo, (c) —OH, (d) —OR ₃ , (e) —SR ₃ , (f) —S (O) _i R ₃ , (g) -CN, (h ) -O 2 CR 3, (i) -NHC (= O) R 3, (j) -NHCO 2 R 3, (k) -NHSO 2 R 3, (l) - _{CO 2 R 4, (m)} -C (= O) n (R 3) 2, (n) -C (= O) R 3, (o) C 1-8 alkyl, (p) C _3-8 cycloalkyl Alkyl, wherein the groups (o) and (p) are one or more of the above groups (a)-(n
(Q) phenyl optionally substituted with one or more of the above groups (a)-(p), (r) -CH = CHCO ₂ Et, or (s) —C (＝ NR ₄ ) R ₅ ; R ₃ is (a) H, (b) C _1-6 alkyl, (c) C _3-8 cycloalkyl, wherein groups (b) and (c) Is one or more halo, —OH, C _1-4 alkoxy, C _1-4 acyl, C _1-4 acyloxy or —OC (＝ O) CH ₂ N (C
R ₃ is (a) —OH, optionally substituted with H ₃ ) ₂ or (d) phenyl optionally substituted with one or more of the above groups (b) to (c); Or (b) —OCH ₃ ; R ₅ is (a) H, or (b) —CH ₃ ; R ₆ is (a) —H, (b) —OR ₁₀ , (c) —SR ₁₀ , (d) —NR ₁₁ R ₁₂ , (e) —CN, (f) C _1-4 alkoxycarbonyl, (g) carboxamide, (h) one or more halo, —OH, C _1-4 alkoxy or C _1-4 which may be C _1-4 acyl substituted with 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 is substituted by one or more halo, C _1-6 alkoxy or phenyl R ₇ is (a) H, (b) —OH, (c) —O (C _1-6 alkyl), (d) C _1-4 alkyl , (e) phenyl, or (f) be F; R ₈ is (a) H, (b) halo, -OH, -CO ₂ C _1-4 alkyl, C _1-3 acyloxy, C _1-3 alkyl oxy or -N (C _1-4 alkyl) ₂ by optionally substituted C _1-3 alkyl, (c) phenyl or, (d) pyridyl; R ₉ is (a) O, (b) S , (c) be a -NR ₁₃ or _{(d) -CR 14 R 15,} ; R 10 is (a) H, (b) 1 or halo beyond that, -CN, -OH, C _1-8 alkoxy, C _1-8 acyloxy, C _1-4 alkoxycarbonyl, or phenyl optionally substituted by optionally C _1-8 alkyl, (c) 1 or -OH beyond that, C _1-8 alkoxy Shi, C _1-8 acyloxy optionally substituted C _1-8 acyl, (d) C _1-8 alkoxycarbonyl, is replacement with C _1-4 alkyl or phenyl on the nitrogen of (e) the carboxamide Or (f) phenyl optionally substituted with one or more halo, —CN, C _1-3 alkoxy, C _1-3 alkoxycarbonyl or C _1-4 alkyl; ₁₁ and R ₁₂ are the same or different, and (a) H, (b) one or more halo, —CN, —OH, C _1-8 alkoxy, C _1-8 acyloxy, C _1-8 alkoxycarbonyl, phenyl C _1-8 alkyl optionally substituted with: (c) optionally substituted with one or more —OH, amino, C _1-8 alkoxy, C _1-8 acyloxy, C _1-4 acylamino C _1-8 acyl, (D) benzoyl optionally substituted with one or more halo, —OH, amino, C _1-8 alkoxy, C _1-8 acyloxy, C _1-4 acylamino, C _1-4 alkoxycarbonylamino, e) C _1-8 alkoxycarbonyl, (f) benzyloxycarbonyl, (g) tert-butoxycarbonyl, (h) carboxamide optionally substituted on the nitrogen of the carboxamide by C _1-4 alkyl or phenyl; (I) trifluoroacetyl, or (j) C _1-6 acyl; R ₁₃ is substituted with (a) H, (b) —OR ₁₀ , (c) —NHR ₁₀ , or (d) phenyl. be a good C _1-8 alkyl optionally; R ₁₄ and R ₁₅ are the same or different, (a) H, (b ) halo, -OH, C _1-4 alkoxy, C _1-4 alkoxycarbonyl, or Fe Good C _1-4 alkyl optionally substituted by Le, (c) C _1-8 acyl, (d) C _1-4 alkoxycarbonyl, be a (e) -CN, or (f) F,; R ₁₆ is (a) O, or, be in (b) S; R ₁₇ and R ₁₈ are identical or different, (a) H, (b ) halo, -OH or C _1-4 optionally C ₁ optionally substituted by alkoxy _-4 alkyl, (c) —OH, (d) —OH or C _1-4 alkoxy optionally substituted with C _1-4 alkoxy, (e) NR ₁₁ R ₁₂ , or (f) C _1-4. There acyloxy; R ₁₉ is an (a) H, or (b) -CH _3,; E is (a) -O-, or (b) -S (= O) m - a is; R ₂₀ is ( a) H, (b) -CH 3, (c) -CN, (d) -CO 2 H, (e) -CO 2 R 22 , or, (f) - (Yes in CH _{2) i} R _23; R ₂₁ is (a) H or (b) —CH ₃ ; R ₂₂ is (a) H, (b) halo, —OH, C _1-4 alkoxy, C _1-4 acyloxy or —O—
C _1-6 alkyl _optionally substituted with CH ₂ -phenyl, (c) C _3-6 cycloalkyl, (d) amino, (e) -N (C _1-6 alkyl) ₂ , (f)- NH (C _1-6 alkyl) or (g) C _1-6 alkoxy; R ₂₃ is (a) —OH, (b) —OR ₂₂ , (c) —OC (＝ O) R ₂₂ , d) amino, (e) —NHC (＝ O) R ₂₂ , or (f) —N (R ₂₄ ) ₂ ; R ₂₄ is (a) H, (b) halo, —OH, C _1-4 Z is alkoxy, amino, —N (C _1-6 alkyl) ₂ , or C _1-4 alkyl optionally substituted with —NH (C _1-6 alkyl), or (c) p-toluenesulfonyl; Is (a) H, (b) —C (＝ O) R ₂₇ , (c) C _1-6 alkyl, (d) benzyl, (e) phenyl, wherein groups (d) and (e) are 1 or Halo beyond that,- It may be substituted by OCH ₃ , —OH, amino or C _1-4 alkyl, (f) —OR ₂₈ , (g) —OC (＝ O) R ₂₉ , (h) —S—C _1-6 alkyl, (i) -SO ₂ -C _1-6 alkyl, (j) phenylsulfonyl, (k) _{p-toluenesulfonyl, (l) -SO 2 -N (} R 30) 2, (m) -C (O ) -OR ₃₁ , (n) -C (O) -N (R ₃₀ ) ₂ , (o) -N (R ₃₀ ) ₂ , or (p) or below xxiv, xxv, xxvi, xxvii, xxviii,
xxix; A 6-membered heterocyclic group having 1 to 3 nitrogen atoms selected from the structure consisting of: (a) H, (b) amino, (c) C _1-4 alkyl, or (d) R ₂₅ and R ₂₆ are the same or different and are (a) H, (b) C _1-6 alkyl, or (c) C _3-6 cycloalkyl; R ₂₇ is (a) C _{1- 6} alkyl, (b) C _1-8 alkyl hydroxyl, (c) phenyl, or (d) R ₂₈ is (a) H, (b) C _1-6 alkyl, (c) vinyl, or (d) one or more halo, C _1-4 alkoxy, —OH, amino or C substituted with _1-4 alkyl it is phenyl optionally; R ₂₉ is an (a) C _1-6 alkyl or (b) phenyl,; R ₃₀ is independently, (a) H, (b ) C _1-4 alkyl, or (c) C _1-4 alkyl or C _1-4 phenyl optionally substituted by alkoxy; R ₃₁ is (a) C _1-6 alkyl, (b) C _{1- 4} alkyl or C _1-4 alkoxy phenyl optionally substituted or (c) C _1-4 alkyl or C _1-4 benzyl which may be substituted by alkoxy; here, R ₃₂ and R ₃₃ are the same or different, (a) H, (b ) halo, is replaced by (c) 1 or R ₄₅ beyond that Which may be C _1-8 alkyl, (d) C _{3-6 cycloalkyl, (e) - (CH 2} ) be _m -OR ₃₆ or (f) -C (= O) -R 38,; R ₃₄ and R ₃₅ are the same or different, and (a) H, (b) C _1-8 alkyl optionally substituted by one or more R ₄₅ , (c) C _1-8 alkoxy, (d) C _{1-8 alkylthio, (e) - (CH 2} ) m -OR 39, (f) -O- (CH 2) m -OR 39, (g) -NR 40 R 41, (h) -N = CH- _{NR 42 R 43, (i)} -C (= O) -NR 40 R 41 _{or, (j) - (CH 2} ) m -C (= a) -R 38, where a is O or Echirenke tar , or linked together with R ₃₄ and _{R 35, (k) = O} , (l) = NR 44, to form a (m) = S, or _{(n) = CR 42 R 43} ,; R 36 and R ₃₇ are the same or Will, (a) H, be a (b) 1 or more than is optionally C _1-8 alkyl substituted with R ₄₅ or _{(c) -CH 2 OCH 3,} ; R 38 is (a) H, _{(b) - (CH 2)} m -OH, (c) 1 or more than which may be C _1-8 alkyl substituted with R _45, (d) C _1-8 alkoxy, (e) -O- CH ₂ —O—C (＝ O) —R ₃₆ , or (f) — (CH ₂ ) _m —C (＝ O) —OR ₃₆ ; R ₃₉ is (a) H, (b) 1 or C _1-8 alkyl _optionally substituted with R ₄₅ , (c) C _2-8 alkenyl, (d)-(CH ₂ ) _m -OR ₃₆ , (e)-(CH ₂ ) _m -C (＝ O) —R ₃₈ , (f) —C (＝ O) — (CH ₂ ) _m —OR ₄₃ , or (g) tosyl; R ₄₀ and R ₄₁ are the same or different; _{(b) - (CH 2)} m -OR 36, (c) Or more than which may be C _1-8 alkyl substituted with _{R 45, (d) -C (} = O) -R 38, (e) -C (= O) -NR 36 R 37, (f) -(CH ₂ ) _p -phenyl, (g) thiazol-2-yl, or R ₄₀ and R ₄₁ are bonded together to form (h) pyrrolidino, (i) piperidino, (j) piperazino, (k ) morpholino or form a (l) thiomorpholino, wherein the, to group (h) no (l) is C _1-8 alkyl or - (CH _{2) m} -OH in well be substitution; R ₄₂ And R ₄₃ are the same or different, and (a) H, (b) C _1-8 alkyl optionally substituted with one or more R ₄₅ , (c) —C (＝ O) —R ₃₈ , or _{(d) - (CH 2)} p - phenyl; R ₄₄ is (a) H, with _{(b) -OR 39, (c} ) 1 or R ₄₅ beyond that Conversion which may C _1-8 alkyl optionally, (d) C _{1-8 alkoxy, (e) - (CH 2} ) p - _{phenyl, (f) -NR 40 R 41} , (g) -NH-C ( _{= NH) -NH 2, (h} ) [1,2,4] triazol-4-yl or (i) be a -CN,; R ₄₅ is (a) halo, (b) -OH, (c ) - CN, (d) C _1-6 alkoxy, (e) amino, (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 an 1 or 2; m is 0, 1 or 2; n is 0 or 1; p is an 1, 2, 3 or 4 Q is 0, 1, 2, 3, or 4] or a pharmaceutically acceptable salt thereof. 2. The compound of formula I according to claim 1, wherein R ₁ is (a) C _1-3 alkyl, (b) C _1-3 alkoxy, or (c) —NH (C _1-3 alkyl). Compound. 3. The compound of formula I according to claim 1, wherein R ₁ is CH ₃ . 4. The compound of formula I according to claim 1, wherein Y is H or F. 5. The compound of formula I according to claim 1, wherein W is O. 6. The compound of formula I according to claim 1, wherein W is S. 7. The compound of formula I according to claim 1, wherein ring P is pyridyl. 8. The method according to claim 1, wherein Q is the following i, ii, iii and vi: Wherein R ₂ is the same as defined in claim 1. A 5-membered heterocyclic group having 1 to 4 nitrogen atoms selected from the structure consisting of: Compound. 9. R ₂ is (a) H, (b) -CN, (c) -C (= O) H, (d) -C (= NH) -OH , or (e) C _1-3, 9. A compound of formula I according to claim 8, which is an alkyl hydroxyl. 10. Q is (a) (B) (C) Or (d) [Wherein E is the same as defined in claim 1]. 11. Z is (a) H, (b) —C (＝ O) R ₂₇ , (c) pyridinyl, (d) 2-pyrimidinyl, (e) 4-myrimidinyl, or (f) pyridazinyl. Wherein the groups (c) to (f) may be substituted by amino, methyl, F or Cl; R ₂₇ is as defined in claim 1, represented by formula I according to claim 10; Compound. 12. R ₂₇ is (a) C _1-3 alkyl, (b) C _1-2 alkyl hydroxyl, or (c) The compound of the formula I according to claim 11, which is: 13. A compound of formula II Wherein R ₁ and W are the same as defined in claim 1; ring T is a 6-membered heteroaromatic group having 1 to 3 nitrogen atoms; The aromatic group has a 5-membered heteroaromatic group fused thereto;
It then 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) -CF 3, (} g) -NO 2, (h) C 1-6 alkoxy, (i) C _1-6 alkoxycarbonyl, (j) C _1-6 alkylthio, (k) C _1-6 acyl, (l) -NR ₄₈ R ₄₉ , (m) C _1-6 alkyl optionally substituted with R ₅₀ , (n) optionally substituted with 1 or 2 R ₅₁ A good C _2-8 alkenylphenyl, (o) a phenyl optionally substituted with one or two R ₅₁ , (p) -CH = NOH, (q) -CH = N- (OC _1-6 Alkyl), (r) consisting of S, N and O, optionally substituted with one or two R ₅₁ A 5- or 6-membered heterocyclic group having 1 to 3 atoms selected from the group: (s) Or (t) R ₄₈ and R ₄₉ are the same or different, and (a) H, (b) C _1-4 alkyl, (c) C _5-6 cycloalkyl, or (d) R ₄₈ and R ₄₉ are nitrogen atoms Together with S, N and O
5-, 6 which may optionally have further heteroatoms selected from the group consisting of and optionally substituted on further nitrogen atoms, optionally with C _1-3 alkyl or C _1-3 acyl. R ₅₀ is (a) —OH, (b) C _1-4 alkoxy, (c) C _1-4 acyl, (d) —NR ₄₈ R ₄₉ , (e) —NHC ( _{= S) NH 2, (f} ) -NHC (= O) NH 2, (g) -NHC (= O) R 49, (h) -SO 2 NR 55 R 56 or (i) -NRSO ₂ R _55, R ₅₁ is (a) carboxyl, (b) halo, (c) —CN, (d) mercapto, (e) formyl, (f) CF ₃ , (g) —NO ₂ , (h) C _{1 -6} alkoxy, (i) C _1-6 alkoxycarbonyl, (j) C _1-6 alkylthio, (k) C _1-6 acyl, optionally (l) H, C _1-5 alkoxy, C _1-5 acyl or -NR ₄₈ may be substituted with R ₄₉ C _1-6 alkyl, (m) phenyl, (n) -C (= O ) NR 52 R 53 _{, (o) -NR 48 R 49} , (p) -N (R 52) (- SO 2 R 54), (q) -SO 2 -NR 52 R 53 or, (r) -S (= O ) i It is R _54; R ₅₂ and R ₅₃ are the same or different, (a) H, be a (b) C _1-6 alkyl or (c) phenyl,; R ₅₄ is (a) C _1-4 alkyl or, (B) phenyl optionally substituted with C _1-4 alkyl; R ₅₅ and R ₅₆ are the same or different; (a) H, or (b) C _1-6 alkyl; and j Is 0 or 1.] or a pharmaceutically acceptable salt thereof. 14. The ring T is The compound of the formula II according to claim 14, which is: 15. X is (a) C _1-4 alkyl optionally substituted with R ₅₀ , (b) phenyl optionally substituted with one or two R ₅₁ , (c) — CH = NOR, be a (d) optionally one or two pyridyl optionally substituted with R _51, (e) optionally substituted with one or two R ₅₁ thienyl; R ₅₀ And R ₅₁ is the same as defined in claim 14.
A compound represented by the formula: 16. R ₄₈ and R ₄₉ are the same or different, a) H, b) C _1-3 alkyl, or c) R ₄₈ and R ₄₉ together with a nitrogen atom form morpholinyl, pyrrolidinyl,
15. The compound of formula II according to claim 14, which is a piperazinyl or piperidyl ring. 17. Treating a microbial infection in a patient in need thereof comprising administering to a patient in need thereof an effective amount of a compound of formula I as set forth in claim 1 or formula II as set forth in claim 13. Method. 18. The method according to claim 17, wherein the compound of the formula I or II is orally, parenterally, topically or transdermally administered in a pharmaceutical composition. 19. The method according to claim 17, wherein the compound represented by the formula I or II is orally administered 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 about 0.1 to about 100 mg / kg body weight / day. 21. A pharmaceutical composition comprising the compound according to claim 1 or 13 and a pharmaceutically acceptable carrier. 22. (a) wherein R ₁ is —CH ₃ , W is O, ring P is 3-pyridinyl,
When Y is H, Q is 6-pyrazol-1-yl, 6-1,2,4-triazol-1-yl, 6- (4-indo-pyrazol-1-yl), 6- ( 4-acetyl-pyrazol-1-yl) or 6- (4-phenyl-pyrazol-1-yl)
(B) when R ₁ is —CH ₃ , W is O, and Y is H, the ring P is not benzofuran-5-yl. Compound.