Substituted 1-benzazepines and derivatives thereof

Details Substituted 1-benzazepines and derivatives thereof Substituted 1-benzazepines and derivatives thereof

2000-11-07

2003-02-04

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S523000

Reexamination Certificate

active

06514965

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel substituted 1-benzazapines and derivatives thereof useful as antibacterials, to pharmaceutical compositions comprising such compounds, to processes for making these compounds and to methods of using these compounds for treating bacterial infections.
BACKGROUND OF THE INVENTION
Benzazepine compounds are useful in a number of pharmaceutical applications. In particular, U.S. Pat. No. 5,786,353 discloses that tricyclic benzazepine is useful as a vasopressin antagonist. U.S. Pat. No. 5,247,080 discloses that substituted benzazepines are useful as intermediates for producing pharmaceutically active compounds, such as intermediates for compounds that have valuable properties in treating psychosis, depression, pain and hypertension. WO 97/24336 discloses a process for the aminocarbonylation of benzazepines and benzodiazepines. These compounds are used as intermediates for preparing pharmaceutically active compounds.
There have been other processes for the preparation of benzazepines. Tetrahydro-1-benzazepines and tetrahydro-1,4-benzodiazepines form the core structure of a variety of pharmaceutically useful compounds. In particular, WO 93/00095 (PCT/US92/05463) and WO 94/14776 (PCT/US93/12436) disclose 7-aminocarbonyl tetrahydro-1-benzazepines and tetrahydro-1,4-benzodiazepines which are reported to be inhibitors of the fibrinogen and vitronectin receptors and useful as inhibitors of platelet aggregation, osteoporosis, angiogenesis and cancer metastasis.
Methods to prepare such compounds typically employ a trisubstituted phenyl derivative as a starting material. The trisubstituted phenyl derivative incorporates two substituents to form the azepine and/or diazepine ring, and a third substituent to introduce the 7-carbonyl substituent. Such starting materials may be difficult and costly to obtain, and may limit the chemistry which may be employed to form the azepine ring. Prior processes generally introduce the aminocarbonyl group into the molecule via a 7-carboxyl group which is coupled to an amino group by conventional methods for forming amide bonds. Methods disclosed in WO 93/00095 and WO 94/14776 are exemplary.
Bacterial infections are a significant and growing medical problem. They occur when the body's immune system cannot prevent the invasion and colonization of the body by disease-causing bacteria. These infections may either be confined to a single organ or tissue, or disseminated throughout the body, and can cause many serious diseases, including pneumonias, endocarditis, osteomyelitis, meningitis, deep-seated soft tissue infections, bacteremia and complicated urinary tract infections.
According to estimates from the United States Centers for Disease Control and Prevention (the “CDC”) in 1995, approximately 1.9 million hospital-acquired infections occurred in the United States, accounting for more than $4.5 billion in additional health care costs each year and contributing to more than 88,000 deaths. While overall per capita mortality rates declined in the United States from 1980 to 1992, the per capita mortality rate due to infectious diseases increased 58% over this period, making infectious diseases the third leading cause of death in the United States.
Antibiotics are administered both to prevent bacterial infections and to treat established bacterial diseases. When administered to prevent an infection, antibiotics are given prophylactically, before definitive clinical signs or symptoms of an infection are present. When administered to treat an established infection, antibiotics are often chosen empirically, before diagnostic testing has established the causative bacterium and its susceptibility to specific antibiotics.
Antibiotics work by interfering with a vital bacterial cell function at a specific cellular target, either killing the bacteria or arresting their multiplication, thereby allowing the patient's immune system to clear the bacteria from the body. Currently available antibiotics work on relatively few targets, through mechanisms such as inhibiting protein or cell wall synthesis. These targets tend to be present in all bacteria and are highly similar in structure and function, such that certain antibiotics kill or inhibit growth of a broad range of bacterial species (i.e., broad-spectrum antibiotics).
Major structural classes of antibiotics include beta-lactams, quinolones, macrolides, tetracyclines, aminoglycosides, glycopeptides and trimethoprim combinations. Penicillin, a member of the beta-lactam class (which also includes extended-spectrum penicillins, cephalosporins and carbapenems), was first developed in the 1940s. Nalidixic acid, the earliest member of the quinolone class, was discovered in the 1960s. The creation of broad-spectrum antibiotics began in the 1970s and 1980s, with major advances seen in the 1970s with the development of newer beta-lactams, and in the 1980s with the development of fluoroquinolones. These antibiotics are still being used extensively. No major new class of antibiotics has been discovered and commercialized in the last 20 years. There remains a need to identify new classes of antibiotics to fight bacterial infections and to overcome the increasing resistance by bacteria to currently marketed antibiotics.
However, none of the prior teachings, described above or elsewhere, disclose the novel 1-benzazepine compounds of the present invention or that 1-benzazepines would be useful as antibacterial agents.
It is therefore an object of this invention to prepare 1-benzazepine derivatives that are useful as agents for the treatment of bacterial, viral or fungal infections both in vivo (including but not limited to parenterally and topically) and for inhibiting bacterial, viral or fungal growth, for example on surfaces and in solution.
SUMMARY OF THE INVENTION
The instant invention is directed to novel substituted 1-benzazepine compounds of the Formula (I):
wherein:
R
1
is H, with the proviso that R
4
and R
5
are not both H, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted —Ar or —(CH
2
)
n
Ar, —(CH
2
)
m
C(═O)R, —(CH
2
)
n
CN, —(CH
2
)
m
C(═Q)OR, —C(═O)N(R)
2
, —OR, —SO
2
R, —C(═O)N(H)(NHR), —(CH
2
)
n
(OAr), —(CH
2
)
n
(OR), —(CH
2
)
m
C(═NH)NH
2
, or —(CH
2
)
n
NHRAr;
R
2
and R
3
are independently H, halogen, —N
3
, —CN, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted —Ar or —(CH
2
)
n
Ar, —(CH
2
)
m
N(R)
2
, —(CH
2
)
m
NH(Aa), —(CH
2
)
m
NC(═O)R, —(CH
2
)
m
C(═O)NHOR, —(CH
2
)
m
C(═O)OR, —(CH
2
)C
m
C(═O)NH(Aa), —(CH
2
)
m
C(═O)N(R)
2
, and —(CH
2
)
n
C(═O)NH(Aa), with the proviso that R
2
and R
3
cannot both be H;
R
4
and R
5
are independently H, halogen, —NO
2
, —CN, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted —Ar or —(CH
2
)
n
Ar, substituted or unsubstituted primary amine or secondary amine, —NHC(═O)R, —NHC(═Q)NHC(═O)OR, —NH(C═Q)NHR, —QR, —OC(═O)N(R
2
), —C(═O)OR, and —OSi(R)
3
, with the proviso that R
4
and R
5
cannot both be H;
Ar is aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic, heterocyclyl, or heteroaryl;
Aa is —CX(NH
2
)CO
2
H, wherein X signifies a group that completes a natural or synthetic amino acid;
R is H, a substituted or unsubstituted straight chain, branched or cyclic lower alkyl, lower alkenyl or lower alkynyl, or a substituted or unsubstituted Ar or (CH
2
)
n
Ar;
Q is O or S;
Z is O or S;
a and b are each a single or double bond, and when a is a double bond, only R
2
or R
3
is present;
m is 0, 1 or 2;
n is 1, 2 or 3;
and pharmaceutically acceptable salts or prodrug forms thereof.
Preferred are compounds of the formula (I) or a pharmaceutically acceptable salt or prodrug form thereof wherein Z is O.
More preferred are compounds of the Formula I, having the formulae II, III, and IV, wherein the substituents ar

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