Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-03-29
2000-05-02
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142298, 514267, 544 32, 544 89, 544252, A61K 31517, A61K 31536, C07D48704, C07D49804, C07D51304
Patent
active
060573155
DESCRIPTION:
BRIEF SUMMARY
The invention pertains to anti-bacterial materials which contain a 4-oxo-1,3-benzoxazine ring structure.
BACKGROUND OF THE INVENTION
Due to ever increasing antibiotic resistance, new anti-bacterials of novel structure have become very important to the treatment of bacterial infections (J. Med. Chem 39, 3853, 1996).
Kinoshita (J. Antibiotics 48, 437, 1995) has revealed various pyralomicins. ##STR2##
These compounds were isolated from Microtetraspora spiralis and display good activity vs Micrococcus luteus, but relatively poor activity versus Staphylococcus aureus. The compounds all contain the sugar moiety and are thus higher molecular weight.
Soliveri reveals pyrazaloisoquinolenones from Streptoverticillium griseocarnum (J. Antibiotics 49, 700, 1996). ##STR3##
These compounds show poor activity versus Staphylococci and contain a ring system substantially different than that shown in Formula I.
Saturated fused ring systems have been reported (Tet. Lett 30, 7321, 1989; and 31, 6765, 1990) where the pyrrolidine and piperidine rings are fully saturated rather than aromatic. No biological activities were reported. ##STR4##
A method of preparation has been disclosed where a S replaces the oxygen of the benzoxazine ring system (J. Org. Chem. 57, 3676, 1992). The phenyl ring is not substituted and no biological activity is disclosed. ##STR5##
Sckrob et al. disclose ring systems where nitrogen has replaced the benzoxazine ring oxygen (J. Gen. Chem. USSR 38, 1970, 1968); no biological activities were revealed. ##STR6##
SUMMARY OF THE INVENTION
Described are compounds of Formula I ##STR7##
X is O, S or N--R.sub.8 ;
R.sub.1, R.sub.2, R.sub.3 and R.sub.8 are independently H, straight or branched alkyl of 1-6 carbons, cycloalkyl of 3-6 carbons, alkenyl or alkynyl of from 2 to 6 atoms, heterocyclic ring of from 5-8 atoms with 1-3 heteroatoms as nitrogen, oxygen or sulfur or phenyl, all of which rings may be optionally substituted up to 3 times by halogen, OR, NR.sub.2, NR'COR', CN, CO.sub.2 R' or CONR.sub.2 ', halogen, CN, CO.sub.2 R, COR, CON(R).sub.2, CON(R").sub.2, SR, SON, SCO.sub.2 R or SCON(R).sub.2 ;
R.sub.4 is H, straight or branched alkyl of from 1-6 carbon atoms, alkenyl or alkynyl of from 2 to 6 atoms, heterocyclic ring of from 5-8 atoms with 1-3 heteroatoms as nitrogen, oxygen or sulfur or phenyl, all of which rings may be optionally substituted up to 3 times by halogen, OR, NR.sub.2, NR'COR', CN, CO.sub.2 R' or CONR.sub.2 ', halogen, CN, NO.sub.2, N(R).sub.2, NRCOR, NRCOR", COR, CO.sub.2 R, CON(R).sub.2, CON(R").sub.2, NRCON(R).sub.2, NRCO.sub.2 R;
R.sub.5 is 1-6 straight or branched alkyl, a cycloalkyl of 3-6 carbons, alkenyl or alkynyl of from 2 to 6 atoms, heterocyclic ring of from 5-8 atoms with 1-3 heteroatoms as nitrogen, oxygen or sulfur or phenyl, all of which rings may be optionally substituted up to 3 times by halogen, OR, NR.sub.2, NR'COR', CN, CO.sub.2 R' or
CONR.sub.2 ', halogen, OR, N(R).sub.2, NRCOR, NRCOR", COR, CON(R).sub.2, CON(R").sub.2, SR or SO.sub.2 R;
R.sub.6, R.sub.7 are independently H, straight or branched alkyl of 1-6 carbons, cycloalkyl of 3-6 carbons, COR, COR", SO.sub.2 NR.sub.2, CONR.sub.2 and these may be optionally substituted by any of the groups listed for R.sub.5 ;
R is H, straight or branched alkyl of 1-6 carbon atoms, cycloalkyl of from 3-6 carbon atoms, heterocyclic ring of from 5-8 atoms with 1-3 heteroatoms as nitrogen, oxygen or sulfur, or phenyl all of which may be optionally substituted by halogen, OR', NR'.sub.2, NR'COR', CN, CO.sub.2 R', CONR'.sub.2 ;
R' is H, alkyl of from 1-3 carbon atoms or Ph;
R" is part of a naturally occurring amino acid connected via an amide or acyl bond as determined by the formula;
halogen is any one of fluoro, chloro, bromo or iodo;
or a pharmaceutically acceptable salt.
The invention is also concerned with treating a mammal in need thereof comprising administering to said mammal an effective antibacterial amount of the compound of Formula I.
The invention is also concerned with pharmaceutical compositions utilizing the compounds
REFERENCES:
Chu et al., "New Directions in Antibacterial Research", J. Med. Chem., 1996, 39:20, 3853-3865.
Cruz et al., "APHE-3 and APHE-4, Two New Pyrazoloisoquinolinone Antibiotics Produced by Streptoverticillium griseocarneum NCIMB 40447", J. Antibiotics, 1996, 49:7, 700-702.
Takacs and Helle, "A Removable Auxiliary For Amidomercuration Reactions: The Stereoselective Preparation of Substituted N-Acyl Pyrrolidines and Piperidines", Tetrahedron Letters, 1989, 30:52, 7321-7324.
Takacs et al., "The Magnitude of the Sterodirecting Effect of an Allylic Alkoxy-Substituent in an Amidomercuration Cyclization", Tetrahedron Letters, 1990, 31:47, 6765-6768.
Tafel and Bates, "Preparation of Pyrrolo[2,1-b][1,3]benzothiazin-9-ones via Intramolecular Sulfenylation of an N-Acylpyrrole", J. Org. Chem., 1992, 57, 3676-3680.
Domagala John Michael
Ellsworth Edmund Lee
Huang Liren
Micetich Ronald George
Roe Michael
Anderson Elizabeth M.
Balasubramanian V
Shah Mukund J.
Warner-Lambertt Company
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