Sélection de la langue

Search

Sommaire du brevet 2318762 

Énoncé de désistement de responsabilité concernant l'information provenant de tiers

Une partie des informations de ce site Web a été fournie par des sources externes. Le gouvernement du Canada n'assume aucune responsabilité concernant la précision, l'actualité ou la fiabilité des informations fournies par les sources externes. Les utilisateurs qui désirent employer cette information devraient consulter directement la source des informations. Le contenu fourni par les sources externes n'est pas assujetti aux exigences sur les langues officielles, la protection des renseignements personnels et l'accessibilité.

Disponibilité de l'Abrégé et des Revendications

L'apparition de différences dans le texte et l'image des Revendications et de l'Abrégé dépend du moment auquel le document est publié. Les textes des Revendications et de l'Abrégé sont affichés :

  • lorsque la demande peut être examinée par le public;
  • lorsque le brevet est émis (délivrance).
(12) Demande de brevet: (11) CA 2318762
(54) Titre français: DERIVES D'ISOXAZOLINE AMINOMETHYLE SUBSTITUES UTILES EN TANT QU'AGENTS ANTIMICROBIENS
(54) Titre anglais: SUBSTITUTED AMINOMETHYL ISOXAZOLINE DERIVATIVES USEFUL AS ANTIMICROBIALS
Statut: Réputée abandonnée et au-delà du délai pour le rétablissement - en attente de la réponse à l’avis de communication rejetée
Données bibliographiques
(51) Classification internationale des brevets (CIB):
  • C7D 413/14 (2006.01)
  • A61K 31/42 (2006.01)
  • C7D 413/10 (2006.01)
  • C7D 491/04 (2006.01)
(72) Inventeurs :
  • BARBACHYN, MICHAEL ROBERT (Etats-Unis d'Amérique)
  • MORRIS, JOEL (Etats-Unis d'Amérique)
  • WISHKA, DONN G. (Etats-Unis d'Amérique)
  • THOMAS, RICHARD CHARLES (Etats-Unis d'Amérique)
  • GRABER, DAVID R. (Etats-Unis d'Amérique)
(73) Titulaires :
  • PHARMACIA & UPJOHN COMPANY
(71) Demandeurs :
  • PHARMACIA & UPJOHN COMPANY (Etats-Unis d'Amérique)
(74) Agent: MACRAE & CO.
(74) Co-agent:
(45) Délivré:
(86) Date de dépôt PCT: 1999-02-10
(87) Mise à la disponibilité du public: 1999-09-02
Licence disponible: S.O.
Cédé au domaine public: S.O.
(25) Langue des documents déposés: Anglais

Traité de coopération en matière de brevets (PCT): Oui
(86) Numéro de la demande PCT: PCT/US1999/004262
(87) Numéro de publication internationale PCT: US1999004262
(85) Entrée nationale: 2000-07-24

(30) Données de priorité de la demande:
Numéro de la demande Pays / territoire Date
60/075,914 (Etats-Unis d'Amérique) 1998-02-25

Abrégés

Abrégé français

L'invention concerne de nouveaux dérivés d'isoxazoline aminohétéroaromatique substitués représentés par la formule (I), dans laquelle R¿1? représente H, alkyle, cycloalkyle, alcoxy ou alkylamino: Y représente H, F ou CH¿3?; W représente O ou S; le noyau P représente une fraction hétéroaromatique à 5 éléments comprenant un à trois atomes sélectionnés dans le groupe constitué d'atomes de soufre, d'azote et d'oxygène, cette fraction hétéroaromatique à 5 éléments pouvant en outre comprendre un naphtyle ou un benzène fusionné, une fraction hétéroaromatique à 6 éléments qui comprend au moins un atome d'azote, cette fraction hétéroaromatique à 6 éléments pouvant en outre comprendre un naphtyle ou un benzène fusionné ou une fraction hétéroaromatique à 5 éléments qui comprend de un à trois atomes sélectionnés dans le groupe constitué d'atomes de soufre, d'azote et d'oxygène; Q représente une fraction hétérocyclique à 4, 5, 6, 7 ou 9 éléments qui comprennent au moins un azote, un soufre et/ou un oxygène. Les composés selon l'invention possèdent une activité antimicrobienne élevée pour prévenir et traiter des maladies infectieuses.


Abrégé anglais


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

Revendications

Note : Les revendications sont présentées dans la langue officielle dans laquelle elles ont été soumises.


We claim:
1. A compound of formula I
<IMG>
or pharmaceutically acceptable salts thereof wherein:
R1 is
(a) H,
(b) C1-8 alkyl, which may be substituted with one or more halo, -OH,
C1-4 alkoxy or C1-4 acyloxy,
(c) C3-6 cycloalkyl,
(d) C1-8 alkoxy,
(e) amino, or
(f) NH(C1-3 alkyl), wherein C1-3 alkyl may be substituted with one or
more halo;
Y is
(a) H,
(b) F, or
(c) CH3;
W is
(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
5-membered heteroaromatic moiety can additionally have a fused-on benzene or
naphthyl,
(b) a 6-membered heteroaromatic moiety having one to three nitrogen
atoms, wherein the 6-membered heteroaromatic moiety can additionally have a
fused-on benzene, naphthyl or 5-membered heteroaromatic moiety having one to
three atoms selected from the group consisting of sulfur, nitrogen and oxygen
atoms,
or
-28-

(c) a phenyl ring fused-on with a benzene, naphthyl, 6-membered
heteroaromatic moiety having at least one nitrogen atom or a 5-membered
heteroaromatic moiety having one to three atoms selected from the group
consisting
of sulfur, nitrogen and oxygen atoms;
Q is
(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;
<IMGS>
(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;
<IMGS>
(c) a heterocyclic ring having a nitrogen atom selected from structures
consisting of xix, xx, xxi, xxii, and xxiii;
-29-

<IMGS>
wherein R2 is
(a) H,
(b) halo,
(c) -OH,
(d) -OR3,
(e) -SR3,
(f) -S(O)i R3,
(g) -CN,
(h) -O2CR3,
(i) -NHC(=O)R3,
-30-

(j) -NHCO2R3,
(k) -NHSO2R3,
(l) -CO2R4,
(m) -C(=O)N(R3)2,
(n) -C(=O)R3,
(o) C1-8 alkyl,
(p) C3-8 cycloalkyl,
wherein groups (o) and (p) may be substituted with one or more of the
preceding
groups (a)-(n),
(q) phenyl, which may be substituted with one or more of the preceding
groups (a)-(p),
(r) -CH=CHCO2Et, or
(s) -C(=NR4)R5;
R3 is
(a) H,
(b) C1-6 alkyl
(c) C3-8 cycloalkyl,
wherein groups (b) and (c) may be substituted with one or more of halo, -OH,
C1-4 alkoxy, C1-4 acyl, C1-4 acyloxy, or -OC(=O)CH2N(CH3)2, or
(d) phenyl, which may be substituted with one or more of the preceding
groups (b) to (c);
R4 is
(a) -OH or
(b) -OCH3;
R5 is
(a) H, or
(b) -CH3;
wherein R6 is
(a) H,
(b) -OR10,
(c) -SR10,
(d) -NR11R12,
(e) -CN,
(f) C1-4 alkoxycarbonyl,
(g) carboxamide,
(h) C1-4 acyl, which may be substituted with one or more halo, -OH,
-31-

C1-4 alkoxy or C1-4 acyloxy,
(i) -N(OH)(C1-5 alkyl),
(j) -N(OH)CH2phenyl,
(k) -NSO2(C1-6alkyl) wherein C1-6 alkyl may be substituted with one or
more halo, C1-6 alkoxy or phenyl, or
(l) F;
R7 is
(a) H,
(b) -OH,
(c) -O(C1-8 alkyl),
(d) C1-4 alkyl,
(e) phenyl, or
(f) F;
R8 is
(a) H,
(b) C1-3 alkyl, which may be substituted with halo, -OH, -CO2 C1-4 alkyl,
C1-3 acyloxy, C1-3 alkyoxy or -N(C1-4 alkyl)2,
{c) phenyl, or
(d) pyridyl;
R9 is
(a) O,
(b) S,
(c) -NR13, or
(d) -CR14R15;
R10 is
(a) H,
(b) C1-8 alkyl, which may be substituted with one or more halo, -CN, -OH,
C1-8 alkoxy, C1-8 acyloxy, C1-4 alkoxycarbonyl, or phenyl,
(c) C1-8 acyl, which may be substituted with one or more -OH,
C1-8 alkoxy, C1-8 acyloxy,
(d) C1-8 alkoxycarbonyl,
(e) carboxamide, which may be substituted with a C1-4 alkyl or phenyl on
the carboxamide nitrogen, or
(f) phenyl, which may be substituted with one or more halo, -CN,
C1-3 alkoxy, C1-3 alkoxycarbonyl or C1-4 alkyl;
R11 and R12 are the same and different and are
-32-

(a) H,
(b) C1-8 alkyl, which may be substituted with one or more halo, -CN, -OH,
C1-8 alkoxy, C1-8 acyloxy, C1-8 alkoxycarbonyl, phenyl,
(c) C1-8 acyl, which may be substituted with one or more -OH, amino,
C1-8 alkoxy, C1-8 acyloxy, C1-4 acylamino,
(d) benzoyl, which may be substituted with one or more halo, -OH, amino,
C1-8 alkoxy, C1-8 acyloxy, C1-4 acylamino, C1-4 alkoxycarbonylamino,
(e) C1-8 alkoxycarbonyl,
(f) benzyloxycarbonyl,
(g) tertbutoxycarbonyl,
(h) carboxamide, which may be substituted with a C1-4 alkyl or phenyl on
the carboxamide nitrogen,
(i) trifluoracetyl, or
(j) C1-8 acyl;
R13 is
(a) H,
(b) -OR10,
(c) -NHR10, or
(d) C1-8 alkyl, which may be substituted with phenyl;
R14 and R15 are the same and different and are
(a) H,
(b) C1-4 alkyl, which may be substituted with halo, -OH, C1-4alkoxy,
C1-4 alkoxycarbonyl, or phenyl,
(c) C1-8 acyl,
(d) C1-4 alkoxycarbonyl,
(e) -CN, or
(f) F;
R16 is
(a) O, or
(b) S;
R17 and R18 are the same and different and are
(a) H,
(b) C1-4 alkyl, which may be substituted with halo, -OH or C1-4 alkoxy,
(c) -OH,
(d) C1-4 alkoxy, which may be substituted with -OH or C1-4 alkoxy,
(e) NR11R12, or
-33-

(f) C1-4 acyloxy;
R19 is
(a) H, or
(b) -CH3;
E is
(a) -O-, or
(b) -S(=O)m-;
R20 is
(a) H,
(b) -CH3,
(c) -CN,
(d) -CO2H,
(e) -CO2R22, or
(f) -(CH2)i R23;
R21 is
(a) H, or
(b) -CH3;
R22 is
(a) H,
(b) C1-6 alkyl, which may be substituted with halo, -OH, C1-4 alkoxy,
C1-4 acyloxy or -O-CH2-phenyl,
(c) C3-6 cycloalkyl,
(d) amino,
(e) -N(C1-6 alkyl)2,
(f) -NH(C1-6 alkyl), or
(g) C1-6 alkoxy;
R23 is
(a) -OH,
(b) -OR22,
(c) -OC(=O)R22,
(d) amino,
(e) -NHC(=O)R22, or
(f) -N(R24)2;
R24 is
(a) H,
(b) C1-4 alkyl, which may be substituted with halo, -OH, C1-4 alkoxy,
-34-

amino, -N(C1-6 alkyl)2, or -NH(C1-6 alkyl), or
(c) p-toluenesulfonyl;
wherein Z is
(a) H,
(b) -C(=O)R27,
(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 C1-4 alkyl,
(f) -OR28,
(g) -OC(=O)29,
(h) -S-C1-6 alkyl,
(i) -SO2-C1-6 alkyl,
(j) phenylsulfonyl,
(k) p-toluenesulfonyl,
(l) -SO2-N(R30)2,
(m) -C(O)-OR31,
(n) -C(O)-N(R30)2,
(o) -N(R30)2, or
(p) a 6-membered heterocyclic moiety having one to three nitrogen atoms
selected from structures consisting of xxiv, xxv, xxvi, xxvii, xxviii, xxix,
<IMGS>
L is
(a) H,
(b) amino,
(c) C1-4 alkyl, or
(d) halo;
R25 and R27 are the same and different and are
(a) H,
-35-

(b) C1-6 alkyl, or
(c) C3-6 cycloalkyl;
R27 is
(a) C1-6 alkyl,
(b) C1-8 alkylhydroxyl,
(c) phenyl, or
(d) <IMG> ;
R28 is
(a) H,
(b) C1-6 alkyl,
(c) vinyl, or
(d) phenyl, which may be substituted with one to more halo, C1-4 alkoxy,
-OH, amino or C1-4, alkyl;
R29 is
(a) C1-6 alkyl, or
(b) phenyl;
R30 is independently
(a) H
(b) C1-4 alkyl, or
(c) phenyl, which may be substituted with C1-4 alkyl or C1-4 alkoxy;
R31 is
(a) C1-6 alkyl,
(b) phenyl, which may be substituted with C1-4 alkyl or C1-4 alkoxy, or
(c) benzyl, which may be substituted with C1-4 alkyl or C1-4 alkoxy;
wherein and R32 and R33 are the same and different and are
(a) H,
(b) halo,
(c) C1-8 alkyl, which may be substituted with one or more R45,
(d) C3-6 cycloalkyl,
(e) -(CH2)m-OR36, or
(f) -C(=O)-R38;
R34 and R35 are the same and different and are
(a) H,
(b) C1-8 alkyl, which may be substituted with one or more R45,
-36-

(c) C1-8 alkoxy,
(d) C1-8 alkylthio,
(e) -(CHa2)m-OR39,
(f) -O-(CH2)m-OR39,
(g) -NR40R41,
(h) -N=CH-NR42R43,
(i) -C(=O)-NR40R41, or
(j) -(CH2)m-C(=A)-R38, wherein A is O or ethyleneketal,
or R34 and R35 may combine together to form
(k) =O,
(l) =NR44,
(m) =S, or
(n) =CR42R43;
R36 and R37 are the same and different and are
{a) H,
{b) C1-8 alkyl, which may be substituted with one or more R46, or
(c) -CH2OCH3;
R38 is
(a) H,
(b) -(CH2)m-OH,
(c) C1-8 alkyl, which may be substituted with one or more R45,
(d) C1-8 alkoxy,
(e) -O-CH2-O-C(=O)-R38, or
(f) -(C)m-C(=O)-OR36;
R39 is
(a) H,
(b) C1-6 alkyl, which may be substituted with one or more R45,
(c) C2-8 alkenyl,
(d) -(CH2)m-OR36,
(e) -(CH2)m-C(=O)-R38,
(f) -C(=O)-(CH2)m-OR43, or
(g) tosyl;
R40 and R41 are the same and different and are
(a) H,
(b) -(CH2)m-OR36,
(c) C1-8 alkyl, which may be substituted with one or more R45,
-37-

(d) -C(=O)-R36,
(e) -C(=O)-NR36R37,
(f) -(CH2)p-phenyl,
(g) thiazol-2-yl,
or R40 and R41 may combine together to form
(h) pyrrolidino,
(i) piperidino,
(j) piperazino,
(k) morpholino, or
(l) thiomorpholino,
wherein groups (h) to (l) may be substituted with C1-8 alkyl or -(CH2)mOH;
R42 and R43 are the same and different and are
(a) H
(b) C1-8 alkyl, which may be substituted with one or more R45,
(c) -C(=O)-R38, or
(d) -(CH2)p-phenyl;
R44 is
(a) H,
(b) -OR39,
(c) C1-8 alkyl, which may be substituted with one or more R45,
(d) C1-8 alkoxy,
(e) -(CH2)p-phenyl,
(f) -NR44R41,
(g) -NH-C(=NH)-NH2,
(h) [1,2,4]triazol-4-yl, or
(i) -CN;
R45 is
(a) halo,
(b) -OH,
(c) -CN,
(d) C1-6 alkoxy,
(e) amino,
(f) -N(C1-6 alkyl)2,
(g) -NH(C1-6 alkyl), or
(h) carboxyl;
~ is a double bond or a single bond;
-38-

its 1 or 2;
m is 0, 1 or 2;
n is 0 or 1;
p is 1, 2, 3 or 4; and
q is 0, 1, 2, 3 or 4.
2. A compound of formula I according to claim 1 wherein R1 is
(a) C1-3 alkyl,
(b) C1-3 alkoxy, or
(c) -NH(C1-3 alkyl).
3. A compound of formula I according to claim 1 wherein R1 is CH3.
4. A compound of formula I according to claim 1 wherein Y is H, or F.
5. A compound of formula I according to claim 1 wherein W is O.
6. A compound of formula I according to claim 1 wherein W is S.
7. A compound of formula I according to claim 1 wherein Ring P is pyridyl.
8. A compound of formula I according to claim 1 wherein Q is a 5-membered
heterocyclic moiety having one to four nitrogen atoms selected from structures
consisting of i, ii, iii, and vi
<IMGS>
wherein R2 is as defined in claim 1.
9. A compound of formula I according to claim 8 wherein R2 is
(a) H
(b) -CN,
(c) -C(=O)H,
(d) -C(=NH)-OH, or
(e) C1-3 alkyl hydroxyl;
-39-

10. A compound of formula I according to claim 1 wherein Q is
<IMG>
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)R27,
(c) pyridinyl,
(d) 2-pyrimidinyl,
(e) 4-pyrimidinyl, or
(f) pyridazinyl;
wherein groups (c) to (f) may be substituted with amino, methyl, F, or Cl;
wherein
R27 is as defined in claim 1.
12. A compound of formula I according to claim 11 wherein R27 is
(a) C1-3 alkyl,
(b) C1-2 alkylhydroxyl, or
<IMG>
-40-

13. A compound of formula II
<IMG>
or pharmaceutically acceptable salts thereof wherein:
R1 and W are the same as defined in claim 1;
Ring T is a 6-membered heteroaromatic moiety having one to three nitrogen
atoms,
wherein the 6-membered heteroaromatic moiety has a fused-on 5-membered
heteroaromatic moiety which in turn has one to three atoms selected from the
group
consisting of sulfur, nitrogen and oxygen atoms;
X is
(a) carboxyl,
(b) halo,
(c) -CN,
(d) mercapto,
(e) formyl,
(f) -CF3,
(g) -NO2,
(h) C1-6 alkoxy,
(i) C1-6 alkoxycarbonyl,
(j) C1-6 alkythio,
(k) C1-6 acyl,
(l) -NR48 R49,
(m) C1-6 alkyl which can be substituted with R50
(n) C2-8 alkenylphenyl optionally substituted with one or two R51,
(o) phenyl optionally substituted with one or two R51,
(p) -CH=NOH,
(q) -CH=N-(OC1-6alkyl),
(r) a 5-, or 6-membered heterocyclic moiety having one to three atoms
selected from the group consisting of S, N, and O, optionally substituted with
one or
two R51,
-41-

<IMG>
(s) , or
(t) <IMG>
R48 and R49 are the same and different and are
(a) H,
(b) C1-4 alkyl,
(c) C5-6 cycloalkyl, or
(d) R48 and R49 taken together with the nitrogen atom is a 5-,
6-membered heterocyclic moiety which optionally has a further hetero atom
selected
from the group consisting of S, N, and O, and can in turn be optionally
substituted
with, including on the further nitrogen atom, C1-3 alkyl, or C1-3 acyl;
R50 is
(a) -OH,
(b) C1-4 alkoxy,
(c) C1-4 acyl,
(d) -NR48R49,
(e) -NHC(=S)NH2,
(f) -NHC(=O)NH2,
(g) -NHC(=O)R49,
(h) -SO2NR55R56, or
(i) -NRSO2R55;
R51 is
(a) carboxyl,
(b) halo,
(c) -CN,
(d) mercapto,
(e) formyl,
(f) CF3,
(g) -NO2,
(h) C1-6 alkoxy,
(i) C1-6 alkoxycarbonyl,
(j) C1-6 alkythio,
(k) C1-6 acyl,
-42-

(l) C1-6 alkyl optionally substituted with OH, C1-5 alkoxy, C1-5 acyl, or
-NR48R49,
(m) phenyl,
(n) -C(=O)NR52 R53,
(o) -NR48R49,
(p) -N(R52)(-SO2R54),
(q) -SO2-NR5253, or
(r) -S(=O)i R54;
R52 and R53 are the same and different and are
(a) H,
(b) C1-6 alkyl, or
(c) phenyl;
R54 is
(a) C1-4 alkyl, or
(b) phenyl optionally substituted with C1-4 alkyl;
R55 and R56 are the same and different and are
(a) H, or
(b) C1-6 alkyl;
and j is 0 or 1.
14. A compound of formula II according to claim 14 wherein Ring T is
<IMG>
15. A compound of formula II according to claim 14 wherein X is
(a) C1-4 alkyl which can be substituted with R50,
(b) phenyl optionally substituted with one or two R51,
(c) -CH=NOR,
(d) pyridyl optionally substituted with one or two R51,
(e) thienyl optionally substituted with one or two R51;
R50 and R51 are the same as defined in claim 14.
16. A compound of formula II according claim 14 wherein R48 and R49 are the
same and different and are
-43-

a) H,
b) C1-3 alkyl, or
c) R48 and R49 taken together with the nitrogen atom are morpholinyl,
pyrrolidinyl, piperazinyl or piperidyl ring;
17. A method for treating microbial infections in patients comprising:
administering to a patient in need thereof an effective amount of a compound
of
formula I as shown in claim 1 or formula II as shown in claim 13.
18 The method of claim 17 wherein said compound of formula I or formula II is
administered orally, parenterally, topically or transdermally in a
pharmaceutical
composition.
19. The method of claim 17 wherein said compound of formula I or formula II is
administered orally in a pharmaceutical composition.
20. The method of claim 17 wherein said compound of formula I or formula II is
administered in an amount of from about 0.1 to about 100 mg/kg of body
weight/day.
21. A pharmaceutical composition comprising a compound of claim 1 or claim 13
and a pharmaceutically acceptable carrier.
22. The compounds of claim 1 having the following provisos:
(a) where R1 is -CH3, W is O, ring P is 3-pyridinyl, Y is H, then Q is not
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 R1 is -CH3, W is O, Y is H, then ring P is not benzofuran-5-yl.
-44-

Description

Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.


CA 02318762 2000-07-24
WO 99/43671 PCT/US99/04262
SUBSTI1'IT~ED AMINOMETHYL ISOXAZOLINE DERIVATIVES USEFUL AS ANTIMICROBIALS
FIELD OF THE INVENTION
The present invention relates to novel substituted aminoheteroaromatic
isoxazoline derivatives, to pharmaceutical compositions containing them as
active
ingredients, and to methods of using them. The compounds of the invention have
antimicrobial activity for preventing and treating infectious diseases.
BACKGROUND OF THE INVENTION
Antibacterial agents such as oxazolidinones are a class of known orally-
active, synthetic antibacterial agents and there are numerous references in
the art
disclosing a variety of oxazolidinone derivatives. For example, U.S. Patent
Nos.
4,?05,799 and 5,523,403 and European Patent Application 0,316,594 disclose
substituted phenyl-2-oxazolidinones, including the sulfides, sulfoxides,
sulfones,
sulfonamides, nitrilea, acetamides and a tropane ring. U.S. Patent Nos.
4,948,801;
5,254,577 and 6,130,316 disclose arylbenzene oxazolidinyl compounds, wherein
the
aryl includes the (un)substituted phenyl and pyridyl groups. European Patent
Applications 0,697,412; 0,694,544; 0,694,543 and 0,693,491 disclose 5 to 9-
membered
heteroaryl-oxazolidinones having one to three atoms selected from the group
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
are replaced by an isoxazoline moiety. These compounds have antibacterial
activity
comparable to the corresponding oxazolidinones. They are effective against a
number of human and veterinary pathogens, including gram-positive aerobic
bacteria such as multiply-resistant staphylococci and streptococci, as well as
anaerobic organisms such as bacteroides and clostridia species, and acid-fast
organisms such as Mycobaccterium tuberculosis and Mycobascterium a~uium.
INFORMATION DISCLOSURE
U.S. Patent No. 4,283,403 discloses 3-aryl-2-isoxazolines useful for the
protection of plants from diseases.
Danish Patent No. 2,725,763 discloses substituted 2-isoxazolines which is
fungicidal against phytophthora infestation on tomatoes. The compounds also
show
-1-

CA 02318762 2000-07-24
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 A1 discloses 3-aryl-2-isoxazolines which is useful in inhibiting
PDEn,, 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 heteroaroraatic compounds via the isoxazoline
route.
U.S. Patent No. 5,547,960 discloses oxazolidinones containing a substituted
diazine moiety and their use as antimicrobials.
International Publication No. WO 95/07271 discloses substituted oxazine and
thiazine oxazolidinone antimicrobials.
International Publication No. WO 9514684 discloses esters of substituted-
hydroxyacetyl piperazine phenyl oxazolidinones.
International Publication No. WO 95/25106 discloses oxazolidinone
derivatives and pharmaceutical compositions containing them.
International Publication No. WO 96/13502 discloses phenyloxazolidinone
antimicrobials.
International Publication No. WO 96/23788 discloses hetero-aromatic ring
substituted phenyloxazolidinone antimicrobials.
International Publication No. WO 97/21708 discloses 4-pyrimidinyl- or 4-
pyrazinyl-piperazinyl-phenyl-oxazolidinone derivatives.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a compound of formula I
~~ i .o w
~1~ \i -R ~
'H ,~r~~
I
or pharmaceutically acceptable salts thereof wherein:
Rl is
(a)
(b) C1:8 alkyl, which may be substituted with one or more halo, -OH,
-2-

CA 02318762 2000-07-24
WO 99/43671 PCT/US99/04262
Cl,~ alkoxy or Cl.~ acyloxy,
(c) Cg.~ cycloalkyl,
(d) Ci.B allioxY~
(e) amino, or
(fl NH(C1~ alkyl), wherein Cl_g alkyl may be substituted with one or
more halo;
Y is H, F, or CHI;
W is O, or S;
Ring P is
(a) a 5-membered heteroaromatic moiety having one to three atoms
selected from the group consisting of sulfur, nitrogen and oxygen atoms,
wherein the
5-membered heteroaromatic moiety can additionally have a fused-on benzene or
naphthyl,
(b) a 6-membered heteroaromatic moiety having at least one nitrogen
atom, wherein the 6-membered heteroaromatic moiety can additionally have a
fused-
on benzene, naphthyl or 5-membered heteroaromatic moiety having one to three
atoms selected from the group consisting of sulfur, nitrogen and oxygen atoms,
or
(c) a phenyl ring fused-on with a benzene, naphthyl, 6-membered
heteroaromatic moiety having at least one nitrogen atom or a 5-membered
heteroaromatic moiety having one to three atoms selected from the group
consisting
of sulfur, nitrogen and oxygen atoms;
Q is
(a) a 5-membered heterocyclic moiety having one to four nitrogen atoms
selected from structures consisting of i, ii, iii, iv, v, vi, vii, viii, and
ix;
~w ~N ~1 NN1
R~N~ R ~N~ R2 N\ R/ C~Nw
i ii iii 2 iv
N=N /~~~ N N N
R~ N\ R ~N\ R ~N\ R ~.N\ R~N
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;
-3-

CA 02318762 2000-07-24
WO 99/43671 PCT/US99104262
R2 R2 RZ N R2
I ~ N I ~ N
\
x ~
R 2 R2 R2
R2~ N 2 \ ' N I / NN ~NN_
N ~ ~N
\ \
xii xiii xiv xv
R2 R2 R2 R2 N
~ N I N NN .~NN_
N \ \
xvi xvii xviii
(c) a heterocyclic ring having a nitrogen atom selected from structures
consisting of xix, ~nc, ~ci, iii, and ~ciii;
Rg R17 R
CH2)n R fig g
s R
R~ N
N\ R N\ R~9 \
Rg g
~x xX XXi
R
Rg Rg \ (CH2)n
''~~R~ R9 Rg
R~ ~N\ R~ I R7
~N
Rs ~ Rg \
Re R~
xxii xxiii
z,
(d) ~N
Rxo
R2T-1
(e) Z-(CH2)~~N- ~ or
R2s
-4-

CA 02318762 2000-07-24
WO 99/43671 PGT/US99/04262
R34 R32
(f)
R35 _ N-
R33 , lCH2)n
wherein R2 is
(a) H,
(b) halo,
(c) -OH;
(d) -OR,9,
(e) -SRB,
(i7 -S(O)~~
(g) -CN,
(h) -02CRg,
(i) -NHC(=O)Rg,
U) -NHC02Rs,
(k) -NHSOZR3,
(1) -COZR4,
(m) -C(=O)N(R$)2,
(n) -C(=O)Rg,
(o) Ci-a ~Yh
(p) C~ cycloalkyl,
wherein groups (o) and (p) may be substituted with one or more of the
preceding
groups (a)-(n),
(q) phenyl, which may be substituted with one or more of the preceding
groups (a)-(p),
(r) -CH=CHC02Et, or
(s) -C(=NR,)R5;
Rs is
(a) H,
(b) Cl$ alkyl,
(c) Cg$ cycloalkyl,
wherein groups (b) and (c) may be substituted with one or more of halo, -OH,
C1~, alkoxy, C1~ acyl, C1.~ acyloxy, or -OC(=O)CH2N(CHg)2, or
(d) phenyl, which may be substituted with one or more of the preceding
groups (b) to (c);
R, is -OH or -OCH9;
-5-

CA 02318762 2000-07-24
WO 99/43671 PCTNS99/04262
R5 is H, or -CH9;
R,o is
(a) H,
(b) -ORIO,
(c) -SRIO,
(d) -~mRiz~
(e) -CN,
(fj C1~ alkoxycarbonyl,
(g) carboxamide,
(h) Cl~, acyl, which may be substituted with one or
more halo, -OH,
C,~ alkoxy or Cl~, acyloxy,
(i) -N(OH)(C1_g alkyl),
(j) -N(OH)CHzphenyl,
(k) -NSOz(C1_gallcyl) wherein C1~ alkyl may be substituted
with one or
more halo, C1~ alkoxy or phenyl, or
(1) F;
R,, is
(a) H,
(b) -OH,
(c) -O(Cl~ alkyl),
(d) Ci.s ~Yh
(e) phenyl,
or
F;
Re is
(a) H,
(b) C1_z alkyl, which may be substituted with halo, -OH, -COz C1.~ alkyl,
C,~ acyloxy, Cl_g alkyoxy or -N(C1~, alkyl)z,
(c) phenyl, or
(d) PY~dYl~
R,~ is O, S, -NR19, or -CR14R~;
Rlo is
(a) H,
(b) C1_8 alkyl, which may be substituted with one or more halo, -CN, -OH,
C1_B alkoxy, C,_8 acyloxy, C,~, alkoxycarbonyl, or phenyl,
(c) C1~ acyl, which may be substituted with one or more =OH,
C1_8 alkoxy, C1_e acyloxy,
-6-

CA 02318762 2000-07-24
WO 99/43671 PCT/US99/04262
(d) Cl.~ alkoxycarbonyl,
(e) carboxamide, which may be substituted with a C,~,
alkyl or phenyl on
the carboxamide nitrogen, or
(f) phenyl, which may be substituted with one or more
halo, -CN,
C1~ alkoxy, C1_3 alkoxycarbonyl or C1~ alkyl;
Rll and R12
are the
same and
different
and are
(a) H
(b) C1_8 alkyl, which may be substituted with one or
more halo, -CN, -OH,
Cl_e allcoxy, C1_8 acyloxy, C1.~ alkoxycarbonyl,
phenyl,
(c) C1_8 acyl, which may be substituted with one or
more -OH, amino,
Cl~ alkoxy, C1_e acyloxy, C,~ acylamino,
(d) benzoyl, which may be substituted with one or more
halo, -OH, amino,
C1_8 alkoxy, C1_e acyloxy, C,_4 acylamino, C1~ alkoxycarbonylamino,
(e) C1_8 alkoxycarbonyl,
(f) benzyloxycarbonyl,
(g) tertbutoxycarbonyl,
(h) carboxamide, which may be substituted with a C1~
alkyl or phenyl on
the carboxamide nitrogen,
(i) trifluoracetyl, or
(j ) C 1.~ acyl;
R19 is H,
-ORIO, -NHRIO,
or C1_8
alkyl, which
may be substituted
with phenyl;
R~4 and R16 are the same and different and are
(a) H,
(b) C1~, alkyl, which may be substituted with halo,
-OH, C1_4alkoxy,
C1~ alkoxycarbonyl, or phenyl,
(c) C1$ aryl,
(d) CIA alkoxycarbonyl,
(e) -CN, or
(f7 F
R18 is S;
O, or
Rl~ and R18 are the same and different and are
(a) H
(b) Cl~ alkyl, which may be substituted with halo, -OH
or C1~ alkoxy,
(c) -OH,
(d) Cl~, alkoxy, which may be substituted with -OH or
C1~ alkoxy,
(e) NR1,R,2, or
-?-

CA 02318762 2000-07-24
WO 99/43671 PCTNS99/04262
C 1~ acyloxy;
Rl9 is H, or -CHI;
E is
(a) -O-, or
(b) -S(=O)m
RZO
is
() H
(b) -CH3,
(c) -CN,
(d) -COzH,
(e) -CO~, or
(17 -(CHZ)fR~~
R21
is
H,
or
-CH9;
R22
18
(a> H,
(b) C1~ alkyl, which may be substituted with halo,
-OH, C1~, alkoxy,
C1~ acyloxy or -O-CHZ-phenyl,
(c) C3.~ cycloalkyl,
(d) amino,
(e) -N(Ci~a ~Yl)a~
(f7 -NH(Cl.~ alkyl), or
(g) C1$ alkoxy;
Raa
is
(a) -OH,
(b) -OR.iz,
(c) -OC(=O)R~,
(d) amino,
(e) -NHC(=O)R~, or
-N(R~)a;
Ru
is
(a) H,
(b) C1~, alkyl, which may be substituted with halo,
-OH, C,~, alkoxy,
amino, -N(Cl_s alkyl)2, or -NH(Cl_s alkyl),
or
(c) p-toluenesulfonyl;
wherein
Z
is
(a) H
_g_

CA 02318762 2000-07-24
WO 99/43671 PCTNS99/04262
(b) -C(=O)~'
(c) C1-s alkYl~
(d) benzyl,
(e) phenyl, wherein groups (d) and (e) may be substituted
with one or
more halo, -OCH9, -OH, amino or C 1.~ alkyl,
-ORza ,
(g) -OC(=O)R~s,
(h) -S-Cl~e alkyl,
(i) -SOZ-C1.8 alkyl,
(j) phenylsulfonyl,
(k) p-toluenesulfonyl,
(1) -SO2-N(R,~)2,
(m) -C(O)'ORsh
(n) -C(O)-N(~o)2,
(o) -N(R~)z, or
(p) a 6-membered heterocyclic moiety having one to
three nitrogen atoms
selected
from structures
consisting
of ~ariv,
xxv, ~cvi,
~cvii, viii,
~cix,
N N~ N ,N
2O L''~ L~N L'
xxiv xxv xxvi
N N N N
L ~N~ N ~ L~N
xxvii xxviii xxix
L is
(a) H, amino, Cl.~ alkyl, or halo;
Rza and Rya are the same and diil'erent and are
(a) H,
(b) C1-a alkyl, or
(c) C3~a cycloalkyl;
R,~., is
(a) Cl.a alkyh
(b) C1-a alkylhydroxyl,
(c) phenyl, or
-g_

CA 02318762 2000-07-24
WO 99/43671 PCTNS99/04262
(d)
0
Rzs is..
(a) H,
(b) CI-a ~Yh
(c) vinyl, or
(d) phenyl, which may be substituted with one to more halo, C1~ alkoxy,
-OH, amino or Cl.~ alkyl;
R,~ is Cl~ alkyl, or phenyl;
R9o is independently
(a) H,
(b) Cl~ alkyl, or
(c) phenyl, which may be substituted with C1.4 alkyl or CI_4 alkoxy;
R.91 is
(a) Cl-8 ~1~
(b) phenyl, which may be substituted with Ch, alkyl
or C1~, alkoxy, or
(c) benzyl, which may be substituted with Cl~ alkyl
or Ch, alkoxy;
wherein Rg2 and R,99 are the same and different and are
(a) H,
(b) halo,
(c) Cl.~ alkyl, which may be substituted with one
or more R4s,
(d) Cg$ cycloalkyl,
(e) -(CHz)m OR3$, or -
(~ -C(=O)-RgB;
R~ and R,96 are the same and different and are
(a) H,
(b) CI-a alkyl, which may be substituted with one
or more R4s,
(c) Cl,g SlkoXy,
(d) CI$ alkylthio,
(e) -(CHZ)m OR39,
(f) ' -O-(CHa),~ ORg9,
-~'~41r
(h) -N=CH-NR,,ZR49~
(1) -C(=O)-NR,,oR4l, or
(j) -(CHa)m C(=A)-R98, wherein A is O or ethyleneketal,
-10-

CA 02318762 2000-07-24
WO 99/43671 PCTNS99/04262
or R94 and
Rgb may
combine
together
to form
(k) =O,
(1) =NR,4"
(m) =S, or
(n) =CR4zR4a~
R9g and
R3~ are
the same
and different
and are
(a) H
(b) Cl~g alkyl, which may be substituted with
one or more R46, or
(c) -CHZOCH9;
lO Rgg 18
(a) H,
(b) -(CHz)m OH,
(c) C,$ alkyl, which may be substituted with
one or more R4s,
(d) Cl_g alkoxy,
(e) -O-CHZ-O-C(=O)-Rgg, or
-(CH2)m C(=O)-OR9g;
R98 is
(a) H,
(b) Cl~g alkyl, which may be substituted with
one or more R4s,
(c) C2$ alkenyl,
(d) -(CHx) ORss
(e) -(CH2)~; C(=O)-Rig,
(f) -C(=O)-(CH2)m OR,~, or
(g) ~sYl~
R4o and are the same and different and are
R41
(a) H
(b) -(CHz)~; ORgg,
(c) Cl~g alkyl, which may be substituted with
one or more R46,
(d) -C(=O)-Rsa
(e) -C(=O)-NRg$Rs.,,
(f7 -(CH2)p phenyl,
(g) thiazol-2-yl,
or R,~ and
R4, may
combine
together
to form
(h) pyrrolidino,
(i) piperidino,
(j) piperazino,
-11-

CA 02318762 2000-07-24
WO 99/43671 PCT/US99/04262
(k) morpholino, or
(1) thiomorpholino,
wherein
groups
(h) to
(1) may
be substituted
with C,_8
alkyl or
-(CH2)m
OH;
R,2 and are the same and different and are
R,~
(a) H,
(b) Cl$ alkyl, which may be substituted with one
or more R4b,
(c) -C(=O)-Rsa~ or
(d) -(CH2)p phenyl;
R~ is
(a) H,
(b) -ORS,
(c) Cl_8 alkyl, which may be substituted with
one or more R,~,
(d) C1.8 alkoxy,
(e) -(CHa)p phenyl,
(fl -~soR4m
(g) -NH_C(-NH)-NH2,
(h) [ 1,2,4]triazol-4-yl, or
(i) -CN;
R4a is
(a) halo,
(b) -OH,
(c) -CN,
(d) Cl.g alkoxy,
(e) amino,
(f) -N(Cl_e alkyl)2,
(g) -NH(Cl$ alkyl), or
(h) carboxyl;
is a double bond or a single bond;
i is 1 or 2; m is 0, 1 or 2; n is 0 or 1; p is 1, 2, 3 or 4; and q is 0, 1, 2,
3 or 4.
In another aspect, the present invention provides compounds of formula II
N
i ~O \
X -
i
H N
H
II
-12-

CA 02318762 2000-07-24
WO 99/43671 PC'f/US99/04262
or pharmaceutically acceptable salts thereof wherein:
Rl and W are the same as defined in claim 1; Ring T is a 6-membered
heteroaromatic moiety having one to three nitrogen atoms, wherein the 6-
membered
heteroaromatic moiety has a fused-on 5-membered heteroaromatic moiety which in
turn has one to three atoms selected from the group consisting of sulfur,
nitrogen
and oxygen atoms;
X is
(a) carboxyl,
(b) halo,
(c) -CN,
(d) mercapto,
(e) formyl,
(f) -CF3,
(g) -NO2,-
(h) C1~ alkoxy,
(i) Cl.~ alkoxycarbonyl,
G ) y.e alkythio,
(k) C~_e a~yh
(1) -NR,~ R,9,
(m) Cl~ alkyl which can be substituted with Rso
(n) Cap alkenylphenyl optionally substituted with one
or two R51,
(o) phenyl optionally substituted with one or two R61,
(p) -CH=NOH,
(q) -CH=N-(OC,_s 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 RS~,
0
(s) (CH2h ~ or
..N
N
(t) N~H s
R48 and R49 are the same and different and are
(a) H,
-13-

CA 02318762 2000-07-24
WO 99/43671 PCTNS99l04262
(b) Cm ~Yl~
(c) Cs.s cycloalkyl, or
(d) R,~e and R49 taken together with the nitrogen atom is a 5-, 6-
membered heterocyclic moiety which optionally has a further hetero atom
selected
from the group consisting of S, N, and O, and can in turn be optionally
substituted
with, including on the further nitrogen atom, C1_3 alkyl, or C1_3 acyl;
R,so is
(a) -OH,
(b) Cm ~~y' ..
(c) Cl~ acyl,
(d) -NR~eR49~
(e) -NHC(=S)NH2,
(f) -NHC(=O)NH2,
(g) -NHC(=O)R,9,
(h) -SOzNR,ssR68, or
(i) -NRSOaR,ss;
R,si is
(a) carboxyl,
(b) halo,
(c) -CN,
(d) mercapto,
(e) formyl,
(f) CF9,
(g) -NOZ,
(h) Cl.s alkoxy,
(i) C1~ allcoxycarbonyl,
~1) Ci-a ~Y'~o~
(k) Ci-a ac3'1~
(1) C1,~ alkyl optionally substituted with OH, C1~
alkoxy, C1-s acyl, or
-NR,~R,9,
(m) phenyl,
(n) -C(=O)NRs2 Rsa
(o) -NR~R~9,
(P) -N~Rsa)(-S02R,s4)~
(q) -S02-NRsZRss, or
(r) _S(=O),R~;
-14-

CA 02318762 2000-07-24
WO 99/43671 PCTNS99/04262
R82 and Rsg are the same and different and are
(a) H,
(b) C1.~ alkyl, or
(c) phenyl;
R,~,, is
(a) Cl~ alkyl, or
(b) phenyl optionally substituted with C 1.~ alkyl;
R,s fi and Rbe are the same and different and are
(a) H, or
(b) C1.~ alkyl;
and j is 0 or 1.
These compounds have antimicrobial activity against a number of human and
veterinary pathogens, including gram-positive aerobic bacteria such as
multiply-
resistant staphylococci and streptococci, as well as anaerobic organisms such
as
bacteroides and clostridia species, and acid-fast organisms such as
Mycobacterium
tuberculosis and Mycobacterium dvium.
DETAILED DESCRIPTION OF THE INVENTION
For the purpose of the present invention, the carbon content of various
hydrocarbon containing moieties is indicated by a prefix designating the
minimum
and maximum number of carbon atoms in the moiety, i.e., the prefix Ci~ defines
the
number of carbon atoms present from the integer "i" to the integer "j",
inclusive.
Thus, Cl_4 alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl,
ethyl,
propyl, butyl and isomeric forms thereof.
The terms "C1_9 alkyl", "C1.4 alkyl", "C1_B alkyl", and "C1.8 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 terns "C2~ alkenyl" refers to at least one double bond alkenyl group
having two eight carbon atoms such as, for example, ethenyl, propenyl,
butenyl,
pentenyl, pentdienyl, hexenyl, hexdienyl, heptenyl, heptdienyl, octenyl,
octdienyl,
octatrienyl, and their isomeric forms thereof.
The terms "Ca.e cycloalkyl", and "C3$ cycloalkyl" refer to a cycloalkyl having
three to six, or three to eight carbon atoms respectively such as, for
example,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and
their
isomeric forms thereof.
-15-

CA 02318762 2000-07-24
WO 99/43671 PCTNS99/04262
The terms "C _ alko " "C alkox " "C alkox " and "C alko " refer to
i a x3' ~ m Y _ ~ i.s Y ~ i.a x3'
an alkyl group having one to three, one to four, one to six, or one to eight
carbon
atoms respectively attached to an oxygen atom such as, for example, methoxy,
ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy and
their
isomeric forms thereof.
The terms "C a 1" "C a 1" and "C ac 1" refer to a -C(=O)R ou
i., cY ~ i.s cY ~ i-s Y fr' P
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 "Cl_~ alkoxycarbonyl", "Cite alkoxycarbonyl", and "C1$
alkoxycarbonyl" refer to a -C02R group, wherein R' is an alkyl group of one to
three,
one to six, or one to eight carbon atoms and their isomeric forms thereof.
The terms "C a to " "C ac 1 " and "C ac lox " refer to a
m cy xY ~ y Y ~3' ~ ~-a Y Y
-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.
The term "Cl.~ 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 "C1.~ 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 "Cl-a hydroxyl" refers to an alkyl group having one to eight carbon
atoms and isomeric forms thereof attached to a hydroxy group.
The term "C1~ alkylthio" refers to an alkyl group having one to six carbon
atoms and isomeric forms thereof attached to a sulfur atom.
The term "halo" refers to fluoro, chloro, bromo, or iodo.
The compounds of the present invention can be converted to their salts,
where appropriate, according to conventional methods.
The term "pharmaceutically acceptable salts" refers to acid addition salts
useful for administering the compounds of this invention and include
hydrochloride,
hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate,
meaylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl
sulfonate,
fumarate and the like. These salts may be in hydrated form.
The compounds of formula I of this invention contain a chiral center at C5 of
the isoxazoline ring, and as such there exist two enantiomers or a racemic
mixture
of both. This invention relates to both the enantiomers, as well as mixtures
containing both the isomers. The preferred enantiomer is the one having
(R) - absolute configuration at C-5 of the isoxazoline ring. In addition,
depending on
the substituents, additional chiral centers and other isomeric forms may be
present
-16-

CA 02318762 2000-07-24
WO 99/43671 PCT/US99/04262
in any of the Q or Rl group, and this invention embraces all possible
stereoisomers
and geometric forms in these groups.
Ring P or Ring T below contained in the compounds formula I or formula II
are typical heteroaromatic isoxazolines of this invention. It will be
understood that
the named heteroaromatic moiety do not limit the scope of the invention, but
are
named merely to help one skilled in the art to understand the invention. They
are
3-isoquinolinyl, 1-isoquinolinyl, 2-quinolinyl, 3-quinolinyl, 3-(5,6,7,8-
tetrahydro)-
isoquinolinyl, 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)-IH-1-
pyrindinyl,
5-faro[2,3-c]pyridinyl, 6-faro[3,2-c)pyridinyl, 4-furo(3,2-c]pyridinyl, 7-
faro[2,3-
c]pyridinyl, 6-faro[2,3-b]pyridinyl, 5-faro[3,2-b]pyridinyl, 5-(2,3-dihydro)-
faro[2,3-
c]pyridinyl, 6-(2,3-dihydro)-faro[3,2-c]pyridinyl, 4-(2,3-dihydro)-faro[3,2-
c]pyridinyl,
7-(2,3-dihydro)-faro[2,3-c)pyridinyl, 6-(2,3-dihydro)-faro[2,3-b)pyridinyl, 5-
(2,3-
dihydro)-faro[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)-faro[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]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)-1H-pyrrolo[3,4-b]pyridinyl, 6-1,7-naphthyridinyl, 6-
2,7naphthyridinyl,
7-2,6-naphthyridinyl, 7-1,6-naphthyridinyl, 5-1,6-naphthyridinyl, 5-2,6-
naphthyridinyl, 8-2,?-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, ?-(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-
-17-

CA 02318762 2000-07-24
WO 99/43671 PCTNS99/04262
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)-f,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-iudenyl, 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-indolyl, 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-dihydro)-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,
6-(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, quinoxalin-2-yl, isoquinolin-3-yl, piperon-5-yl, 4,7-
dichlorobenzoxazol-2-yl, 4,6-dimethylpyrimidin-2-yl, 4-methylpyrimidin-2-yl,
2,4-
dimethylpyrimidin-6-yl, 2-methylpyrimidin-4-yl, 4-methylpyrimidin-6-yl, 6-
chloropiperon-5-yl, 5-chloroimidazo[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-isopropenylcylcohexen-1-
yl,
and 4-dihydronaphth-2-yl.
The compounds of this invention can be prepared in accordance to one or
more of the processes discussed below. In SCHEMES I, II, III, IV and V below,
X,
Y, Q and R~ 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 nitrite oxide 2. via three steps: formation of
the
corresponding oxime, halogenation of resultant oxime to generate an
intermediate
hydroximinoyl halide, and treatment of this intermediate with a suitable base
such
-18-

CA 02318762 2000-07-24
WO 99/43671 PCTIUS99/04262
as triethylamine to afford nitrite oxide 2. The resultant nitrite oxides 2
undergo a
1,3-dipolar cycloaddition with 3, either allylic amides (wherein Rl is Cl~
alkyl) or
carbamates (Rl is O-alkyl), to generate isoxazolines of structure 4 (wherein W
is
oxygen atom).
SCHEME I
A
Y~'CHO
1
1~ 1
A
Y~'C~'ly _
O
2
~~NHCOR~
N~O W~~
Y ~ ~R,
a N
H
1
W
N~O ~~
Y J'-R,
N
I H
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 "Nitrite Oxides and
Imines",
A. Padwa, Ed., John Wiley & Sons, Inc., New York, 1984, pp. 291-392, and
references cited therein; C. J. Easton et al., "Advances in Heterocyclic
Chemistry",
Vol. 60 of "Cycloaddition Reactions of Nitrite Oxides with Alkenes", A. R.
Katritzky,
Ed., Academic Press, San Diego, 1994, pp. 261-327, and references cited
therein; C.
Grundmann, et al., J. Org. Chem., 1968, Vol. 33, p. 476; K. C. Liu et al., J.
Org.
Chem. 1980, Vol. 45, p. 3916; T. Mukaiyama et al., J Am. Chem. Soc., 1960,
Vol. 82,
p. 5339. If desirable, the corresponding thioamide isoxazolines 4 are readily
prepared by treatment of carbonyl amide isoxazolines 4 with Lawesson's Reagent
in
-19-

CA 02318762 2000-07-24
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
(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, tent-butanol, neat amine, etc., at a suitable temperature
in the
range 40-140 °C and sometimes in a sealed pressure vessel, affords the
compound I
of the present invention.
As shown in SCHEME II, the nitrile oxide 2 can be reacted with allyl alcohol
to generate 5-(hydroxymethyl)isoxazolinea 6. Then, the stricture 6 is
converted to
the corresponding alkylsulfonate or arylsulfonate 6. A representative
alkylsulfonyl
derivative, the mesylate (Rc = CHg), is prepared by reacting 6 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-nitrobenzenesuifonyl chloride and
triethylamine in dichloromethane, affords aryl sulfonates such as tosylate (R~
is p-
tolyl) or nosylate (R,~ is 3-nitrophenyl), respectively. The mesylate or
nosylate
- derivative 8 is then converted to the corresponding 5-(aminomethyl)
isoxazoline 7 by
treatment with aqueous ammonia in a suitable solvent system, for example
acetonitrile/isopropanol or tetrahydrofuran/isopropanol, in a sealed reaction
vessel,
and at a suitable temperature in the range from 40 to 90 °C.
It will be apparent to those skilled in the art that alternative synthetic
procedures for the introduction of the requisite aminomethyl side chain are
available. For example, the sulfonate 6 can be reacted with an azide source
such as
sodium or potassium azide in an aprotic solvent such as N,N-dimethylformamide
or
1-methyl-2-pyrrolidinone optionally in the presence of a catalyst such as 18-
crown-6
at a temperature of 50 to 90 °C to generate the corresponding 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 ?.
Alternatively, the azidomethyl intermediate can be reduced to the
corresponding
amine 7 by a two-step process involving treatment with a trivalent phosphorus
compound such as triphenylphosphine in a suitable solvent such as
tetrahydrofuran
followed by hydrolysis of the resultant iminophosphorane with water. See: M.
-20-

CA 02318762 2000-07-24
WO 99/43671 PCTNS99/04262
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 triethyiamine/dichloromethane at a
temperature ranging from -30 to 30 °C to provide the acylated compound
4 (wherein
W is oxygen atom).
SCHEME II
A
~O'
2
~~OH
A~ P
N'o
5 ~OH
A~ P N'O
'-OS02R°
a
A~~ N,o
~NHp
,l
A ~ N,o
~R
N
4 H
Various methods for acylation reactions are discussed further in J. March,
"Advanced Organic Chemistry", 3rd ed., John Wiley & Sona, Inc., New York,
1985,
pp. 370-375. The corresponding thioamides phenyl isoxazoline 4 (W is sulfur
atom)
are readily prepared by treatment of amide phenyl isoxazoline with Lawesson's
-21-

CA 02318762 2000-07-24
WO 99/43671 PCTNS99/04262
Reagent in a suitable solvent such as 1,4-dioxane at reflex temperature. It
will be
apparent to those skilled in the art that other carbonyl-containing groups
within the
scope of this invention can be readily appended to the amine 7 by standard
acylation
techniques to give additional examples of 4. The remaining synthetic steps
which
lead structure 4 to the compound of formula I are the similar to that
described in
SCHEME I.
SCHEME III outlines an alternative reaction procedure which permits
synthetic access to selected compounds of formula I of the present invention.
It will
be apparent to one skilled in the art that the exemplified Q substituent,
morpholine
or thiomorpholine, is merely representative and that other heterocyclic ring
systems
are possible. A halogenated heteroaromatic ester of structure 8 (wherein
halogen is
preferably a fluorine atom) is reacted with morpholine (wherein E is oxygen
atom) or
thiomorpholine (wherein E is sulfur atom), in the preseace of a suitable base
such
as dipotassium hydrogenphosphate, in an appropriate solvent such as
dimethylsulfoxide, and at a suitable temperature in the range from 60 to 100
°C, to
provide the morpholino adduct 9. The ester moiety of 9 is then reduced to the
corresponding heteroaromatic alcohol 10 with an appropriate reducing agent,
such
as lithium aluminum hydride and the like, in a suitable solvent, for example
tetrahydrofuran, and at a suitable temperature in the range from -20 to 0
°C.
SCHEME III
E~NH E I E
halo~~ ~ ~N~~ ~ ~N~~
Y '~1 \C02R Y C~l ~CO2R Y ~~l ~C02pH
30 ~~~ ~ ~ ~ ~N.
Y~~CHO ~~Ca + ~ ~ 'O W
Y Ny Y ~ ~.._R
11 12 13
The product alcohol 10 is then oxidized, employing catalytic
35 tetrapropyiammonium perruthenate and N-methylmorpholine-N oxide in
dichloromethane, to the corresponding carboxaldehyde 11. The remaining
synthetic
-22-

CA 02318762 2000-07-24
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
step or at the end of synthetic step if desirable. The detailed procedure for
this
oxidation is discussed in international publication No. WO 97/09328.
Enantiomerically enriched heteroaromatic isoxazolines of formula I may be
obtained through the racemic phenylisoxazolines 3 or 4 by employing high
pressure
liquid chromatography (HPLC) over a chiral stationary phase. In a typical
separation, the mixture of enantiomers is chromatographed with a 5x50 cm
Chiralpak AD column, eluting with heptane/isopropanol/chloroform mixtures as
the
mobile phase, to provide the individual (R)- or (S)-enantiomer. If desired,
the
separation of enantiomers can be conducted either on the early intermediates 3
or 4
or on the final product.
Enantiomerically enriched heteroaromatic isoxazolines may also be prepared
according to procedures outlined in SCHEMES IV and V.
SCHEME IV
Ate'
P
Y cwc~r~
'o-
1~R°
O 14
P C N'O
Y ~ ~
15 H II Rd
0
P i ,O
Y ~
~g ~OH
H
A~
Y P C N.O W
~--,,.~N ~R ~
4A H
-23-

CA 02318762 2000-07-24
WO 99/43671 PCT/US99/04262
As illustrated in SCHEME IV, reaction of nitrile oxides 2 with
a,~-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
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 chino-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;
W. Oppolzer, et al., Tetrahedron Lett., 1991, Vol. 32, p. 4893; T. Akiyama et
al.,
Tetrahedron Lett., 1992, Vol. 33, p. 5763; Y. H. Kim et al., Tetrahedron
Lett., 1993,
Vol. 34, p. 6063; C. J. Easton et al., "Advances in Heterocyclic Chemistry",
Vol. 60 of
"Cycloaddition Reactions of Nitrile Oxides with Alkenes", A. R. Katritzky,
Ed.,
Academic Press, San Diego, 1994, pp. 261-327, and references cited therein.
Use of
appropriate chiral auxiliaries to control the steroselectivity of the
asymmetric 1,3-
dipolar cycloaddition provides access, ultimately, to both enantiomers of 15.
For
simplicity, only one enantiomer is presented. Racemic esters of structural
formula
18 (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.
469.
The enantiomeric cycloadducts 15 maybe further purified by recrystallization
or chromatography. Treatment of the cycloadducts 18 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)
isoxazolines 18. The remaining synthetic steps which lead 18 to
enantiomerically
enriched heteroaromatic isoxazolines 4A are similar to the procedures outlined
in
SCHEME II.
Alternatively, compound 16 may prepared by treatment of nitrite oxide 2 with
an allyl alcohol via a highly enantioselective 1,3-dipolar cycloaddition as
shown in
SCHEME V.
The reaction occurs in the presence of diethylzinc and (R,R)- and (S,S)-
tartaric acid esters, preferably, diisopropyl esters, in a suitable solvent
such as
chloroform or dichloromethane and at a temperature in the range of about -20
to
0 °C. See Y. Uk~ji et al., Chem. Letters, 1993, p. 1847. The remaining
synthetic
steps which lead compound 16 to enantiomerically enriched heteroaromatic
-24-

CA 02318762 2000-07-24
WO 99/43671 PCTNS99/04262
isoxazolines of formula 4A are similar to the procedures outlined in SCHEME
II.
SCHEME V
~ OOH Ay
l 'P
Re02C ; C02Re y~C N~O
y $N+ ~OH
2 ~O H ~OH lg H
A~
P N.O ~
y~~N~R~
4A H H
Following the procedures outlined in SCHEMES I-V, and making non-critical
variations but starting with heteroaromatic moiety Ring T, compounds of
formula II
can be obtained.
The pharmaceutical compositions of this invention may be prepared by
combining the compounds of formula I of this invention with a solid or liquid
pharmaceutically acceptable carrier, and optionally, with pharmaceutically
acceptable adjuvants and excipients employing standard and conventional
techniques. Solid form compositions include powders, tablets, dispersible
granules,
capsules and suppositories. A solid carrier can be at least one substance
which may
also function as a diluent, flavoring agent, solubilizer, lubricant,
suspending agent,
binder, tablet disintegrating agent, and encapsulating agent. Inert solid
carriers
include magnesium carbonate, magnesium atearate, talc, sugar, lactose, pectin,
dextrin; starch, gelatin, cellulosic materials, low melting wax, cocoa butter,
and the
like. Liquid form compositions include solutions, suspensions and emulsions.
For
example, there may be provided solutions of the compounds of this invention
dissolved in water, water-propylene glycol, and water-polyethylene glycol
systems,
optionally containing conventional coloring agents, flavoring agents,
stabilizers and
thickening agents.
The pharmaceutical composition is provided by employing conventional
techniques. Preferably the composition is in unit dosage form containing an
effective
amount of the active component, that is, the compounds of formula I according
to
-25-

CA 02318762 2000-07-24
WO 99/43671 PCTNS99/04262
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
method; the potency of the particular compound and the desired concentration.
Generally, the quantity of active component will range between 0.5% to 90% by
weight of the composition.
In therapeutic use for treating bacterial infections in humans and other
animals that have been diagnosed with bacterial infections, the compounds or
pharmaceutical compositions thereof will be administered orally, parenterally,
transdermally and/or topically at a dosage to obtain and maintain a
concentration,
that is, an amount, or blood-level of active component in the animal
undergoing
treatment which will be antibacterially effective. Generally, such
antibacterially
effective amount of dosage of active component will be in the range of about
0.1 to
about 100 mg/kg, more preferably about 3.0 to about 50 mg/kg of body
weight/day.
It is to be understood that the dosages may vary depending upon the
requirements
of the patient, the severity of the bacterial infection being treated, and the
particular
compounds being used. Also, it is to be understood that the initial dosage
administered may be increased beyond the above upper level in order to rapidly
achieve the desired blood-level or the initial dosage may be smaller than the
optimum and the daily dosage may be progressively increased during the course
of
treatment depending on the particular situation. If desired, the daily dose
may also
be divided into multiple doses for administration, e.g., two to four times per
day.
These compounds are useful for the treatment of microbial infections in
humans and other warm blooded animals by either oral, parenteral, topical, or
transdermal administration. In general, the preferred form of administration
is
orally. Pharmaceutical compositions for parenteral administration will
generally
contain a pharmaceutically acceptable amount of the compounds according to
formula I as a soluble salt (acid addition salt or base salt) dissolved in a
pharmaceutically acceptable liquid carrier such as, for example, water-for-
injection
and a suitably buffered isotonic solution having a pH of about 3.5 - 6.
Suitable
buffering agents include, for example, trisodium orthophosphate, sodium
bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine,
to
name a few. The compounds according to formula I generally will be dissolved
in
the carrier in an amount sufficient to provide a pharmaceutically acceptable
injectable concentration in the range of about 1 mg/ml to about 400 mg/ml. The
-26-

CA 02318762 2000-07-24
WO 99/43671 PCTNS99/04262
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.
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
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-

Dessin représentatif
Une figure unique qui représente un dessin illustrant l'invention.
États administratifs

2024-08-01 : Dans le cadre de la transition vers les Brevets de nouvelle génération (BNG), la base de données sur les brevets canadiens (BDBC) contient désormais un Historique d'événement plus détaillé, qui reproduit le Journal des événements de notre nouvelle solution interne.

Veuillez noter que les événements débutant par « Inactive : » se réfèrent à des événements qui ne sont plus utilisés dans notre nouvelle solution interne.

Pour une meilleure compréhension de l'état de la demande ou brevet qui figure sur cette page, la rubrique Mise en garde , et les descriptions de Brevet , Historique d'événement , Taxes périodiques et Historique des paiements devraient être consultées.

Historique d'événement

Description Date
Demande non rétablie avant l'échéance 2004-02-10
Le délai pour l'annulation est expiré 2004-02-10
Réputée abandonnée - omission de répondre à un avis sur les taxes pour le maintien en état 2003-02-10
Inactive : Page couverture publiée 2000-10-30
Inactive : CIB en 1re position 2000-10-24
Lettre envoyée 2000-10-11
Inactive : Notice - Entrée phase nat. - Pas de RE 2000-10-11
Demande reçue - PCT 2000-10-06
Demande publiée (accessible au public) 1999-09-02

Historique d'abandonnement

Date d'abandonnement Raison Date de rétablissement
2003-02-10

Taxes périodiques

Le dernier paiement a été reçu le 2001-12-28

Avis : Si le paiement en totalité n'a pas été reçu au plus tard à la date indiquée, une taxe supplémentaire peut être imposée, soit une des taxes suivantes :

  • taxe de rétablissement ;
  • taxe pour paiement en souffrance ; ou
  • taxe additionnelle pour le renversement d'une péremption réputée.

Les taxes sur les brevets sont ajustées au 1er janvier de chaque année. Les montants ci-dessus sont les montants actuels s'ils sont reçus au plus tard le 31 décembre de l'année en cours.
Veuillez vous référer à la page web des taxes sur les brevets de l'OPIC pour voir tous les montants actuels des taxes.

Historique des taxes

Type de taxes Anniversaire Échéance Date payée
TM (demande, 2e anniv.) - générale 02 2001-02-12 2000-07-24
Taxe nationale de base - générale 2000-07-24
Enregistrement d'un document 2000-07-24
TM (demande, 3e anniv.) - générale 03 2002-02-11 2001-12-28
Titulaires au dossier

Les titulaires actuels et antérieures au dossier sont affichés en ordre alphabétique.

Titulaires actuels au dossier
PHARMACIA & UPJOHN COMPANY
Titulaires antérieures au dossier
DAVID R. GRABER
DONN G. WISHKA
JOEL MORRIS
MICHAEL ROBERT BARBACHYN
RICHARD CHARLES THOMAS
Les propriétaires antérieurs qui ne figurent pas dans la liste des « Propriétaires au dossier » apparaîtront dans d'autres documents au dossier.
Documents

Pour visionner les fichiers sélectionnés, entrer le code reCAPTCHA :



Pour visualiser une image, cliquer sur un lien dans la colonne description du document (Temporairement non-disponible). Pour télécharger l'image (les images), cliquer l'une ou plusieurs cases à cocher dans la première colonne et ensuite cliquer sur le bouton "Télécharger sélection en format PDF (archive Zip)" ou le bouton "Télécharger sélection (en un fichier PDF fusionné)".

Liste des documents de brevet publiés et non publiés sur la BDBC .

Si vous avez des difficultés à accéder au contenu, veuillez communiquer avec le Centre de services à la clientèle au 1-866-997-1936, ou envoyer un courriel au Centre de service à la clientèle de l'OPIC.


Description du
Document 
Date
(yyyy-mm-dd) 
Nombre de pages   Taille de l'image (Ko) 
Dessin représentatif 2000-10-29 1 2
Description 2000-07-23 27 1 075
Revendications 2000-07-23 17 388
Abrégé 2000-07-23 1 64
Page couverture 2000-10-29 1 60
Avis d'entree dans la phase nationale 2000-10-10 1 193
Courtoisie - Certificat d'enregistrement (document(s) connexe(s)) 2000-10-10 1 120
Courtoisie - Lettre d'abandon (taxe de maintien en état) 2003-03-09 1 178
Rappel - requête d'examen 2003-10-13 1 112
PCT 2000-07-23 12 417