AU2002327172A1

AU2002327172A1 - Substituted 1-benzazepines and derivatives thereof

Info

Publication number: AU2002327172A1
Application number: AU2002327172A
Authority: AU
Inventors: Joanna Clancy; Huang Liren; Alenka Tomazic; Kenneth D. Tucker
Original assignee: Antex Pharma Inc
Current assignee: Emergent Product Development Gaithersburg Inc
Priority date: 2001-05-16
Filing date: 2002-05-15
Publication date: 2003-05-15
Anticipated expiration: 2022-05-15

Description

SUBSTITUTED 1 -BENZAZEPINES AND DERIVATIVES THEREOF

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. Patent No. 5,786,353 discloses that tricyclic benzazepine is

useful as a vasopressin antagonist. U.S. Patent 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-l,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. Additional

broad-spectrum antibiotics were discovered or synthesized 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 except the oxazolidinones have 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.

ST TM AKV OF TPTF INVENTION

The instant invention is directed to novel substituted 1 -benzazepine

compounds of the Formula (I):

wherein:

R¹ is H, with the proviso that if R! is H R⁴ and R⁵ are not both H, substituted or

unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mC(=O)R, -(CH₂)_nCN,

(CH₂)_mC(=Q)OR, -C(=O)N(R)₂, -OR, -SO₂R, -C(=O)N(H)(NHR), -(CH₂)_n(OAr),

-(CH₂)_n(OR), -(CH₂)_mC(=NH)NH₂, -(CH₂)_nNHAr or

wherein R is N,N-dimethylethylenediamino, 2-methoxyethylamino,

benzylamino, 3-trifluormethylbenzylamino, cyclopropylamino, propylamino,

allylamino, 3-methoxybenzylamino, 2-(4-methoxyphenyl)ethylamino,

cyclohexanemethylammo, 2,4-dichlorophenethylamino, 3-diehylaminopropyldiamino,

3-ethoxypropylamino, N,N-di-N-butylethylenediamino, 1 -(2-aminoethyl)piperidino,

l-(3-aminopropyl)imidazole, 4-(2-aminnoethyl)morpholine, 2-(amino methyl)- 1

ethyl-pyrrolidine, 2-(2-aminoethyl)pyridine or 3-(aminomethyl)pyridine

R² and R³ are independently H, halogen, -N₃, -CN, substituted or unsubstituted, straight

chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted -Ar

or -(CH₂)_nAr, -(CH₂)_mN(R)₂, -(CH₂)_mNH(Aa), -(CH₂)_mNC(=O)R,

-(CH₂)_mC(=O)NHOR, -(CH₂)_mC(=O)OR, -(CH₂)_mC(=O)NH(Aa),

-(CH₂)_mC(=O)N(R)₂, -(CH₂)_nC(=O)NH(Aa), and

with the proviso that R² and R³ cannot both be H; R⁴ and R⁵ are independently H, halogen, -NO₂, -CN, substituted or unsubstituted, straight

or -(CH₂)_nAr, substituted or unsubstituted primary amine or secondary amine,

-NHC(=O)R, -NHC(=Q)NHC(=O)OR, -NH(C=Q)NHR, -QR, -OC(=O)N(R₂),

-C(=O)OR, and -OSi(R)₃> -C(=O)N(R2), NH-SO2-R⁷ wherein R⁷ is

2,4-difluorophenyl, 2-fluorophenyl, 4-isopropylphenyl,

2,5-dimethoxyphenyl, 3,4 -dichlorophenyl, 2,3,5,6-tetramethylphenyl,

2-chlorophenyl, 3-nitrophenyl, 4-acetylphenyl, 4-methyl-3-nitrophenyl,

4-butylphenyl, 4-nitrophenyl, 4-propylphenyl, 5-fluoro-2-methylphenyl,

4-chloro-2,5-dimethylphenyl,

or R⁴ and R⁵ are independently a functional group of the following structure:

with the proviso that R⁴ and R⁵ cannot both be H.

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 (CH₂)_nAr; Ar is, aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic, heterocyclyl, or heteroaryl; Aa is an amino acid; Q is O or S; Z is O or S; a and b are a single or double bond and when a is a double bond, only R² and R³ are present; m is 0, 1 or 2; n is 1, 2 or 3; and pharmaceutically acceptable salts or prodrug forms thereof.

The instant invention is also directed to novel substituted 1 -benzazepine

compounds of the Formula II

wherein:

unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted

or unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mC(=O)R, -(CH₂)_nCN,

-(CH₂)_n(OR), -(CH₂)_mC(=NH)NH₂, , -(CH₂)_nNHAr or a functional group of the

following structure:

wherein R is N,N-dimethylethylenediamino, 2-methoxyethylamino,

benzylamino, 3-trifiuormethylbenzylamino, cyclopropylamino, propylamino,

allylamino, 3-methoxybenzylamino, 2-(4-methoxyphenyl)ethylamino,

cyclohexanemethylammo, 2,4-dichlorophenethylamino, 3 -diehylaminopropyldiamino,

3-ethoxypropylamino, N,N-di-N-butylethylenediamino, l-(2-aminoethyl)piperidine,

l-(3-aminopropyl)imidazole, 4-(2-aminnoethyl)mo holine, 2-(aminomethyl)-l-

ethyl-pyrrolidine, 2-(2-aminoethyl)pyridine or 3-(aminomethyl)pyridine;

R² and R³ are independently H, halogen, -N₃, -CN, substituted or unsubstituted,

straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or

unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mN(R)₂, -(CH₂)_mNH(Aa), -(CH₂)_mNC(=O)R,

-(CH₂)_mC(=O)NHOR, -(CH₂)_mC(=O)OR, -(CH₂)_mC(=O)NH(Aa),

-(CH₂)_mC(=O)N(R)₂, and (CH₂)_nC(=O)NH(Aa),

or a functional group of the following structure:

R⁴ and R⁵ are independently H, halogen, -NO₂, -CN, substituted or unsubstituted, straight

or -(CH₂)_nAr, substituted or unsubstituted primary amine or secondary amine,

-NHC(=O)R, -NHC(=Q)NHC(=O)OR, -NH(C=Q)NHR, -QR, -OC(=O)N(R₂),

-C(=O)OR, -OSi(R)₃> -C(=O)N(R₂), NH-SO - R⁷> where R⁷ is 2,4-difluorophenyl, 2-fluorophenyl, 4-isopropylphenyl,

2,5-dimethoxyphenyl, 3,4 -dichlorophenyl, 2,3,5,6-tetramethylphenyl,

2-chlorophenyl, 3-nitrophenyl, 4-acetylphenyl, 4-methyl-3-nitrophenyl,

4-butylphenyl, 4-nitrophenyl, 4-propylphenyl, 5-fluoro-2-methylphenyl,

4-chloro-2 , 5 -dimethylphenyl,

with the proviso that R and R cannot both be H.

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 (CH₂)_nAr; Ar is, aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic, heterocyclyl, or heteroaryl; Aa is an amino acid; Q is O or S; Z is O or S; 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 Formula II or a pharmaceutically acceptable salt or prodrug form thereof wherein Z is O.

More preferred are compounds of the Formula I, having the formulae III, IV and V, wherein the substituents are as defined above:

Still more preferred are compounds of the formula (I) or a pharmaceutically

acceptable salt or prodrug form thereof wherein R² and R³ are independently H, halogen

substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl,

substituted or unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mC(=O)OR, and

(CH₂)_mC(=O)NH(Aa) with the proviso that R² and R³ cannot both be H; one of a or b is a

double bond and m is 0. In a preferred embodiment of Formula I, R^ is

In another preferred embodiment of Formula (I) R¹ is a unsubstituted straight chain

alkyl, R² is H, R³ is (CH2)_m CO₂R, m=0, R^ is substituted secondary amine, R^ is

QR, Q =O, wherein 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 -(CH₂)_nAr; Ar is, aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic,

heterocyclyl, or heteroaryl. In another preferred embodiment of Formula I, R^ is at

position 7 and R^ is at position 8. In another preferred embodiment of Formula I, R! is

3-fluorobenzyl or CH CN and R³ is H or CO But.

Preferred are compounds of Formula I where in R¹ is H, R² is H, R³ is

R⁴ is NH-C(=Q)-NHC(=O)OR, R⁵ is OR where 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 -(CH₂)_nAr; Ar is, aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic, heterocyclyl, or heteroaryl.

Most preferred are compounds of the formulae (III-V) or a pharmaceutically

acceptable salt or prodrug form thereof wherein R¹ is H; R² and R³ are independently H,

halogen, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or

alkynyl, substituted or unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mC(=O)OR,

-(CH₂)_mC(=O)N(R)₂ and -(CH₂)_mC(=O)NH(Aa) with the proviso that R² and R³ cannot both

be H; R⁴ and R⁵ are independently H, halogen, -NO₂, -CN, substituted or unsubstituted,

straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted -Ar or -(CH₂)_nAr, substituted or unsubstituted primary amine or secondary amine, and -QR, with

the proviso that R⁴ and R⁵ cannot both be H; m is 0; Q is O; and Z is O.

Particularly preferred are compounds of the formula (I) or a pharmaceutically

acceptable salt or prodrug form thereof wherein R¹ is alkyl, alkylfluorophenyl, cyano alkyl;

R² or R³ is H, halogen, ethyl, propyl, benzyl, fluorobenzyl, -C(=O)OR, -C(=O)OAa and

-C(=O)N(R)₂ with the proviso that R² and R³ cannot both be H, R⁴ and R⁵ are independently

H, halogen, alkoxy, -OR, substituted or unsubstituted piperazinyl with the proviso that R⁴ and

R⁵ cannot both be H; and a and b are single bonds.

Still more preferred are compounds of the Formula (II) or a pharmaceutically

substituted or unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mC(=O)OR, and

-(CH₂)_mC(=O)NH(Aa) and m is 0.

VI VII VIM

Most preferred are compounds of the formulae (VI- VIII) or a pharmaceutically acceptable salt or prodrug form thereof wherein R¹ is H; R² and R³ are independently H, halogen, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mC(=O)OR, - (CH₂)_mC(=O)N(R)₂ and -(CH₂)_mC(=O)NH(Aa); R⁴ and R⁵ are independently H, halogen, -NO₂, -CN, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted -Ar or -(CH₂)_nAr, substituted or unsubstituted primary amine or secondary amine, and -QR, with the proviso that R⁴ and R⁵ cannot both be H; m is 0; Q is O; and Z is O.

Particularly preferred are compounds of the formula (II) or a pharmaceutically

acceptable salt or prodrug form thereof wherein R¹ is alkyl, alkylfluorophenyl, cyanoalkyl,

fluorobenzyl, (heterocyclyl)alkoxy, butoxycarbonlalkyl; R² or R³ is H, halogen, ethyl,

propyl, benzyl, fluorobenzyl, -C(=O)OR, -C(=O)OAa and -C(=O)N(R)₂, R⁴ and R⁵ are

independently H, halogen, alkoxy, -OR, substituted or unsubstituted piperazinyl with the

proviso that R⁴ and R⁵ cannot both be H . In another preferred embodiment of Formula

II, R¹ is

In still another preferred embodiment of Formula II, R¹ is

R⁶ is 3-trifluo romethylbenzylamine, R² is H , R³ is H, R⁴ is -NH-SO₂R⁷ , wherein R⁷

is 2-fluorophenyl, R^ is OR where 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 (CH₂)_nAr; Ar is, aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic, heterocyclyl, or heteroaryl. In another preferred embodiment R⁴ is at position 7 and R^ is position 8. In another

preferred embodiment R^ is at position 8 and is OH or NH(C=Q)NR.

In another preferred embodiment, R! is fluorobenzyl or CH₂CN and R³ is H or

CO₂But.

Specifically preferred embodiments of the present invention include:

• 3(R,S)-Carboxyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

• l,3-Diethyl-3(R,S)-ethoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-

2-one;

• 3(R,S)-Carboxyl-l,3-diethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

l-Ethyl-8-methoxy-7-[(4-methylpiperazin)-l-yl)]-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one;

3(R,S)-tert-Butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

3 (R, S)-tert-Butoxycarbonyl- 1 -ethyl-8-methoxy-2 ,3,4,5 -tetrahydro- 1 H- 1 -b enzazepine-

2-one;

7-Bromo-3(R,S)-tert-butoxycarbonyl- 1 -ethyl-8-methoxy-2,3,4,5-tetrahydro- 1 H- 1 -

benzazepine-2-one;

3(R,S)-tert-Butoxycarbonyl-7-[(4-tert-butoxycarbonylpiperazin)-l-yl]-l-ethyl-8-

methoxy-2,3 ,4,5 -tetrahydro- 1 H- 1 -benzazepine-2-one;

3(R,S)-Carboxyl-l-ethyl-8-methoxy-7-(piperazin-l-yl)-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one hydrochloride;

• 3(R,S)-tert-Butoxycarbonyl-l-ethyl-8-methoxy-2,3-dihydro-lH-l-benzazepine-2-one; 7-Bromo-3(R,S)-carboxyl- 1 -ethyl-8-methoxy-2,3 ,4,5-tetrahydro- IH- 1 -benzazepine-2-

one;

3(R,S)-tert-Butoxycarbonyl-l-ethyl-8-methoxy-7-(piperazin-l-yl)-2,3,4,5-tetrahydro-

1 H- 1 -benzazepine-2-one;

1 ,4-Di-[(3(R,S)-tert-butoxycarbonyl- 1 -ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro- 1 H-

1 -benzazepine)-7-yl]-piperazine;

l,4-Di-[(3(R,S)-carboxyl-l-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-lH-l-

benzazepine)-7-yl] -piperazine;

7-[(4-tert-butoxycarbonylpiperazin)- 1 -yl]-l -ethyl-8-methoxy-2,3,4,5-tetrahydro- 1 H-

1 -benzazepine-2-one;

l-ethyl-8-methoxy-7-(piperazin-l-yl)-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

hydrochloride;

i-tert-Butoxycarbonyl-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-

1 -benzazepine-2-one;

3(R,S)-tert-Butoxycarbonyl-l-(3-fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one;

7-[(4-benzyloxycarbonyl)piperazin- 1 -yl]-3(R,S)-tert-butoxycarbonyl- 1 -ethyl-8-

methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

3,7-dibromo-l-ethyl-3(R,S)-methoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one;

7-bromo-l-ethyl-3(R,S)-methoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one; 7-bromo-3(R,S)-N-(tert-butyl)aminocarbonyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-

1 H- 1 -benzazepine-2-one;

7-Bromo-3(R,S)-tert-butoxycarbonyl-l-(3-fluorobenzyl)-8-methoxy-2,3,4,5-

tetrahydro- 1 H- 1 -benzazepine-2-one;

8-(tert-butyldimethylsilyloxy)-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

3(R,S)-tert-butoxycarbonyl-l-cyanomethyl-8-methoxy-7-nitro-2,3,4,5-tetrahydro-lH-

1 -benzazepine-2-one;

7-[(4-Benzyloxycarbonyl)piperazin-l-yl]-3(R,S)-tert-butoxycarbonyl-l-(3-

fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

7-Bromo-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one;

8-Phenoxy-2,3, 4,5 -tetrahydro- lH-l-benzazepine-2-one;

3(R,S)-tert-Butoxycarbonyl-l-ethyl-8-hydroxy-2,3,4,5-tetrahydro-lH-l- benzazepine-2-one;

3(R,S)-tert-Butoxycarbonyl-8-tert-Butyldimethylsilyloxy-l-ethyl-2,3,4,5- tetrahydro- IH- 1 -benzazepine-2-one;

8-Ethoxy-3(R,S)-tert-butoxycarbonyl-l-ethyl-2,3,4,5-tetrahydro-lH-l-benzazepine- 2-one;

8-Nitro-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine-2-one;

8-Nitro-l-ethyl-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

l,3(R,S)-Di(tert-butoxycarbonyl)-8-hydroxy-2,3,4,5-tetrahydro-lH-l-benzazepine- 2-one;

3(R,S)-carboxyl- 1 -(3-fluorobenzyl)-8-methoxy-2,3 ,4,5-tetrahydro- 1 H- 1 - benzazepine-2-one;

7-Methoxy-2,3 ,4,5-tetrahydro- 1 H- 1 -benzazepine-2-one;

6-Methoxy-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine-2-one; 2,3 ,4,5 -tetrahydro- 1 H- 1 -benzazepine-2-one;

6-Hydroxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

-Hydroxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

8- Amino- 1 -ethyl-2,3 ,4,5 -tetrahydro- 1 H- 1 -benzazepine-2-one;

8-Bromo-l-ethyl-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

3(R,S)-carboxyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

3-Benzyloxyaminocarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

3-(3-dimethylaminopropyl)aminocarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l- benzazepine-2-one;

l,3(R,S)-Di(tert-butoxycarbonyl)-8-methoxy-7-nitro-2,3,4,5-tetrahydro-lH-l- benzazepine-2-one;

3(R,S)-tert-Butoxycarbonyl-l-cyanomethyl-8-methoxy-7-nitro-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine-2-one;

3-Hydoxyaminocarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

3(R,S)-tert-Butoxycarbonyl-8-methoxy-7-nitro-2,3,4,5-tetrahydro-lH-l- benzazepine-2-one;

7-Amino-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l- benzazepine-2-one;

l-(tert-Butoxycarbonyl)methyl-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5- tetrahydro- 1 H- 1 -benzazepine-2-one;

l-(Aminocarbonyl)methyl-3(R,S)-tert-butyloxycarbonyl-8-methoxy-2,3,4,5- tetrahydro- 1 H- 1 -benzazepine-2-one;

l-Carboxylmethyl-3(R,S)-carboxyl -8-methoxy-2,3,4,5-tetrahydro-lH-l- benzazepine-2-one;

3(R,S)-Carboxyl -8-methoxy-7-nitro-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

3(R,S)-tert-Butoxycarbonyl-7-di(ethoxycabonylaminocarbonyl)amino-8-methoxy- 2,3,4,5-tetrahydro-lH-l-benzazepine-2-one; 3(R,S)-tert-Butoxycarbonyl-7-[(ethoxycabonylamino)thiacarbonyl)]amino-8- methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

8-Hydroxy-7-nitro-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

8-Hydroxy-7-nitro-3-carboxyl-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

8-Hydroxy-3-carboxyl-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

7-(4-Benzyloxycarbonyl)piperazinyl-3(R,S)-carboxyl-l-ethyl-8-methoxy-2,3,4,5- tetrahydro- 1 H- 1 -benzazepine-2-one;

7-Amino-3(R,S)-carboxyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

3(R,S)-Carboxyl-7-[(ethoxycabonylamino)thiacarbonyl)]amino-8-methoxy-2,3,4,5- tetrahydro- 1 H- 1 -benzazepine-2-one;

3(R,S)-Carboxyl-7-[(ethoxycabonylamino)carbonyl)]amino-8-methoxy-2,3,4,5- tetrahydro- 1 H- 1 -benzazepine-2-one;

7-Amino-3(R,S)-carboxyl-8-hydroxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

3(R,S)-tert-Butoxycarboxyl-7-[(ethoxycabonylamino)carbonyl)]amino-8-methoxy- 2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

3(R,S)-tert-Butoxycarboxyl-8-methoxy-l-[2-(4-moφholinyl)]ethyl-2,3,4,5- tetrahydro- 1 H- 1 -benzazepine-2-one;

l-Amidinomethyl-3(R,S)-Carboxyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine- 2-one;

3(R,S)-tert-Butoxycarbonyl-7-[(ethoxycabonylamino)thiacarbonyl)]amino-8-hydroxyl -2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

3(R,S)-Carboxyl-7-[(ethoxycabonylamino)thiocarbonyl)]amino-8-hydroxyl -2,3,4,5- tetrahydro- 1 H- 1 -benzazepine-2-one;

3(R,S)-Carboxyl-7-[(ethoxycabonylamino)carbonyl)]amino-8-hydroxyl -2,3,4,5- tetrahydro- 1 H- 1 -benzazepine-2-one;

3(R,S)-tert-Butoxycarbonyl-7-[(ethoxycabonylamino)carbonyl)]amino-8-hydroxyl - 2,3,4,5-tetrahydro-lH-l-benzazepine-2-one;

7-Amino-3(R,S)-tert-butoxycarbonyl-8-hydroxyl -2,3 ,4,5-tetrahydro- IH- 1 - benzazepine-2-one;

3(R,S)-tert-Butoxycarbonyl-8-hydroxyl-7-nitro-2,3,4,5-tetrahydro-lH-l- benzazepine-2-one ;

• 3(R,S)-tert-Butoxycarbonyl-8-methoxy-l-[2-(tetrahydro-2H-pyran-2-yl)oxyethyl]- 2,3,4,5-tetrahydro- 1 H- 1 -benzazepine-2-one;

3(R,S)-tert-Butoxycarbonyl-l-(2-hydroxy)ethyl-8-methoxy-7-2,3,4,5-tetrahydro-lH- 1 -benzazepine-2-one;

3(R,S)-tert-Butoxycarbonyl-8-methoxy-l-[2-(l,3-dioxolan-2-yl)ethyl]-2,3,4,5- tetrahydro- 1 H- 1 -benzazepine-2-one;

• 3(R,S)-tert-Butoxycarbonyl-8-methoxy-7-nitro-l-[2-(tetrahydro-2H-pyran- 2-yloxy)]ethyl-2,3 ,4,5-tetrahydro- 1 H- 1 -benzazepine-2-one;

3(R,S)-tert-Butoxycarbonyl-8-methoxy-7-nitro-l-(2-hydroxyethyl)-2,3,4,5- tetrahydro- IH- 1 -benzazepine-2-one;

or a pharmaceutically acceptable salt or prodrug form thereof.

In the present invention it has been discovered that the compounds above are

useful as inhibitors of bacterial, viral, fungal and protozoan growth, and for the treatment of

bacterial, viral, fungal and protozoan infections.

The present invention also provides methods for the treatment of bacterial,

viral, protozoan or fungal infection by administering to a host infected with bacteria, virus,

protozoa or fungus a pharmaceutically effective amount of a compound of formula (I)

wherein: R¹ is H, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or

alkynyl, substituted or unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mC(=O)R,

-(CH₂)_mC(=Q)OR, -C(=O)N(R)₂, -OR, -SO₂R, -C(=O)N(H)(NHR), -CH₂(OR),

-(CH₂)_n(OAr), -(CH₂)_mC(=NH)NH₂, -(CH₂)_nNHAr;

or a functional group of the following structure

wherein R is N,N-dimethylethylenediamino, 2-methoxyethylamino,

benzylamino, 3-trifluormethylbenzylamino, cyclopropylamino, propylamino,

allylamino, 3-methoxybenzylamino, 2-(4-methoxyphenyl)ethylamino,

cyclohexanemethylammo, 2,4-dichlorophenethylamino, 3-diehylaminopropyldiamino,

3-ethoxypropylamino, N,N-di-N-butylethylenediamino, 1 -(2-aminoethyl)piperidine,

l-(3-aminopropyl)imidazole, 4-(2-aminnoethyl)moφholine, 2-(aminomethyl)-l-

ethyl-pyrrolidine, 2-(2-aminoethyl)pyridine or 3-(aminomethyl)pyridine

chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or

unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mN(R)₂, -(CH₂)_mNH(Aa), -

(CH₂)_mNC(=O)R, -(CH₂)_mC(=O)NHOR -(CH₂)_mC(=O)OR,

-(CH₂)_mC(=O)NH(Aa), -(CH₂)_mC(=O)N(R)₂, (CH₂)_nC(=O)NH(Aa),

or are a functional group of the following structure:

with the proviso that R² and R³ cannot both be H.

or -(CH₂)_nAr, substituted or unsubstituted primary amine or secondary amine,

-NHC(=O)R, -NHC(=Q)NHC(=O)OR, -NH(C=Q)NHR, -QR, -OC(=O)N(R₂),

-C(=O)OR, -OSi(R)₃> -C(=O)N(R₂), NH-SO₂-R⁷ wherein R⁷ is

2,4-difluorophenyl, 2-fluorophenyl, 4-isopropylphenyl,

2,5-dimethoxyphenyl, 3,4 -dichlorophenyl, 2,3,5,6-tetramefhylphenyl,

2-chlorophenyl, 3-nitrophenyl, 4-acetylphenyl, 4-methyl-3-nitrophenyl,

4-butylphenyl, 4-nitrophenyl, 4-propylphenyl, 5-fluoro-2-methylphenyl,

4-chloro-2,5-dimethylphenyl,

with the proviso that R⁴ and R⁵ cannot both be H.

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 (CH₂)_nAr;

Ar is, aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic, heterocyclyl, or

heteroaryl;

Aa is an amino acid;

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 R² or R³ is

present;

m is 0, 1 or 2;

n is 1, 2 or 3;

and pharmaceutically acceptable salts or prodrug forms thereof.

The present invention also provides methods for the treatment of bacterial,

viral, protozoan or fungal infection by administering to a host infected with bacteria, virus or

fungus a pharmaceutically effective amount of a compound of Formula II

wherein:

R¹ is H, with the proviso if R¹ is H that R⁴ and R⁵ are not both H, substituted or unsubstituted,

straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or

unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mC(=O)R, -(CH₂)_nCN,

-(CH₂)_mC(=Q)OR, -C(=O)N(R)₂, -OR, -SO₂R, -C(=O)N(H)(NHR), -(CH₂)_n(OAr),

-(CH₂)_n(OR), -(CH₂)_mC(=NH)NH₂, -(CH₂)_nNHAr or wherein R¹ is a functional group

of the following structure:

wherein R is N,N-dimethylethylenediamino, 2-methoxyethylamino,

benzylamino, 3-trifluormethylbenzylamino, cyclopropylamino, propylamino,

allylamino, 3-methoxybenzylamino, 2-(4-methoxyphenyl)ethylamino,

cyclohexanemefhylamino, 2,4-dichlorophenethylamino, 3-diehylaminopropyldiamino,

1 -(3 -aminopropyl)imidazole, 4-(2-aminnoethyl)morpholine, 2-(aminomethyl)- 1 -

ethyl-pyrrolidine, 2-(2-aminoethyl)pyridine or 3-(aminomethyl)pyridine;

straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or

-(CH₂)_mC(=O)NHOR, -(CH₂)_mC(=O)OR, -(CH₂)_mC(=O)NH(Aa), -(CH₂)_mC(=O)N(R)₂, and (CH₂)_nC(=O)NH(Aa), or where R² and R³ can be a

functional group of the following structure:

or -(CH₂)_nAr, substituted or unsubstituted primary amine or secondary amine, -

NHC(=O)R, -NHC(=Q)NHC(=O)OR, -NH(C=Q)NHR, -QR, -OC(=O)N(R₂), -

C(=O)OR, -OSi(R)₃> -C(=O)N(R₂), NH-SO -R⁷ , wherein R⁷ is

2,4-difluorophenyl, 2-fluorophenyl, 4-isopropylphenyl,

2,5-dimethoxyphenyl, 3,4 -dichlorophenyl, 2,3,5,6-tetramethylphenyl,

2-chlorophenyl, 3-nitrophenyl, 4-acetylphenyl, 4-methyl-3-nitrophenyl,

4-butylphenyl, 4-nitrophenyl, 4-propylphenyl, 5-fluoro-2-methylphenyl,

4-chloro-2,5-dimethylphenyl,

with the proviso that R⁴ and R⁵ cannot both be H.

alkenyl or lower alkynyl, or a substituted or unsubstituted Ar or (CH₂)_nAr;

heteroaryl;

Aa is an amino acid;

Q is O or S;

Z is O or S;

m is 0, 1 or 2;

n is 1, 2 or 3;

and pharmaceutically acceptable salts or prodrug forms thereof.

Preferred are methods which use compounds of the Formula I and Formula II

or a pharmaceutically acceptable salt or prodrug form thereof wherein Z is O.

Also preferred are methods which use compounds of Formula II or a pharmaceutically

acceptable salt or prodrug wherein R¹ is

R is N,N-dimethylethylenediamino, 2-methoxyethylamino, benzylamino, 3-

trifluormethylbenzylamino, cyclopropylamino, propylamino, allylamino, 3-

methoxybenzylamino, 2-(4-methoxyphenyl)ethylamino, cyclohexanemethylammo, 2,4-dichlorophenethylamino, 3-diehylaminopropyldiamino,

l-(3-aminopropyl)imidazole, 4-(2-aminnoethyl)moφholine, 2-(aminomethyl)-l-

ethyl-pyrrolidine, 2-(2-aminoefhyl)pyridine or 3-(aminomethyl)pyridine,

R² is H , R³ is H, R⁴ is -NH-SO₂R⁷ and R⁷ is 2-fluorophenyl, R⁵ is OR where 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 -(CH₂)_nAr. Ar is, aryl, arylalkyl,

heterocycle, heterocyclic group, heterocyclic, heterocyclyl, or heteroaryl.

Also preferred are methods which use compounds of Formula I and Formula II

or a pharmaceutically acceptable salt or prodrug wherein R⁴ is at position 7 and R^ is position 8. In another preferred embodiment R^ is at position 8

and is OH or NH(C=Q)NR . Also preferred are methods which use compound of

Formula I or Formula II or pharmaceutically acceptable salt or prodrug wherein , R! is

3-fluorobenzyl or CH₂CN and R³ is H or CO₂But.

Compounds of invention are also useful in a method of treating neoplastic

disorders, proliferative disease, psoriasis, lichen planus, verruca vulgaris, verruca

plana juvenile, osteoporosis, osteomyelitis, seborrheic keratosis, central nervous

system disorders, psychosis, depression, pain, cardiovascular disorders,

neurodegenerative disorders, stroke, phlebitis, pulmonary emboli, renal disorders, diseases

of the ear, inflammatory disease, transplantation rejection, graft versus host disease, and

autoimmune disease in a host in need of such treatment, which method comprises

administering a therapeutically effective amount of compounds represented by general

Formula I . The present invention also relates to benzazepines which are useful as vasodilators, vasopressin antagonists, vasopressin agonist, oxytocin antagonist, anti-

hypertensive agents, anti-arrhythmic, anti-fibrillatory, diuretics, platelet aggregation

inhibitors, anti-coagulants, immunomodulatory agent, or agents that promote release of

growth hormone by administering a pharmaceutically effective amount of a compound of

formula (I)

wherein:

R¹ is H, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or

alkynyl, substituted or unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mC(=O)R,

-(CH₂)_mC(=Q)OR, -C(=O)N(R)₂, -OR, -SO₂R, -C(=O)N(H)(NHR), -CH₂(OR),

-(CH₂)„(OAr), -(CH₂)_mC(=NH)NH₂, -(CH₂)_nNHAr;

or a functional group of the following structure

wherein R is N,N-dimethylethylenediamino, 2-methoxyethylamino,

benzylamino, 3-trifluormethylbenzylamino, cyclopropylamino, propylamino,

allylamino, 3-methoxybenzylamino, 2-(4-methoxyphenyl)ethylamino,

cyclohexanemethylamino, 2,4-dichlorophenethylamino, 3- diehylaminopropyldiamino, 3-ethoxypropylamino, N,N-di-N-

butylethylenediamino, 1 -(2-aminoethyl)piperidine,

1 -(3-aminopropyl)imidazole, 4-(2-aminnoethyl)moφholine, 2-(aminomethyl) 1 -

ethyl-pyrrolidine, 2-(2-aminoethyl)pyridine or 3-(aminomethyl)pyridine

chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or

unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mN(R)₂, -(CH₂)_mNH(Aa), -

(CH₂)_mNC(=O)R, -(CH₂)_mC(=O)NHOR -(CH₂)_mC(=O)OR,

-(CH₂)_mC(=O)NH(Aa), -(CH₂)_mC(=O)N(R)₂, and

(CH₂)_nC(=O)NH(Aa), or a functional group of the following structure:

or -(CH₂)_nAr, substituted or unsubstituted primary amine or secondary amine,

-NHC(=O)R, -NHC(=Q)NHC(=O)OR, -NH(C=Q)NHR, -QR, -OC(=O)N(R₂),

-C(=O)OR, -OSi(R)₃> -C(=O)N(R₂), NH-SO₂-R⁷, wherein R? is

2,4-difluorophenyl, 2-fluorophenyl, 4-isopropylphenyl, 2,5-dimethoxyphenyl, 3,4 -dichlorophenyl, 2,3,5,6-tetramethylphenyl,

2-chlorophenyl, 3-nitrophenyl, 4-acetylphenyl, 4-methyl-3-nitrophenyl,

4-butylρhenyl, 4-nitrophenyl, 4-propylphenyl, 5-fluoro-2-methylphenyl,

4-chloro-2 , 5 -dimethylphenyl,

with the proviso that R⁴ and R⁵ cannot both be H;

alkenyl or lower alkynyl, or a substituted or unsubstituted Ar or (CH₂)_nAr;

heteroaryl;

Aa is an amino acid;

Q is O or S;

Z is O or S;

present;

m is 0, 1 or 2;

n is 1, 2 or 3;

and pharmaceutically acceptable salts or prodrug forms thereof. Compounds of invention are also useful in a method of

treating neoplastic disorders, proliferative disease, psoriasis, lichen planus, verruca

vulgaris, verruca plana juvenile, osteoporosis, osteomyelitis, seborrheic keratosis,

central nervous system disorders, psychosis, depression, pain, cardiovascular disorders,

autoimmune disease in a host in need of such treatment, which method comprises

Formula II. The present invention also relates to benzazepines which are useful as

vasodilators, vasopressin antagonists, vasopressin agonist, oxytocin antagonist, anti-

hypertensive agents, anti-arrhythmic, anti-fϊbrillatory, diuretics, platelet aggregation

formula (II)

wherein:

straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or

unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mC(=O)R, -(CH₂)_nCN, -(CH₂)_mC(=Q)OR, -C(=O)N(R)₂, -OR, -SO₂R, -C(=O)N(H)(NHR), -(CH₂)_n(OAr),

-(CH₂)_n(OR), -(CH₂)_mC(=NH)NH₂ -(CH₂)_nNHAr or wherein R¹ is a functional group

of the following structure:

wherein R is N,N-dimethylethylenediamino, 2-methoxyethylamino,

benzylamino, 3-trifluormethylbenzylamino, cyclopropylamino, propylamino,

allylamino, 3-methoxybenzylamino, 2-(4-methoxyphenyl)ethylamino,

cyclohexanemethylamino, 2,4-dichlorophenethylamino,

3-diehylaminopropyldiamino, 3-ethoxypropylamino, N,N-di-N-

butylethylenediamino, 1 -(2-aminoethyl)piperidine,

1 -(3-aminopropyl)imidazole, 4-(2-aminnoethyl)moφholine, 2-(aminomefhyl)-

1-ethyl-pyrrolidine, 2-(2-aminoethyl)pyridine or 3-(aminomethyl)pyridine;

straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or

unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mN(R)₂, -(CH₂)_mNH(Aa),

-(CH₂)_mNC(=O)R, -(CH₂)_mC(=O)NHOR, -(CH₂)_mC(=O)OR,

(CH₂)_mC(=O)NH(Aa), -(CH₂)_mC(=O)N(R)₂, and (CH₂)_nC(=O)NH(Aa), or where R²

or R³ can be a functional group of the following structure:

NHC(=O)R, -NHC(=Q)NHC(=O)OR, -NH(C=Q)NHR, -QR, -OC(=O)N(R₂), -

C(=O)OR, -OSi(R)₃. -C(=O)N(R₂), NH-SO -R⁷ wherein R⁷ is

2,4-difluorophenyl, 2-fluorophenyl, 4-isopropylphenyl,

2,5-dimethoxyphenyl, 3,4 -dichlorophenyl, 2,3,5,6-tetramethylphenyl,

2-chlorophenyl, 3-nitrophenyl, 4-acetylphenyl, 4-methyl-3-nitrophenyl,

4-butylphenyl, 4-nitrophenyl, 4-propylphenyl, 5-fluoro-2-methylphenyl,

4-chloro-2,5-dimethylphenyl,

with the proviso that R and R cannot both be H.

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 (CH₂)_nAr;

heteroaryl;

Aa is an amino acid;

Q is O or S;

Z is O or S;

m is 0, 1 or 2;

n is 1, 2 or 3;

and pharmaceutically acceptable salts or prodrug forms thereof.

Preferred are methods which use compounds of the Formula I and Formula II or a

pharmaceutically acceptable salt or prodrug form thereof wherein Z is O. Also preferred are

methods which use compounds of Formula II or a pharmaceutically acceptable salt or

prodrug wherein R¹ is

wherein R" is N,N-dimethylethylenediamino, 2-methoxyethylamino, benzylamino, 3-

trifluormethylbenzylamino, cyclopropylamino, propylamino, allylamino, 3-

methoxybenzylamino, 2-(4-methoxyphenyl)ethylamino, cyclohexanemethylamino,

2,4-dichlorophenethylamino, 3-diehylaminopropyldiamino, 3-ethoxypropylamino, N,N-di-N-butylethylenediamino, 1 -(2-aminoethyl)piperidine,

1 -(3-aminopropyl)imidazole, 4-(2-aminnoethyl)moφholine, 2-(aminomethyl)- 1 -

ethyl-pyrrolidine, 2-(2-aminoethyl)pyridine or 3-(aminomethyl)pyridine

and R² is H , R³ is H, R⁴ is -NH-SO₂R⁷ R⁷ is 2-fluorophenyl, R⁵ is OR where R is H, a

lower alkynyl, or a substituted or unsubstituted Ar or -(CH₂)_nAr. Ar is, aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic, heterocyclyl, or heteroaryl . Also preferred are methods which use compounds of Formula I and Formula II or a pharmaceutically acceptable

salt or prodrug wherein R⁴ is at position 7 and R^ is position 8. In another preferred

embodiment, R! is 3 -fluorobenzyl or CH₂CN and R³ is H or CO Bu^t .

Another aspect of the invention is directed to processes for making the compounds of the

present invention, including the steps of introduction of a carboxyl group into the 3-

benzazepine skeleton.

The present invention may be more fully understood by reference to the

following detailed description of the invention, non- limiting examples of specific

embodiments of the invention.

DESCRIPTION OF THE INVENTION

The compounds of the Formula I or Formula II herein described may have

asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present

invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in

the present invention.

When any variable (for example, R¹ through R⁵, R, Ar, Aa, Q, Z, m, n, etc.)

occurs more than one time in any constituent or in Formula I or Formula II, or any other

formula herein, its definition on each occurrence is independent of its definition at every other

occurrence. Also, combinations of substituents and/or variables are permissible only if such

combinations result in stable compounds.

The term "alkyl" means a branched or unbranched saturated aliphatic

hydrocarbon radical, having the number of carbon atoms specified, or if no number is

specified, having up to 12 carbon atoms. Examples of alkyl radicals include methyl, ethyl, n-

propyl, isopropyl, n-butyl, zso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-

dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-heptyl, 2-methylhexyl, and the

like. The terms "lower alkyl" and "C,-C₆ alkyl" are synonymous and used interchangeably.

A preferred "C_rC₆ alkyl" group is methyl or ethyl.

The term "alkenyl" means a branched or unbranched hydrocarbon radical

having the number of carbon atoms designated containing one or more carbon-carbon double

bonds, each double bond being independently cis, trans, or a nongeometric isomer.

The term "alkynyl" means a branched or unbranched hydrocarbon radical

having the number of carbon atoms designated containing one or more carbon-carbon triple

bonds.

The term "substituted alkyl, alkenyl, alkynyl" denotes the above alkyl, alkenyl

or alkynyl groups that are substituted by one, two or three; halogen (F, CI, Br, I), nitro, cyano,

hydroxy, alkoxy, haloalkoxy, cyclic, branched or unbranched lower alkyl, cyclic, branched or unbranched lower alkenyl, cyclic, branched or unbranched lower alkynyl, protected hydroxy,

amino, protected amino, C,-C₆ acyloxy, carboxy, protected carboxy, carbamoyl,

carbamoyloxy, and methylsulfonylamino. The substituted alkyl, alkenyl, and alkynyl groups

may be substituted once, twice or three times with the same or with different substituents.

Examples of the above substituted alkyl groups include but are not limited to:

cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl,

aminomethyl, carboxymethyl, alkyloxycarbonylmethyl, allyloxycarbonylaminomethyl,

carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl,

chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-

butyl), 2-amino(isopropyl), 2-carbamoyloxyethyl and the like. A preferred group of

examples within the above "substituted alkyl" group includes the substituted methyl group

and substituted ethyl group. Examples of the substituted methyl group include groups such as

hydroxymethyl, protected hydroxymethyl (e.g., tetrahydro-pyranyloxymethyl),

acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, bromomethyl and

iodomethyl.

The terms "alkyloxy" or "alkoxy" are used interchangeably herein and denote

groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups.

The terms "acyloxy" or alkanoyloxy" are used interchangeably and denote

herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy,

hexanoyloxy, heptanoyloxy and the like.

The terms "alkylcarbonyl", "alkanoyl" and "acyl" are used interchangeably

herein encompass groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl,

heptanoyl, benzoyl and the like. The term "cycloalkyl" as used herein refers to a mono-, bi- or tricyclic

aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms.

The terms "alkylthio" and "substituted alkylthio" denote alkyl and substituted

alkyl groups, respectively, attached to a sulfur which is in turn the point of attachment of the

alkythio or substituted alkylthio group to the group or substituent designated.

The term "Ar" as used herein and in the claims denotes any partially saturated

aromatic, or aromatic, aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic,

heterocyclyl, and heteroaryl generally known to those skilled in organic chemistry and as

further described herein below.

The term "Substituted Ar" denotes any substituted, partially saturated

aromatic, or aromatic, aryl, substituted arylalkyl, and substituted heteroaryl which are

generally known to those skilled in organic chemistry and as further described herein below,

that include but are not limited to those groups wherein one or more hydrogens are

substituted by one, two or three: halogen (F, CI, Br, I), nitro, cyano, hydroxy, protected

hydroxy, alkoxy, haloalkoxy, cyclic, branched or unbranched lower alkyl, cyclic, branched or

unbranched lower alkenyl, cyclic, branched or unbranched lower alkynyl, substituted with

amino, protected amino, cyano, nitro, aminomethyl, Cj- acyloxy, carboxy, protected

carboxy, carboxymethyl, hydroxymethyl, carbamoyl, carbamoyloxy, trifluoromethyl, N-

(methylsulfonylamino), methylsulfonylamino or other groups specified.

The term "aryl" denotes any mono-, bi- or tricyclic partially saturated aromatic

ring or aromatic ring having 5-21 carbon atoms, where at least one ring is a 5-, 6- or 7-

membered hydrocarbon ring, and containing from zero to four heteroatoms selected from

nitrogen, oxygen and sulfur. Preferred hydrocarbon aryl groups include phenyl, napthyl, biphenyl, phenanthrenyl, naphthacenyl and the like (see Lang's Handbook of Chemistry

(Dean, J.A., ed) 14^th Ed., [1992]).

Examples of the term "substituted phenyl" include but are not limited to a

mono- or di(halo)phenyl group such as 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-

dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-

dibromophenyl, 3-chloro-4-fluoφhenyl, 2-fluorophenyl and the like; a group such as 4-

hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives

thereof and the like; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenyl group,

for example, 4-cyanophenyl; a mono or di(lower alkyl)phenyl group such as 4-methylphenyl,

2,4-dimethylphenyl, 2-methylphenyl, 4-(wo-propyl)phenyl, 4-ethylphenyl,

3-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group, for example, 2,6-

dimethoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4-(tso-propoxy)phenyl, 4-(t-

butoxy)phenyl, 3-ethoxyphenyl-4-methoxyphenyl and the like; 3- or 4-trifluoromethylphenyl;

a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such as 4-carboxyphenyl; a

mono- or di(hydroxymethyl)phenyl or (protected hydroxymefhyl)phenyl such as 3-(protected

hydroxymethly)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl

or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected

aminomethyl)phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 3-(N-

methylsulfonylamino)phenyl.

Also, the term "substituted phenyl" represents disubstituted phenyl groups

wherein the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro- 4-

hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-

nitrophenyl, 2-hydroxy-4-chlorophenyl and the like. Preferred substituted phenyl groups include the 2- and 3-trifluoromethylphenyl, the 4-hydroxyphenyl, the 2-aminomefhylphenyl

and the 3-(N-(methylsulfonylamino))phenyl groups.

The term "arylalkyl" means one, two or three aryl groups having 3 to 14

carbon atoms, appended to an alkyl radical having 1 to 12 carbon atoms including but not

limited to: benzyl, napthylmethyl, phenethyl, benzyhydryl (diphenylmethyl), trityl

piperazinylmethyl, pyrimidinylethyl, pyridazinylpropyl, indolylbutyl, purinylmethyl and the

like.

The term "substituted arylalkyl" denotes an alkyl group substituted at any

carbon with a C₆-C₁₂ aryl group bonded to the alkyl group through any aryl ring position and

substituted on the C_rC₆ alkyl portion with one, two or three groups chosen from halogen (F,

CI, Br, I), straight chain, branched or cyclic C,-C₆ alkyl, straight chain, branched or cyclic C,-

C₆ alkenyl, straight chain, branched or cyclic C,-C₆ alkynyl, hydroxy, protected hydroxy,

amino, protected amino, C_rC₆ acyloxy, nitro, carboxy, protected carboxy, carbamoyl,

carbamoyloxy, cyano, -Cg alkylthio, N-(methylsulfonylamino) or C,-C₆ alkoxy.

Optionally, the aryl group may be substituted with one, two or three groups chosen from

halogen, straight chain, branched or cyclic C_rC₆ alkyl, straight chain, branched or cyclic C,-

nitro, C C₆ alkyl, C,-C₄ alkoxy, carboxy, protected carboxy, carboxymethyl, protected

carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected

aminomethyl or an N-(methylsulfonylamino) group. As before, when either the C,-C₆ alkyl

portion or the aryl portion or both are disubstituted, the substituents can be the same or

different. Examples of the term "substituted arylalkyl" include groups such as 2-phenyl-

1 -chloroethyl, 2-(4-methoxyphenyl)ethyl, 2,6-dihydroxy-4-phenyl(n-hexyl),

5-cyano-3-methoxy-2-phenyl(n-pentyl), 3-(2,6-dimethylphenyl)n-propyl, 4-chloro-3-

aminobenzyl, 6-(4-methoxyphenyl)-3-carboxy(n-hexyl), and the like.

Unless otherwise specified, the terms "heterocycle", "heterocyclic group",

"heterocyclic" or "heterocyclyl" are used interchangeably herein and includes any mono-, bi-

or tricyclic saturated, unsaturated or aromatic ring where at least one ring is a 5-, 6- or 7-

membered hydrocarbon ring containing from one to four heteroatoms selected from nitrogen,

oxygen and sulfur, preferably at least one heteroatom is nitrogen (Lang's Handbook of

Chemistry, vide supra).

Preferably, the heterocycle is a 5-, 6- or 7-member saturated, unsaturated or

aromatic hydrocarbon ring containing 1, 2, or 3 heteroatoms selected from O, N and S.

Typically, the 5-membered ring has 0 to 2 double bonds and the 6- or 7-membered ring has 0

to 3 double bonds and the nitrogen or sulfur heteroatoms may optionally be oxidized, and any

nitrogen heteroatom may optionally be quarternized. Included in the definition are any

bicyclic groups where any of the above heterocyclic rings are fused to a benzene ring.

Heterocyclics in which nitrogen is the heteroatom are preferred.

The following ring systems are examples of the heterocyclic (whether

substituted or unsubstituted) radicals denoted by the term "heterocyclic": thienyl, furyl,

pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,

thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl,

pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl,

oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, dihydropyrimidyl, tetrahydropyrimidyl, tetrazolo-(l, 5b)-pyridazinyl and purinyl, as well as benzo-fused

derivatives for example benzoxazolyl, benzthiazolyl, benzimidazolyl and indolyl.

Heterocyclic 5-membered ring systems containing a sulfur or oxygen atom and

one to three nitrogen atoms are also suitable for use in the instant invention. Examples of

such preferred groups included thiazolyl in particular thiazol-2-yl and thiazol-2-yl N-oxide,

thiadiazolyl, in particular l,3,4-thiadiazol-5-yl and l,2,4-thiadiazol-5-yl, oxazolyl, preferably

oxazol-2-yl, and oxadiazolyl, such as l,3,4-oxadiazol-5-yl, and l,2,4-oxadiazol-5-yl. A

group of further preferred examples of 5-membered ring systems with 2 to 4 nitrogen atoms

include imidazolyl, preferably imidazol-2-yl; triazolyl, preferably l,3,4-triazol-5-yl; 1,2,3-

triazol-5-yl, l,2,4-triazol-5-yl and tetrazolyl, preferably lH-tetrazol-5-yl. A preferred group

of examples of benzo-fused derivatives are benzoxazol-2-yl, benzthiazol-2-yl and

b enzimidazol-2-y 1.

Further suitable specific examples of the above heterocylic ring systems are 6-

membered ring systems containing one to three nitrogen atoms. Such examples include

pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, preferably pyrimid-2-yl and

pyrimid-4-yl; triazinyl, preferably l,3,4-triazin-2-yl and l,3,5-triazin-4-yl; pyridazinyl, in

particular pyridazin-3-yl and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and

the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the l,3,4-triazin-2-yl radicals are a

preferred group. Optionally, preferred 6-membered ring heterocycles are: piperazinyl,

piperazin-2-yl, piperidyl, piperid-2-yl, piperid-3-yl, piperid-4-yl, moφholino, moφholin-2-yl

and moφholin-3-yl. The substituents for the optionally substituted heterocyclic ring systems and

further examples of the 6- and 7-membered ring systems discussed above can be found in W.

Durckheimer, et. al, U.S. Pat. No. 4,278,793.

An optionally preferred group of "heterocyclics" include: l,3-thiazol-2-yl, 4-

(carboxymethyl)-5-methyl-l,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-l,3-thiazol-2-yl

sodium salt, l,2,4-thiadiazol-5-yl, 3-methyl-l,2,4-thiadiazol-5-yl, l,3,4-triazol-5-yl, 2-

methyl-l,3,4-triazol-5-yl, 2-hydroxy-l,3,4-triazol-5-yl, 2-carboxy-4-methyl-l,3,4-triazol-5-yl

sodium salt, 2-carboxy-4-methyl-l,3,4-triazol-5-yl, l,3-oxazol-2-yl, l,3,4-oxadiazol-5-yl, 2-

methyl-l,3,4-oxadiazol-5-yl, 2-(hydroxymethyl)-l,3,4-oxadiazol-5-yl, l,2,4-oxadiazol-5-yl,

l,3,4-thiadiazol-5-yl, 2-thiol-l,3,4-oxadiazol-5-yl, 2-(methylthio)-l,3,4-thiadiazol-5-yl, 2-

amino- 1 ,3 ,4-thiadiazol-5-yl, 1 H-tetrazol-5 -yl, 1 -methyl- 1 H-tetrazol-5 -yl, 1 -( 1 -

dimethylamino)eth-2-yl)-lH-tetrazol-5-yl, 1 -(carboxymethyl)- lH-tetrazol-5-yl, 1 -

(carboxymethyl)- 1 H-tetrazol-5 -yl sodium salt, l-(methylsulfonic acid)- 1 H-tetrazol-5 -yl, 1-

(methylsulfonic acid)-lH-tetrazol-5-yl sodium salt, 2-methyl-lH-tetrazol-5-yl, 1,2,3-triazol-

5-yl, l-methyl-l,2,3-triazol-5-yl, l-methyl-l,2,3-triazol-5-yl, 2-methyl-l,2,3-triazol-5-yl, 4-

methyl-l,2,3-triazol-5-yl, pyrid-2-yl N-oxide, 6-methoxy-2-(N-oxide)-pyridazin-3-yl, 6-

hydroxypyridazin-3-yl, l-methylpyridin-2-yl, l-methylpyridin-4-yl, 2-hydroxypyrimidin-4-

yl, 1 ,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1 ,4,5,6-tetrahydro-4-

(formylmethyl)-5,6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-

3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-

6-methoxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl,

tetrazolo[l,5-b]pyridazin-6-yl and 8-aminotetrazolo[l,5-b]-pyridazin-6-yl. An alternative group of "heterocyclics" includes: 4-(carboxymethyl)-5-methyl-

l,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-l,3-thiazol-2-yl sodium salt, l,3,4-triazol-5-yl,

2-methyl-l,3,4-triazol-5-yl, lH-tetrazol-5-yl, l-methyl-lH-tetrazol-5-yl, 1-(1-

(dimethylamino)eth-2-yl)-lH-tetrazol-5-yl, l-(carboxymethyl)-lH-tetrazol-5-yl, 1-

(carboxymethyl)-l -H-tetrazol-5 -yl sodium salt, l-(methylsulfonic acid)-lH-tetrazol-5-yl, 1-

(methylsulfonic acid)- 1 H-tetrazol-5 -yl sodium salt, l,2,3-triazol-5-yl, l,4,5,6-tetrahydro-5,6-

dioxo-4-methyl-as-triazin-3-yl, l,4,5,6-tetrahydro-4-(2-formylmethyl)-5,6-dioxo-as-triazin-3-

yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-

hydroxy-2-methyl-as-triazin-3-yl,tetrazolo(l ,5-b)pyridazin-6-yl and 8-aminotetrazolo(l ,5-

b)pyridazin-6-yl.

The terms "heteroaryl group" or "heteroaryl" are used interchangeably herein

and includes any mono-, bi- or tricyclic aromatic rings having the number of ring atoms

designated where at least one ring is a 5-, 6- or 7-membered hydrocarbon ring containing

from one to four heteroatoms selected from nitrogen, oxygen and sulfur, preferably at least

one heteroatom is nitrogen. The aryl portion of the term "heteroaryl" refers to aromaticity, a

term known to those skilled in the art and defined in greater detail in "Advanced Organic

Chemistry", J. March, 4^th Ed., John Wiley & Sons, New York, N.Y. (1992).

The term "Aa" as used herein and in the claims refers to "amino carboxylic

acid" as that term is generally understood by those skilled in the art and denotes any naturally

occurring or non-naturally occurring or amino acid. Typical natural amino acids include but

are not limited to alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic

acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenyl-alanine, proline, serine, threonine, tryptophan, tyrosine, and valine. Any other amino acid, naturally occurring

or non-naturally occurring, are contemplated within the scope of this invention.

Examples of Aa, wherein" Aa" represents an amino acid, includes the

racemates and all optical isomers thereof. The amino acid of Aa include, but are not limited

to, alanine, serine, phenylalanine, cysteine, glutamic acid alanine, asparagine, N-β-trityl-

asparagine, aspartic acid, aspartic acid-β-butyl ester, arginine, N⁸-Mtr-arginine, cysteine, S-

trityl-cysteine, glutamic acid, glutamic acid-γ-t-butyl ester, glutamine, N-γ-trityl-glutamine,

glycine, histidine, N ^ιm-trityl-histidine, isoleucine, leucine, lysine, N ^ε-Boc-lysine,

methionine, phenylalanine, proline, serine, O-t-butyl-serine, threonine, tryptophan, N ^m-Boc-

tryptophan, tyrosine, valine, sarcosine, L-alanine, chloro-L-alanine, 2-aminoisobutyric acid,

2-(methylamino)isobutyric acid, D,L-3-aminoisobutyric acid, (R)-(-)-2 aminoisobutyric acid,

α-amino isobutyric (S)-(+)-2-aminoisobutyric acid, D-leucine, L-leucine, D-norvaline, L-

norvaline, L-2-amino-4-pentenoic acid, D-isoleucine, L-isoleucine, D-norleucine, 2,3-

diaminopropionic acid, 3-amino propionic acid, L-norleucine, D,L-2-aminocaprylic acid, β-

alanine, D,L-3-aminobutyric acid, 4-aminobutyric acid, 4-(methylamino)butyric acid, 5-

aminovaleric acid, 5-aminocaproic acid, 7-aminoheptanoic acid, 8-aminocaprylic acid, 11-

aminodecanoic acid, 12-aminododecanoic acid, carboxymethoxylamine, D-serine, D-

homoserine, L-homoserine, D-allothreonine, L-allothreonine, D-threonine, L-threonine, D,L-

4-amino-3-hydroxybutyric acid, D-,L-3-hydroxynorvaline, (3S,4S)-(-)-statine, 5-hydroxy-

D,L-lysine, 1 -amino- 1-cyclopropanecarboxylic acid, 1 -amino- 1-cyclopentanecarboxylic acid,

1 -amino- 1-cyclohexanecarboxy lie acid, 5 -amino- 1, 3 -cyclohexadiene-1 -carboxy lie acid, 2-

amino-2-norbornanecarboxylic acid, (S)-(-)-2-azetidinecarboxylic acid, cis-4-hydroxy-D-

proline, cis-4-hydroxy-L-proline, trans-4-hydroxy-L-proline, 3,4-dehydro-D,L-proline, 3,4- dehydro-L-proline, D-pipecolinic acid, L-pipecolinic acid, nipecotic acid, isonipecotic acid,

mimosine, 2,3-diaminopropionic acid, D,L-2,4-diaminobutyric acid, (S)-(+)-diaminobutyric

acid, D-ornithine, L-ornithine, 2-methylornithine, N-ε-methyl-L-lysine, N-methyl-D-aspartic

acid, D,L-2-methylglutamic acid, D,L-2-aminoadipic acid, D-2-aminoadipic acid, L-2-

aminoadipic acid, (+/-)-3-aminoadipic acid, D-cysteine, D-penicillamine, L-penicillamine,

D,L-homocysteine, S-methyl-L-cysteine, L-methionine, D-ethionine, L-ethionine, S-

carboxymethyl-L-cysteine, (S)-(+)-2-phenylglycine, (R)-(-)-2-phenylglycine, N-

phenylglycine, N-(4-hydroxyphenyl)glycine, D-phenylalanine, (S)-(-)indoline-2-carboxylic

acid, α-methyl,D,L-phenylalanine, β-methyl-D,L-phenylalanine, D-homophenylalanine, L-

homophenylalanine, D,L-2-fluorophenylglycine, D,L-2-fluorophenylalanine, D,L-3-

fluorophenylalanine, D,L-4-fluorophenylalanine, D,L-4-chlorophenylalanine, L-4-

chlorophenylalanine, 4-bromo-D,L-phenylalanine, 4-iodo-D-phenylalanine, 3,3',5-triiodo-L-

thyronine, (+)-3,3',5-triiodo-L-thyronine, D-thyronine, L-thyronine, D,L-m-tyrosine, D-4-

hydroxyphenylglycine, D-tyrosine, L-tyrosine, O-methyl-L-tyrosine, 3-fluoro-D,L-tyrosine,

3-iodo-L-tyrosine, 3 -nitro-L- tyrosine, 3,5-diiodo-L-tyrosine, D,L-dopa, L-dopa, 2,4,5-

trihydroxyphenyl-D,L-alanine, 3-amino-L-tyrosine, 4-amino-D-phenylalanine, 4-amino-L

phenylalnine, 4-amino-D,L-phenylalanine, 4-nitro-L-phenylalanine, 4-nitro-D,L-

phenylalanine, 3,5-dinitro-L-tyrosine, D,L-α-methyltyrosine, L-α-methyltyrosine, (-)-3-(3,4-

dihydroxyphenyl)-2-methyl-L-alanine, D,L-threo-3-phenylserine, trans-4

(aminomethyl)cyclohexane carboxylic acid, 4-(aminomethyl)benzoic acid, D,L-3-

aminobutyric acid, 3- aminocyclohexane carboxylic acid, cis-2-amino-l-cyclohexane

carboxylic acid, γ-amino-β-(p-chlorophenyl) butyric acid (Baclofen), D,L-3- aminophenylpropionic acid, 3-amino-3-(4-chlorophenyl) propionic acid, 3-amino-3-(2-

nitrophenyl)propionic acid, and 3-amino-4,4,4 trifluorobutyric acid.

The term "primary amine" as used herein and in the claims is generally

understood by those skilled in the art and denotes any group which is attached to an amine (-

NH₂) moiety, and includes but is not limited to alkyl-amines, alkenyl-amines, alkynyl-

amines, aryl-amines and herteroaryl-amines, as such terms are described herein above.

Examples of primary amines include, but are not limited to any of those listed

above, as well as for example, guanidine, methylguanidine, 1,10-diaminodecane, 1,4-

diaminobutane, 5-amino-indazole, 7-amino-4-(trifluoromethyl)-coumarin, 4-bromo-3-

(trifluoromethyl)aniline, 3-chloro-4-fluoroaniline, 2-chloro-5-(trifluoromethyl)aniline, 3,5-

difluorobenzylamine, 2-(difluoromethoxy)aniline, 3-fluoro-p-anisidine, 2-fluoroethylamine,

3-fluoro-4-methylaniline, 4-fluorophenylethylamine, 3-fluoro-d-phenylalanine, 3-fluoro-l-

phenylalanine, d,l,-3-fluorophenylalanine, 4-fluoro-3-(trifluoromethyl)benzylamine, 6-fluoro-

tryptamine, 5 -fluoro-1- tryptophan, 5-fluoro-d,l,-tryptophan, 4-(trifluoromethyl)aniline, 4-

(trifluoromethyl)benzylamine, 4-(trifluoromethylthio)aniline, and 2-(4-

moφholino)ethylamine.

The term "secondary amine" as used herein and in the claims is generally

understood by those skilled in the art and denotes any two groups which are attached

symmetrically or unsymmetrically to an amino (-NH-) moiety.

Examples of secondary amines include, but are not limited to any of those

listed above, as well as for example, piperazine, pyrrolidine, 3-(tert-butoxycarbonylamino)-

pyrrolidine, 1-benzylpiperazine, benzyl- 1 -piperazine carboxylate, 4-benzylpiperidine, l-(2- chlorophenyl)piperazine, 2,6 dimethylmoφholine, ethyl isonipecotate, ethyl- 1-

piperazinecarboxylate, l-(4-fluorophenyl)piperazine, heptamethyleneimine, l-(2-

methoxyphenyl)piperazine, 1-methylhomopiperazine, 1-methylpiperazine, moφholine, l-(4-

nitrophenyl)piperazine, 1-phenylpiperazine, 1-phenylpiperazine,

4'-piperazinoacetophenone, piperidine, 4-piperidinopiperidine, l-(2-pyridyl)piperazine, l-(2-

pyrimidyl)piperazine, 4-(l-pyrrolidinyl)piperidine, 1,2,3,4-tetrahydroisoquinoline,

thiomoφholine, l-(o-tolyl)piperazine, l-(α, α, α,-trifluoro-m-tolyl)piperazine,

1 -(2,3 -xylyl)piperazine, tert-butyl- 1 -piperazinecarboxylate,

l-(2,5-dimethylphenyl)piperazine, 4,4'-bipiperidine, cis-2,6-dimethylpiperazine, and

3,5-dimethylpiperazine.

As used herein, "pharmaceutically acceptable salts and prodrugs" refer to

derivatives of the disclosed compounds that are modified by making acid or base salts, or by

modifying functional groups present in the compounds in such a way that the modifications

are cleaved, either in routine manipulation or in vivo, to the parent compounds.

Pharmaceutically acceptable salts of the compounds of the invention can be

prepared by reacting the free acid or base forms of these compounds with a stoichiometric

amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the

two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or

acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical

Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995, p. 1418, the disclosure of

which is hereby incoφorated by reference.

Pharmaceutically acceptable acid addition salts are those salts which retain the

biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, sulfuric acid,

nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid,

glycolic acid, pyruvic acid, oxalic acid, maleic acid, maloneic acid, succinic acid, fumaric

acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic

acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.

Pharmaceutically acceptable base addition salts are those derived from

inorganic bases such as sodium, potasium, lithium, ammonium, calcium, magnesium, iron,

zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the

ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from

pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary and

tertiary amines, substituted amines including naturally occurring substituted amines, cyclic

amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine,

triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,

dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine,

ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine,

piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic

non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine,

dicyclohexylamine, choline and caffeine.

"Prodrugs" are considered to be any covalently bonded carriers which release

the active parent drug in vivo when such prodrug is administered to a subject. Prodrugs of the

compounds of the parent compound are prepared by modifying functional groups present in

the compounds in such a way that the modifications are cleaved, either in routine

manipulation or in vivo, to the parent compounds. Prodrugs include, but are not limited to, compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when

administered to a subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group,

respectively. Examples of prodrugs include, but are not limited to, acetate, formate and

benzoate derivatives of alcohol and acetyl and benzoyl derivatives of amine functional groups

in the compounds of the invention and the like.

By "stable compound" or "stable structure" is meant herein a compound that is

sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture,

and formulation into an efficacious therapeutic agent.

Synthesis

There are many ways well known by those skilled in the art of organic

chemistry to prepare the compounds of the present invention. Some of these are described by

the General Schemes A to D and specific examples presented below. Each of the references

cited below and elsewhere within are hereby incoφorated herein by reference in their

entireties.

General transformations are well reviewed in "Comprehensive Organic

Transformation" by Richard Larock and the following series: "Organic Syntheses", Collective

Volumes 1 to 9, "Compendium of Organic Synthetic Methods" and "Reagents for Organic

Synthesis" by Fieser & Fieser. Protecting groups may be used when appropriate throughout

general and specific schemes of this invention. The choice and use of protecting groups is

well known in the art and is not limited to the specific examples bellow. A general reference

for protecting group preparation and deprotection is "Protecting Groups in Organic

Synthesis" by Theodora Green. The term "carboxy-protecting group" as used herein refers to one of the ester

derivatives of the carboxylic acid group commonly employed to block or protect the

carboxylic acid group while reactions are carried out on other functional groups of the

compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyl, 4-

methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl,

pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl,

2,2',4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-

dimethoxytrityl, 4,4',4"trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-

butyldimethylsilyl, 2,2,2-trichloroethyl, β-(trimethylsilyl)ethyl, β-(di(n-

butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl,

l-(trimethylsilyl)prop-l-en-3-yl and like moieties. The species of carboxy-protecting group

employed is not critical so long as the derivatized carboxylic acid is stable to the condition of

subsequent reaction(s) on other positions of the 1 -benzazepine molecule and can be removed

at the appropriate point without disrupting the remainder of the molecule. In particular, it is

important not to subject the carboxy-protected 1 -benzazepine molecule to strong nucleophilic

bases or reductive conditions employing highly activated metal catalysts such as Raney

nickel. (Such harsh removal conditions are also to be avoided when removing amino-

protecting groups and hydroxy-protecting groups, discussed below.) Preferred carboxylic

acid protecting groups are the allyl, tert-butyl and p-nitrobenzyl groups. Similar carboxy-

protecting groups used in the cephalosporin, penicillin and peptide arts can also be used to

protect a carboxy group substituents of the 1 -benzazepine.

As used herein, the term "amino-protecting group" refers to any group

typically used in the peptide art for protecting the peptide nitrogens from undesirable side reactions. Such groups include 3,4-dimethoxybenzyl, benzyl, p-nitrobenzyl, di-(p-

methoxyphenyl)methyl, triphenymethyl, (p-methoxyphenyl)diphenylmethyl, N-5-

dibenzosuberyl, trimethylsilyl, t-butyl dimethylsilyl and the like. Further descriptions of

these protecting groups can be found in "Protective Groups in Organic Synthesis" by

Theodora W. Greene, 1999, John Wiley and Sons, New York, N.Y.

General Schemes

In general the starting materials were obtained from commercial sources

unless otherwise indicated. The compounds of the present invention may be synthesized

from the key intermediate 3 shown in General Scheme A. Benzo-fused lactams 3 are

conveniently prepared from appropriately substituted α-tetralones which are, in some cases,

commercially available. In addition, substituted α-tetralones are well known in the art of

organic synthesis and numerous methods for their preparation are published. Conversion of

substituted α-tetralones 1 to benzo-fused lactams 3 can be achieved by a number of methods

proceeding via the intermediate, corresponding oxime 2, that may be isolated or used as is.

Suitable methods for transformation 1 to 3 involve the use of the Beckmann Rearrangement

or Schmidt reaction. The key intermediate 3 is then deprotonated with an inert base such as

LDA or Li-hexamethyl disilazide and the like. Typically such reactions are carried out in, for

instance, but not limited to THF, dioxane, ether at temperatures -78°C to 25°C. Numerous

electrophilic reagents can capture an anion, formed on α-position relative to amide

functionality. In some cases, the intermediate 4 may be again reacted with an inert base in an

inert solvent, followed by an attack of an electrophile to give disubstituted products on 3-

position of the 1- benzazepine-2-one ring. Subsequently, an alkyl group may be introduced on the hetero-atom as shown in General Scheme A. Typically bases may include, but are not

limited to Cs₂CO₃, K₂CO₃, NaH, KH while alkylating reagents would include, but are not

limited to ethyl bromide, ethyl iodide, diethyl sulfate, 2-bromoethanol and the like. Solvents

would include, but are not limited to acetonitrile, acetone, DMA, DMF and the like.

Alkylations of this kind are usually run at 25°C to 100°C. Thus obtained intermediate 5 may

represent a final NCE or may be further elaborated.

GENERAL SCHEME A In General Scheme B, the synthetic sequence for an appendage of an amino

functionality on aromatic ring of benzo-fused lactams is depicted. Intermediate 5 can be

halogenated on the aromatic ring using the methods well known in the art. Preferred halogens

are bromo, iodo and chloro because of the feasibility of the subsequent palladium catalyzed

coupling reaction. Typically bromination reagents would include, but are not limited to N-

bromosuccinimide, N-bromosuccinimide + co-reagent, N-bromoacetamide, bromine, bromine

+ co-reagent, pyridinium bromide perbromide and the like. Commonly, chloroform, carbon

tetrachloride, THF, dioxane, DMF, DMA, DMSO and the like are used as solvents at 25°C to

100°C. These reactions require 2 to 12 hours. Intermediate 6 is converted to intermediate 7

by using an analogous methodology to that of palladium catalyzed animation of aryl

bromides. Detailed reaction conditions for the latter coupling reactions are summarized in a

discussion of the Specific Scheme 3 (vide infra). The method employed is taken from

Sadighi J. P., et al. (1998) Tetrahedron Letters 39:5327. Displacement of a halogeno leaving

group includes, but is not limited to, nitrogen heterocycles. Other primary and secondary

alkyl/aryl amines would also displace Br, CI and I leaving groups. The 7-bromo of the

intermediate 6 is displaced preferentially using a nucleophilic amine such as piperazine,

methyl piperazine, tert-butyl 1- piperazinecarboxylate and benzyl 1-piperazinecarboxylate.

Co-bases such as K₂CO₃, Cs₂CO₃, NaOBu', KOBu', K₃PO₄ and the like are usually used to

capture hydrogen halides that are generated in the relevant reactions. This type of reaction is

performed in toluene, xylenes, acetonitrile, DMA, THF, DMF at 25°C to 120°C and requires 2

to 48 hours. In Schemes B and C, R₄Y represents a compound wherein R₄ is defined according to the invention and Y is a leaving group that allows R₄ to be inserted into the ring.

Y includes but is not limited to -SnBu₃ (tributyl tin), Sn(CH₃)₃ and -B(OH)₂.

X= Halogen ( Br )

GENERAL SCHEME B In addition to amination of the intermediate 6, carbocyles, aryls and

heteroaryls may also be introduced at X on the benzo-fused lactams ring when X is Br, I, CI

or triflate using palladium or cupric catalyzed couplings of tin or boronate carbocycles, aryls

and heteroaryls. The relevant methodologies are well known in the art and are described by

literature methods such as those published by Chan D.M.T., et al (vide infra); Kamikawa K.,

et al J. Org. Chem. 1998, 63, 8407-8410 and Stille, et al., Angew. Chem. Int. Ed.Eng.1986,

25,508. Recently reported advances in the field of Suzuki-type reactions include the

development of improved conditions for the coupling of arylboronic acids with aryl chlorides

catalyzed by either palladium or nickel complexes as reported in the following publications:

Tetrahedron Lett. 1997, 38, 5575; Tetrahedron Lett. 1997, 38, 3513; J. Org. Chem., 1997, 62,

8024.

Hydroxy, alkoxy and aryloxy groups may be introduced in 1 -benzazepine 2-

one system as shown in General Scheme C. It should be noted that groups R„ R₂, R₃ of the

starting compound 8 could be chosen from an array of groups or precursors thereof indicated

in the Structural Formula I and Formula II, wherever they are disclosed in this application.

When one of the substituents on the aromatic ring of the benzo- fused seven membered

lactam is a methoxy group it can be deprotected using BBr₃, BI₃, A1I₃, A1C1₃, A1C1₃ +NaSEt,

HBr/AcOH or any other appropriate reagent known in the deprotection art. Solvents such as

DCM, chloroform, toluene are generally employed in the latter deprotection reactions which

are run at ambient temperature to 70°C and require 2 hours to 48 hours. The resulting

hydroxyl group should be protected again in order to further embellish the intermediate 9

according to the synthetic steps that follow those of the General Scheme A. The dimethyl tert-butyl silyl protecting group of the intermediate 12 may be removed by

tetrabutylammonium fluoride or acid treatment.

GENERAL SCHEME C 14 An alkylation of 13 can be carried out with inert bases such as K₂CO₃, Cs₂CO₃,

NaHCO₃ and the like. Solvents are typically, but are not limited to dioxane, DMF, DMA, and

DMSO, acetone, acetonitrile and the like. Temperatures are 25°C to 125°C. Alkylating

reagents in the latter cases are limited to alkyl and substituted benzyl iodides and bromides.

In a transformation of 13 to 14 where R" equals aryl the use of the boronic

acids in forming a heteroatom-carbon bond has been employed. Indeed, intermediate 13

appears to be an appropriate substrate for O-arylations with phenylboronic acids and cupric

acetate as described by Evans, D. A., et al; in Tetrahedron Lett., 1998, 39, 2937-2940 and

Chan D. M. T., et al, in Tetrahedron Lett.1998, 39, 2933-2936. An alternative methodology

for O-arylations is an analogous method to that of the tertiary amine promoted reaction of N-

H bonds with triarylbismuth and cupric acetate. It is known in the art of organic synthesis that

phenylboronic acids are also efficient arylating agents and the relevant reaction represents a

relatively new, robust, and convenient methodology to arylate O-H and N-H bonds containing

compounds. Thus, using essentially the same reaction conditions as in the triarylbismuth

arylation as originally reported by Burton (Barton, D.H. R., et al; Tetrahedron Lett. 1987, 28,

887-890) one can in many cases replace the bismuth reagent with the corresponding

arylboronic acids. We believe that the latter reaction is broadly applicable to a large variety

of the substituted l-benzazepines-2-one substrates and is also very tolerant to many sensitive

functional groups. As in the bismuth arylation, the reaction can be performed under very mild

reaction conditions, i. e. room temperature and with an amine base. It should be noted that the

yield of the reaction can be quite dependent on the nature of the substrate and the substitution

on the boronic acid. The choice of the tertiary amine base, i.e., triethylamine versus pyridine also plays a critical role in determining the yield of the reaction. Arylboronic acids in place of

triarylbismuth represent an attractive alterantive in O-arylations since a large number of

organo boronic acids are either commercially available or their syntheses are well described

in the literature. Some arylboronic acids can be obtained from Aldrich Chem Coφ. or

Lancaster Synthesis Inc., and can be used without further purification.

The phenol type derivative 13 of substituted l-benzazepine-2-one can be

transformed into the corresponding triflate intermediate by any method known in the

protecting art. Subsequently, the intermediate 15 can be subjected to a coupling reaction with

a variety of the amines using Pd(0) catalyst mediated reactions. When the leaving group is a

triflate, organotin reagents and organoboronates may be used with palladium catalysts to

render a carbon nucleophile. In this way all sorts of alkyl, aryl and heteroaryl groups may be

introduced in the l-benzazepine-2-one ring as it was discussed before and indicated in the

General Scheme B.

In General Scheme D, synthetic methodologies to prepare l-benzazepines-2-

ones bearing an additional oxo group on 5-position and a double bond at different positions of

seven membered lactam ring are shown.

24

GENERAL SCHEME D Substituted anilines, exemplified by 17, serve as a starting material, which can

be alkylated by using reductive condensation with a variety of aldehydes (alkyl, aryl and

heteroaryl). It should be noted that the substituents R₃, R₄, R₅ of the starting aniline 17 can be

chosen from an array of groups that are indicated on the aromatic ring in the Structural

Formula I or Formula II, wherever they are disclosed in the specification. Reductive

animations are well known in the art and are typically performed in alcohols, water/alcohol

mixtures or in water/DMF mixtures at temperatures 25°C to 80°C. Thus obtained N-alkylated

anilines can be further acylated using any 3-chloro 3-oxopropionate (alkyl/benzyl malonyl

chloride) as a reagent of choice to synthesize the intermediate 19 as shown in General

Scheme D. The ester group of the intermediate 19 can be later in the synthesis transformed

into carboxyl, amino carbonyl or hydroxymethyl group. The 19-type intermediates are very

well known in the chemistry of quinolones. Elongation of a carbon chain on the hetero-atom

with tert-butylbromoacetate, for instance, provides an appropriate substrate for a subsequent

Friedel Crafts reaction. Typically these reactions are run in the presence of inert bases such as

LDA, Li-hexamethyl disilazide and the like. Solvents would typically include THF, ether, 1,4

-dioxane and DMF at temperatures -78°C and 25°C.

A cyclization of 20 can be achieved by a number of methods well known in

the literature as Friedel-Crafts reaction. A cyclization of 20 to 21 can be effected, for instance,

in one pot reaction via the mixed anhydride formed with triflic acid. Introduction of a double

bond is exemplified but not limited to a conversion of 21 to 22. Dehydrogenation of the

intermediate 21 can be carried out using diphenyl diselenide+ LDA, phenylselenyl chloride,

DDQ, benzeneselenic anhydride, formed in situ, selenium dioxide in water or any appropriate reagent known in the dehydrogenation art. Typically solvents would include dioxane, THF,

benzene, chlorobenzene, acetic acid, ethanol at temperatures 25°C to 120°C. These latter

reactions usually require 2 hrs to 48 hours.

When a prolongation of the chain on the hetero-atom of the intermediate 19 is

effected by using bromoacetaldehyde ethylene acetal, for instance, in the presence of inert

bases such as LDA or Cs₂CO₃ the intermediate 23 is obtained. Subsequent cyclizatin of 23,

followed by a dehydration in strong acidic reaction conditions affords the desired compound

24. Typically strong acids would include p-toluene sulfonic acid or PPA at elevated

temperatures. 24 can be considered a NCE or an intermediate that can be further embellished.

Specific compounds depicted by a general Formula I or Formula II, wherever

they are disclosed in the specification, of the present invention can be prepared from 8-

methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (3A) as a common intermediate. The

preparation of some key intermediates and final NCEs are described in the following reaction

schemes: Schemes 1, 2, 3, 4, 5, and 6. The syntheses of some intermediates in this instant

invention are described in a narrative way.

8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (3A) is conveniently

prepared from 7-methoxy-l-tetralone (1A), using known procedures described by Eaton, et

al, J. Org. Chem. (1973) 38, 4071. 7-Methoxy-l-tetralone, which is commercially available,

was transformed to 8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (3A) via the

corresponding oxime (2A) followed by the Beckmann rearrangement as illustrated in Scheme

1. The Beckmann rearrangement can be achieved by a number of methods well known in the

literature, including treatment of 7-methoxy-l-tetralone oxime (2 A) with methanesulfonic

acid and anhydrous phosphorous pentoxide at elevated temperatures.

Scheme 1 8-Hydroxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one was designed to

investigate utility of boron tribromide as a deprotective agent for the l-benzazepine-2-one

substrate bearing methoxy group. Deprotection of 8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one using BBr₃ in DCM was successful. Other substituted l-benzazepine-2-

ones bearing the methoxy functionality are deemed to be subjected to the above-mentioned

deprotection. Therein also lies a problem- applicability of this deprotection reaction

conditions to 8-methoxy-l-benzazepine-2-ones bearing tert-butoxycarbonyl group.

Conversion of 8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (3A) to

the 3-ethoxycarbonyl intermediate (4A) can be achieved by a number of methods familiar to

those skilled in the art. A suitable method involves use of LDA and diethyl carbonate or

diethyl pyrocarbonate. It was observed that carboxylation easily occurred on unprotected 8-

methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (3A) while the same reaction failed

when l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one was employed as a

starting material. 3(R,S)-Ethoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-

one (4A) was protected on the hetero-atom using iodoethane as an alkylating agent in a

cesium carbonate mediated reaction. A saponification of l-ethyl-3(R,S)-efhoxycarbonyl-8-

methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (5A) in basic reaction conditions

afforded the desired NCE, 3(R,S)-carboxyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one (6A).

When 3 (R,S)-ethoxycarbonyl-8-methoxy-2,3 ,4,5 -tetrahydro- 1 H- 1 -

benzazepine-2-one (4 A) was treated with two equivalents of sodium hydride as a base and

iodoethane as an alkylating reagent dialkylation was observed resulting in a formation of 1,3- diethyl-3(R,S)-ethoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (7A)

as illustrated in Scheme 2. Further saponification in basic reaction conditions produced 1,3-

diethyl-3(R,S)-carboxyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (8A).

4M K₂C0₃

MeOH/H₂0 reflux

8A

Scheme 2 As shown in Scheme 3, 8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-

one (3A) was alkylated using iodoethane as an alkylating reagent and one equivalent of

sodium hydride as a base to provide l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-

2-one (9 A). A bromination in methanol at ambient temperature using bromine as a

brominating agent afforded exclusively 7- bromo regioisomer (10 A) which was transformed

further employing a catalytic cross coupling methodology. This coupling reaction was

conveniently carried out by use of 4- methylpiperazine as a reagent, BINAP as a chelating

reagent, palladium acetate as a catalyst in the presence of cesium carbonate as a base.

3A Br₂

11 A

Scheme 3 Synthesis of 3(R,S)-carboxyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one (6A) and 3(R,S)-carboxyl-l-ethyl-8-methoxy-7-piperazinyl-2,3,4,5-

tetrahydro-lH-l-benzazepine-2-one (6B) have been designed in such a manner that a

common route proceeds via the intermediacy of 8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one (3A). In this particular reaction sequence as illustrated in Scheme 4, 8-

methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (3A) was transformed to the 3(R,S)-

ethoxycarbonyl (2B) and 3-tert-butoxycarbonyl (IB) derivatives of their common precursor

using diethyl pyrocarbonate or di-tert-butyl carbonate, respectively. 3(R,S)-tert

Butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (IB) was chosen as a

preferable intermediate over its ethyl ester counteφart due to a higher yield in the relevant

carboxylation step. Furthermore, it is a common knowledge that tert-butyl ester groups are

easier to be removed than ethyl ester groups. A protection of the heteroatom was effected by

using iodoethane as an alkylating reagent in a cesium carbonate mediated reaction.

R=»Et 34% 2B

l-tert-Butoxycarbonyl-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-

tetrahydro-lH-l-benzazepine-2-one was obtained in a low yield as a side product in a

synthesis of 3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-

one. To improve the yield in a synthesis of l-tert-butoxycarbonyl-3(R,S)-tert-

butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydiO-lH-l-benzazepine-2-one, 3(R,S)-tert-

butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one was exposed to di-

tert-butyl dicarbonate in a cesium carbonate or sodium hydride mediated reaction. Indeed, the

desired l-tert-butoxycarbonyl-3(R,S)-tert-butoxycarbonyl-8-r ethoxy-2,3,4,5-tetrahydro-lH-

l-benzazepine-2-one was obtained in good yield.

A synthesis of 3-tert-butoxycarbonyl-l-(3-fluorobenzyl)-8-methoxy-2,3,4,5-

tetrahydro-lH-l-benzazepine-2-one demonstrated that substituted l-benzazepine-2-ones are

appropriate substrates for benzylic alkylation on the hetero-atom.

A bromination of 3(R,S)-tert-butoxycarbonyl-l-ethyl-8-methoxy-2,3,4,5-

tetrahydro-lH-l-benzazepine-2-one (3B) using N-bromosuccinimide as a brominating

reagent in the presence of a catalytic amount of acetic acid produced exclusively 7-bromo

regioisomer (4B). The same bromination procedure was used to synthesize the 7-bromo

derivatives of 3(R,S)-tert-butoxy carbonyl-l-(3-fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-

1 H- 1 -benzazepine-2-one and 3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3 ,4,5-tetrahydro- 1 H-

l-benzazepine-2-one. A formation of 7-bromo-3(R,S)-tert-butoxycarbonyl-8-mefhoxy-

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one indicated that a bromination of l-benzazepine-2-

one skeleton could be performed although the heteroatom is unprotected. Bromination of 8-

methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one with NBS and a catalytic amount of benzoyl peroxide (BPO) in carbon tetrachloride resulted in 7-bromo-8-methoxy-2,3,4,5-

tetrahydro- 1 H- 1 -benzazepine-2-one.

Conversion of 7-bromo-3(R,S)-tert-butoxy-carbonyl-l -ethyl-8-methoxy-

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (4B) to the requisite 7-piperazinyl derivative can

be achieved by a number of cross coupling methodologies familiar to those skilled in the art

including that described by L. Buchwald, et al, Tet. Lett. (1998) 39, 5327-5330. The

chelating ligand BINAP in combination with palladium acetate forms a highly effective

catalyst system for the coupling of anilines with aryl bromides. This catalyst system is

effective in coupling reactions involving a variety of substrates, including electron poor

anilines or electron-rich aryl bromides. In addition, this cross coupling reaction tolerates a

high degree of steric congestion at both aniline and aryl bromide. We have employed the

latter cross coupling methodology for the coupling of piperazine/protected piperazine with an

electron rich arylbromide moiety, which probably exhibits steric congestion at the reactive

site imposed by a bulky ortho methoxy group. Precisely, a cross coupling of 7-bromo-

3 (R,S)-tert-butoxycarbonyl- 1 -ethyl-8-methoxy-2,3 ,4,5 -tetrahydro- 1 H- 1 -benzazepine-2-one

(4B) with 1-tert-butoxycarbonyl-piperazine in the presence of BINAP as a chelating reagent,

palladium acetate as a catalyst and sodium tert-butoxide as a base gave 3(R,S)-tert-

butoxycarbonyl-7-[(4-tert-butoxycarbonylpiperazine)-l-yl]-l-ethyl-8-methoxy-2,3,4,5-

tetrahydro-lH-l-benzazepine-2-one (5B) as a penultimate precursor of the desired NCE.

Deprotection of piperazine moiety of the molecule and removal of tert-butyl ester group in a

one pot reaction using a concentrated solution of hydrochloric acid in dioxane provided

3(R,S)-carboxyl-l-ethyl-8-methoxy-7-piperazinyl-2,3,4,5-tetrahydro-lH-l-benzazepine-2-

one hydrochloride salt (6B). Furthermore, utilization of 1-benzyloxycarbonylpiperazine as a secondary amine component in the former cross coupling reaction offered 7-[(4-

benzyloxycarbonyl)piperazin- 1 -yl]-3(R,S)-tert-butoxycarbonyl- 1 -ethyl-8-methoxy-2,3 ,4,5-

tetrahydro- IH- 1 -benzazepine-2-one when 7-bromo-3(R,S)-tert-butoxycarbonyl- 1 -ethyl-8-

methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one was used as a starting compound. Thus,

a strategy of cross coupling of a piperazine/protected piperazine with an electron rich hetero-

arylbromide has considerable flexibility to vary structure and should be a versitile route to the

preparation of biologically active anti-infectives using automatic parallel syntheses. A

synthesis of l-ethyl-8-methoxy-7-piperazinyl- 2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

hydrochloride was executed via 7-[(4-tert-butoxycarbonylpiperazin)-l-yl]-l-ethyl-8-

methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one as an immediate precursor.

7-[(4-Benzyloxycarbonyl)piperazin-l-yl]-3-tert-butoxycarbonyl-l-(3-

fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one has been thus far the

most complex ring system in our development of new strategies for syntheses of the 1-

benzazepine anti-infectives.

When 3(R,S)-tert-butoxycarbonyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-

l-benzazepine-2-one (3B) was treated with N-bromosuccunimide in the presence of a

catalytic amount of benzoyl peroxide at elevated temperature, a bromination probably

occurred at the benzylic position as illustrated in Scheme 5. A consequent elimination of HBr

afforded 3(R,S)-tert-butoxycarbonyl-l-ethyl-8-methoxy-2,3-dihydro-lH-l-benzazepine-2-

one (7B).

7B

3B

Scheme 5

Several derivatives of 7-bromo-3(R,S)-tert-butoxycarbonyl- 1 -ethyl-8-

methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (4B) were prepared as depicted on

Scheme 6. Removal of an ester group using concentrated trifluoroacetic acid at ambient

temperature afforded 7-bromo-3(R,S)-carboxyl- 1 -ethyl-8-methoxy-2,3,4,5-tetrahydro- 1 H- 1 -

benzazepine-2-one (8B). A cross coupling reaction of 7-bromo-3(R,S)-tert-butoxycarbonyl-

l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (4B) with piperazine in the

presence of BINAP as a chelating reagent, palladium acetate as a catalyst and cesium

carbonate as a base gave 3(R,S)-tert-butoxy carbonyl-l-ethyl-8-methoxy-7-piperazinyl-

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (9B). A low yield in this cross coupling reaction

was due to a formation of l,4-di-[(3(R,S)-tert-butoxycarbonyl-l-ethyl-8-methoxy-2-oxo-

2,3,4,5-tetrahydro-lH-l-benzazepine)-7-yl]-piperazine (10B). Saponification of 1,4-di-

[(3(R,S)-tert-butoxycarbonyl-l-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-lH-l-

benzazepine)-7-yl]-piperazine using concentrated trifluoroacetic acid as a deprotecting

reagent produced l,4-di-[(3(R,S)-carboxyl-l-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-lH-

1 -benzazepine)-7-yl] -piperazine (1 IB).

Scheme 6 When 7-bromo-3(R,S)-tert-butoxycarbonyl-l-ethyl-8-methoxy-2,3,4,5-

tetrahydro-lH-l-benzazepine-2-one was treated with bromine in MeOH at ambient

temperature, bromination occurred at 3-position of the l-benzazepine-2-one ring system. In

addition, a transesterification due to the presence of methanol was observed which resulted in

a formation of 7-bromo-3(R,S)-methoxycarbonyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-

1 -benzazepine-2-one.

Replacement of an ester functional group by an aminocarbonyl group in the

substituted l-benzazepine-2-one system has been successfully employed in a synthesis of 7-

bromo-3(R,S)-N-(tert-butyl)aminocarbonyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one. The latter compound was synthesized by a coupling reaction of 7-bromo-

3(R,S)-carboxyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one with tert-

butyl amine using l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride

(EDCiyi-hydroxybenzotriazole (HOBT) and triethylamine as reaction mediators. A series of

N-terminal groups of the aminocarbonyl functionality are under investigation. This amide

bond formation offers a possibility of the use of an appropriately protected amino acid as an

amino component. In addition, it is perceived that this coupling strategy could be used to

introduce a peptidomimetic side chain on 3-position of the l-l-benzazepine-2-one ring

system including hydrophobic spacers, such as substituted 4-aminobenzoyl group.

The compounds of this invention, herein referred to as l-benzazepine-2-one

ureas and thioureas, encompass any of a variety of l-benzazepine-2-ones having a urea or

thiourea containing substitutent at any position on the aromatic ring of l-benzazepine-2-one skeleton. In general, l-benzazepine-2-one ureas and thioureas can be synthesized according

to a general procedure depicted in General Scheme E.

ROCONCX X=0,S

General Scheme E

EXAMPLES

The following specific examples are provided for the puφose of further

illustration only and are not intended to limit the disclosed invention.

Melting points were measured with Mel-Temp melting point apparatus and

were uncoπected.

Η and ¹³C NMR spectra were recorded on Varian VXR 4000 in

deuterochloroform(CDCl₃) with chloroform as an internal reference or in deuterated DMSO

(DMSO-d₆) with DMSO as an internal reference unless noted otherwise. 'H and ¹³C chemical

shift assignments are based on detailed analysis of two dimensional or decoupled spectra

when necessary. 'H spectra were recorded at 400, usually 3.7 sec. acquisition time. ¹³C

spectra were recorded at 100MHz, 1.1 sec acquisition time. DEPT spectra were recorded at

400 MHz using 135 degree Η read pulse, usually 256 or 512 transients, 4 sec relaxation delay

containing homospoil pulse.

Samples analyzed by GC-MS were acquired using Finnigan 4500 single

quadrropole mass spectrometer utilizing electron impact (El) ionization; samples analyzed

using direct probe El ionization or fast atom bombardment (FAB) ionization were acquired

using a VG 70 SQ high resolution double- focusing magnetic sector instrument (EB

geometry); and samples analyzed by electrospray ionization were acquired on a VG Trio 3

triple quadropole mass spectrometer.

TLC was performed on EM Reagents precoated Silica Gel 60 F-254 analytical

plates (0.25 mm). Normal phase flash column chromatography was performed on ICN Silica,

6θA (18-32 Mesh, 32-63 Mesh). Normal phase gravity chromatography was performed on

ICN Silica, 6θA (63-200 Mesh). Purity and homogeneity of all materials were determined chromatographically, from MS, 'H and ¹³C NMR or combustion analysis. THF was distilled

from sodium-benzophenone ketyl. Other reagents were obtained commercially and used as

received unless otherwise specified. All reactions were performed under a static argon or

nitrogen atmosphere in flame/oven dried glassware. Elemental analyses were performed by

QTI Whitehouse, New Jersey.

Example 1

7-Methoxy-l-tetralone oxime,

Method A.

A mixture of 7-methoxy-l-tetralone (500 mg, 2.84 mmol), hydroxylamine sulfate (492 mg,

2.99mmol) and anhydrous pyridine (20ml) was heated at 100°C under argon. The course of

the reaction was monitored by TLC (THF 3: n-hexane 7). After 5.5 hours the reaction mixture

was allowed to cool to room temperature and poured on crushed ice (30 ml). pH of the

resulting solution was adjusted to 3.5 with cone, solution of HC1 at 0° C. After cooling the

resulting suspension in an ice bath for 4 hours, the precipitate was collected by filtration to

yield first crop of the crude product. The corresponding filtrate was extracted three times with

chloroform, the combined organic extracts washed with brine and dried over anhydrous

magnesium sulfate. After removing the drying agent the solution was evaporated under

reduced pressure to dryness. Thus obtained second crop was combined with first crop to yield

crude 7-methoxy-l-tetralone oxime (382mg) that was dried in a desiccator over P₂O₃ under

vacuum at ambient temperature for 12 hours. The crude product was purified by silica gel

gravity chromatography using 20% THF in n-hexane as an eluent to give 331 mg (61% yield)

of white crystalline product. Method B

The title compound was prepared by the same procedure as stated above: Reaction of 7-

methoxy-1-tetralone (10.00 g, 56.8 mmol) with (H₂NOH)₂H₂SO₄ (9.84 g, 59.8 mmol) in

anhydrous pyridine (200 mL) provided a crude product which was recrystallized from a

solvent mixture of hexane/chloroform (1 : 1). The final product was obtained as a white

crystalline product (9.43 g, 87%).

M.P.= 80°-82° C.

C_πH₁₃NO₂ (191.23): MS (FAB, NBA) m/e 192 (M+ H) ⁺.

This product was also analyzed by Η and ¹³C NMR. The corresponding NMR spectra were

consistent with the structure of the anticipated product.

Example 2:

8-Methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Method A

To a vigorously stirred neat methanesulfonic acid, (25ml) phosphorus pentoxide (2.83g, 10

mmol) was added under a stream of argon. The resulting reaction mixture was vigorously

stirred and heated at 100°C for an hour. After the reaction mixture was allowed to cool to

ambient temperature 7-methoxy-l-tetralone oxime (300 mg, 1.57 mmol) was added as a dry

powder under a stream of argon. The resulting reaction mixture turned immediately from

colorless to dark brown solution that was vigorously stirred and heated at 100°C for 30 min.

After cooling the reaction mixture at 0°C for 30 min it was neutralized with a saturated

solution of sodium hydrogencarbonate. The resulting suspension was stirred at 0°C for 4 hours and the precipitate collected by filtration to give first crop of a crude product. The

corresponding filtrate was extracted three times with chloroform, the combined organic

extracts washed with brine and dried over anhydrous magnesium sulfate. After removing the

drying agent the solution was evaporated under reduced pressure and thus obtained second

crop was combined with first crop to yield 271 mg of a crude product. A silica gel flash

chromatography using 20% THF in n-hexane as eluent produced 210 mg (70% yield) of beige

crystalline product.

Method B

The title compound was prepared by the same procedure as stated above. The reaction of 7-

methoxy-1-tetralone oxime (9.00 g, 47.1 mmol) and P₂O₅ (11.00 g) in methanesulfonic acid

(100 mL) gave a crude product which was purified by flash chromatography on silica column

with EtOAc/hexane (7:3) as an eluent. Purification procedure provided 6.56 g (73%) of the

desired intermediate and 0.27 g of the recovered starting material.

M.P.= 105° - 106° C

C_HH₁₃NO₂ (191.23); MS (El +) m/e 191(M)+

consistent with the structure of the anticipated product.

Example 3:

3(R,S)-Ethoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Method A To a solution of 8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (300 mg, 1.6 mmol)

in THF(25 ml) at -78°C was slowly added a solution of LDA (1.8 ml, 3.52 mmol, 2M

solution of LDA in heptane/THF/ethylbenzene). The resulting reaction mixture was

vigorously stirred at -78°C under stream of argon for 30 min and then at -5°C for 45 min.

After this reaction period a solution of diethyl carbonate in THF (3.4 ml, c= 136 mg/ml.) was

added at -5°C and the reaction mixture was stirred at -5°C for 20 min and allowed to warm to

ambient temperature. The reaction mixture was stirred for three hours before quenching with

saturated aqueous ammonium chloride. Extraction of aqueous phase with a solvent mixture of

THF and ether (20% THF in ether), washing the combined extracts with saturated solution of

ammonium chloride and brine, drying and solvent evaporation gave a beige crude product. A

flash chromatography of a crude product on silica gel column with 30% THF in n- hexane as

an eluent produced 119mg (28%) of a white solid.

Method B

An oven-dried flask was charged with 8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

(0.976 g, 5.10 mmol) and anhydrous THF (30 mL). 1.9 M LDA in heptane/THF/ethylbenzene

(5.90 mL, 11.24 mmol) was added dropwise via syringe at -78°C under the protection of

argon. The reaction mixture was allowed to warm up to room temperature, stirred for 1.5 hrs

and cooled down to -78°C again. A solution of diethyl pyrocarbonate (0.93 mL, 6.12 mmol)

in anhydrous THF (5 mL) was added dropwise. After being stirred at -78°C for 2 hrs and at

room temperature for 1.5 hrs, the reaction mixture was quenched with saturated aqueous

solution of NH₄C1 (3 mL) and evaporated under reduced pressure. The residue was dissolved

in dichloromethane, washed with water and dried over MgSO₄. A purification of the crude product by flash chromatography on silica column with EtOAc/hexane (7:3) as an eluent

provided 0.45 g (34%) of the desired compound as an oil that gradually crystallized at 0°C

over an extended period of time.

M.P .= 89-91° C

C₁₄ H₁₈ N O₄ (264.29) MS (El +) m/e 264(M)+

consistent with the structure of the anticipated product.

Example 4:

3(R,S)-Ethoxycarbonyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

A suspension of 3(R,S)-ethoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-

one (0.45 g, 1.71 mmol), ethyl iodide (0.41 mL, 5.1 mmol) and Cs₂CO₃ (1.672 g, 5.1 mmol)

in acetonitrile (5 mL) was stirred at room temperature for 6 hrs. The reaction mixture was

filtered and the solid was washed with acetonitrile. The combined filtrate and washer were

evaporated under reduced pressure. The crude product was purified by flash chromatography

on a short silica gel column using EtOAc/hexane (3:7) as an eluent. The title compound

(0.241 g, 48%) was obtained as an oil.

B.P.>200°C

C₁₆ H₂₁ N O₄ (291.35); MS (El) m/e 291 (M⁺).

This product was also analyzed by 'H and ¹³C NMR. The corresponding NMR spectra were

consistent with the structure of the anticipated product. Example 5:

3(R,S)-Carboxyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

A solution of 3(R,S)-ethoxycarbonyl- 1 -ethyl-8-methoxy-2,3 ,4,5 -tetrahydro- 1 H- 1 -

benzazepine-2-one (90 mg, 0.31 mmol) in 1M KOH in 90% MeOH (1.5 mL) was refluxed

overnight. The course of the reaction was monitored by TLC. Then, pH of the reaction

mixture was adjusted to 4.0 with HCl/MeOH solution (10%(V) cone. HCl in MeOH ), filtered

and evaporated. The residue was dissolved with DCM (30mL), dried over MgSO₄, filtered

and evaporated to dryness. Thus obtained solid residue was washed with hexane and dried

over P₂O₅ in vacuum. The desired product (73 mg, 90%) was obtained as white powder.

M.P= 120 -121°C.

C₁₄ H₁₇ N O₄(263.10); MS (El) m e 263 (M⁺)

consistent with the structure of the anticipated product.

Example 6:

l,3-Diethyl-3(R,S)-ethoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-

one

A mixture of 3(R,S)-ethoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

(260 mg, 1 mmol), NaH (60 mg, 2.5 mmol), Etl (400 μl, 5 mmol) and anhydrous DMF (25

ml) was stirred at room temperature under argon for 18 hrs. After this reaction period the

reaction mixture was evaporated under reduced pressure to dryness. Ice cold water was added

and the resulting emulsion/suspension was stirred at 0°C for 20 min. Organic phase was

extracted with a mixture of THF and ether (20% THF in ether) and the combined extracts

were washed with 2% solution of HCl and brine. After drying over magnesium sulfate the solution was evaporated to dryness. Thus obtained crude product was purified by flash

chromatography to yield 230 mg (73%) of white solid.

M.P.= amoφhous compound

C₁₈ H₂₅ N O₄ (319.41); MS (El ⁺) m/e 319(M)⁺

This product was also analyzed by 'H and ^l3C NMR. The corresponding NMR spectra were

consistent with the structure of the anticipated product.

Example 7:

3(R,S)-Carboxyl-l,3-diethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

A mixture of 3(R,S)-ethoxycarbonyl-l,3-diethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one (200 mg, 0.63 mmol), potassium carbonate (3.5 g, 25mmol), and 50%

methanol (20 ml) was refluxed for 48 hrs. The resulting reaction mixture was cooled at 0°C

and pH adjusted to 3.5 with a methanolic solution of HCl (30% (V) cone. HCl in methanol).

The precipitate was collected by filtration, the filter cake washed with methylene chloride and

the corresponding filtrate evaporated to dryness. This crude product was purified by gravity

chromatography on Floresil using gradient elution starting with 5% methanol in chloroform

followed by 10% methanol in chloroform. 139 mg (76%) of white amoφhous solid was

obtained.

M.P.: amoφhous compound

C₁₆ H₂₁ N O₄ (291.35); MS (FAB, NBA) m/e 292 (M+ H)⁺.

consistent with the structure of the anticipated product. Example 8:

l-Ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

A mixture of 8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (2.6g, 13.6 mmol), NaH

(648 mg, 27 mmol) and iodoethane (3ml, 37 mmol) in anhydrous DMF (50 ml) was

vigorously stirred and heated at 100°C for one hour. The reaction mixture was evaporated

under reduced pressure to dryness and the residue dissolved in 100 ml ice-cold water. The

resulting brown emulsion was extracted three times with chloroform, the combined extracts

were washed with 2% solution of HCl and brine. The organic phase was treated with

decolorizing carbon, stiπed at room temperature for an hour and filtered through Celite. After

drying over anhydrous magnesium sulfate the filtrate was evaporated to dryness. The residual

oil was purified by gravity column chromatography on silica gel using 30% THF in n-hexane

as an eluent to yield 2.2 g (74%) of the desired compound as a pale yellow oil.

B.P.> 200°C

C₁₃H₁₇NO₂ (219.29); MS (FAB, NBA) m/e 318 (M+H) ⁺.

consistent with the structure of the anticipated product.

Example 9:

7-Bromo-l -ethyl-8-methoxy-2,3,4,5-tetrahydro-l H-l -benzazepine-2-one

A mixture of l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (200 mg, 0.91

mmol) and bromine (581 mg, 3.64 mmol) in anhydrous methanol was stirred at room

temperature for an hour. After this reaction period the reaction mixture was diluted with 150

ml of methanol and treated with decolorizing carbon. After stirring the reaction mixture at ambient temperature for an hour it was filtered through celite, evaporated under reduced

pressure to dryness. The crude residue was dissolved in ice-cold water and extracted with a

solvent mixture of THF and ether (20% THF in ether). The combined organic extracts were

washed with 5% solution of sodium hydrogencarbonate and brine. After drying the organic

phase over magnesium sulfate it was evaporated to dryness and the crude product purified by

gravity chromatography using 30% THF in n-hexane as an eluent. 220 mg (81%) of pure

product was obtained as a white crystalline solid.

M.P.= 133-135°C; C₁₃H₁₆BrNO₂ (298.18); MS (EI⁺) m/e 298(M)⁺

consistent with the structure of the anticipated product.

Example 10:

l-Ethyl-8-methoxy-7-[(4-methylpiperazin)-l-yl)]-2,3,4,5-tetrahydro-lH-l-benzazepine-

2-one

A mixture of 7-bromo-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (200

mg, 0.67 mmol), BINAP (50 mg, 0.08 mmol), palladium acetate (12 mg, 0.053 mmol),

cesium carbonate (238 mg, 0.73 mmol) in 3ml of anhydrous toluene was heated at 100°C

under strictly inert atmosphere for 24 hours. After this reaction period the reaction mixture

was diluted with 100 ml of methanol and filtered through Celite. The filtrate was evaporated

to dryness and the crude product purified by flash chromatography on silica gel column using

5% methanol as an eluent. 118 mg (56%) of pure product was obtained as an off- white

crystalline solid.

M.P.= 138-140°C C_lgH₂₇N₃O₂ (317.44); MS (FAB, NBA) m/e 318 (M+ H)⁺.

consistent with the structure of the anticipated product.

Example 11:

3(R,S)-ι'ert-Butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

(0.956 g, 5.00 mmol) and anhydrous THF (30 mL). 1.9 M LDA in heptane/THF/ethylbenzene

(5.79 mL, 11.00 mmol) was added dropwise at -78°C under argon. The reaction mixture was

then allowed to warm to room temperature, stirred for 1.5 hrs and cooled to -78°C again. A

solution of di-tert-butyl dicarbonate (1.09 g, 5.00 mmol) in anhydrous THF (5 mL) was

added dropwise through a syringe. After stirring the reaction mixture at -78°C for 1.5 hrs, it

was allowed to warm to ambient temperature, quenched with saturated aqueous solution of

NH₄C1 (5 mL) and evaporated to dryness under reduced pressure. The crude product was

dissolved in dichloromethane, washed with water and dried over anhydrous Purification by flash chromatography on silica column eluted with EtOAc/n-hexane (3:7 -

5:5) provided the desired compound (0.537 g, 53%) as white powder and recovered starting

material (0.294 g, conversion 69%).

M.P.: 145-147°C; C₁₆H₂₁NO₄(291.35); MS (FAB, NBA) m e 292 (M+ H)⁺

consistent with the structure of the anticipated product. Example 12:

3(R,S)-te/-t-Butoxycarbonyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-

one

A suspension of 3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one (3.645 g, 12.51 mmol), ethyl iodide (2.01 mL, 25.02 mmol) and Cs₂CO₃

(8.153 g, 25.02 mmol) in acetonitrile (35 mL) was stiπed at room temperature for 6 hrs. The

reaction mixture was evaporated to dryness, the residue dissolved in water and extracted with

DCM. The organic layer was washed with water, dried over filtered and evaporated

to dryness. The solid residue was washed with n-hexane and dried in vacuum. The desired

compound (3.50 g, 88%) was obtained as white crystalline powder.

M.P.: 132 - 133°C; C₁₈H₂₅NO₄(319.40); MS (FAB, NBA) m/e 320 (M+ H)⁺

consistent with the structure of the anticipated product.

Example 13

7-Bromo-3(R,S)-teri'-butoxycarbonyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one

A solution of 3(R,S)-tert-butoxycarbonyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one (3.38 g, 10.58 mmol) and N-bromosuccinimide (2.072 g, 11.64 mmol) in

acetic acid (2.5 mL) and chloroform (25 mL) was heated at reflux for 2 hrs. The reaction

mixture was diluted with chloroform (25 mL), washed with saturated aqueous solution of

NaHCO₃ and water, dried over Na^O^ filtered and evaporated to dryness. Purification of the

crude product by flash chromatography on silica gel column eluted with EtOAc/hexane (3:7)

provided the desired compound (3.25 g, 77%) as white powder. M.P.:131-132°C.

C₁₈H₂₄BrNO₄(398.30); MS (El) m/e 398 (M⁺).

consistent with the structure of the anticipated product.

Example 14:

3(R,S)-tert-Butoxycarbonyl-7-[(4-terι'-butoxycarbonyl-piperaziιι)-l-yl]-l-ethyl-8-

methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

An oven-dried flask was charged with 7-bromo-3(R,S)-tert-butoxycarbonyl-l-ethyl-8-

methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (1.20 g, 3.00 mmol), tert-butyl-1-

piperazinecarboxylate (0.67 g, 3.60 mmol), Pd(OAc)₂ (33.6 mg, 0.150 mmol, 5 mol %),

BINAP (140.2 mg, 0.225 mmol) and purged with argon for 5 min. Anhydrous toluene (15

mL) was added through a syringe, resulted in a clear yellowish solution. Sodium tert-

butoxide (0.40 g, 4.2 mmol) was added in one portion as a dry powder. After purging with

argon for 3 min, the reaction mixture was heated and vigorously stirred at 100°C for 2 hrs.

The course of the reaction was monitored by TLC. The reaction mixture was diluted with

DCM (20 mL), washed with water, dried over anhydrous Na_jSO^ filtered and evaporated to

dryness. The crude product was purified by flash chromatography on silica column eluted

with MeOH/DCM (1:19). Thus obtained solid was further purified by crystallization from

chloroform/EtOAc (1 :3) to afford the desired compound (1.34 g, 89%) as a white crystalline

product.

M.P.: 135-137°C. C₂₇H₄₁N₃O₆ (503.65); MS (FAB) m/e 504 (M+l)⁺

This product was also analyzed by Η and ¹³C NMR. The coπesponding NMR spectra were

consistent with the structure of the anticipated product.

Example 15:

3(R, S)-Carboxyl-l-ethyl-8-methoxy-7-(piperazin-l-yl)-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one hydrochloride

3(R,S)-tert-butoxycarbonyl-l-ethyl-8-methoxy-7-[(4-tert-butoxycarbonylpiperazin)-l-yl]~

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (0.50 g, 0.993 mmol) was added portionwise to a

solution of 4 M HCl in 1,4-dioxane (6 mL) at 0°C . After stirring the reaction mixture at room

temperature for 3 hrs it was cooled at 0°C. Precipitation of the product was effected by adding

anhydrous ether (15 mL). The precipitate was collected by filtration, washed with anhydrous

ether and dried in vacuum. The desired compound (378 mg, 91%) was obtained as a white

powder.

M.P.: 173-176°C (decomp).

C₁₈H₂₅N₃O₄ (347.42); MS (FAB) m/e 348 (M+l)⁺

consistent with the structure of the anticipated product. Example 16:

3(R,S)-tert-Butoxycarbonyl-l-ethyl-8-methoxy-2,3-dihydro-lH-l-benzazepine-2-one

A mixture of 3 (R,S)-tert-butoxycarbonyl- 1 -ethyl-8-methoxy-2,3 ,4,5 -tetrahydro- 1 H- 1 -

benzazepine-2-one (0.80 g, 2.51 mmol) and N-bromosuccinimide (0.49 g, 2.76 mmol) in

chloroform (20 mL) was heated at reflux for 5 hrs. The resulting reaction mixture was washed

with saturated aqueous solution of NaHCO₃ and water, dried over anhydrous Na^O^ filtered

and evaporated to dryness. The crude product was purified by flash chromatography on silica

gel column eluted with EtOAc/n-hexane (3:7). The fractions containing the fast running

component were collected and evaporated to dryness. The desired compound (60 mg, 8%)

was obtained as a white crystalline powder.

M.P.:173-174°C

C₁₈H₂₁NO₄(317.38); MS (FAB) m/e 318 (M+l)⁺.

This product was also analyzed by H and ¹³C NMR. The coπesponding NMR spectra were

consistent with the structure of the anticipated product.

Alternative procedure to prepare 3-tørt-Butoxycarbonyl-l-ethyl-8-methoxy-2,3-dihydro-

1 H-l -benzazepine-2-one

A three-necked flask, equipped with reflux condenser, was charged with 3-tert-

butoxycarbonyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (4.0 g, 12.52

mmol), NBS (2.452 g, 13.76 mmol), N,O-bis(trimethylsilyl)acetamide (1.712 mL, 6.88

mmol), BPO (ca. 20 mg) and carbon tetrachloride (160 mL). The suspension was heated to

reflux when another portion (ca. 20 mg) of BPO was added. After being refluxed for 3 hrs,

the reaction mixture was diluted with DCM (100 mL), washed with water and dried over N-^SO,,. The reaction was repeated for another 5 times and the combined organic layers were

filtered and evaporated. The residue was repeatedly purified by flash chromatography on

silica column eluted by ethyl acetate/DCM (2.5%) or ethyl acetate/hexane (20%ι). The crystal

residue was further washed with ethyl acetate/hexane (20%) and dried in vacuum, giving the

title compound (4.970 g, 21%) as white crystal.

Example 17:

7-Bromo-3(R,S)-carboxyl-l-ethyl-8-methoxy-2,3,4,5tetrahydro-lH-l-benzazepine-2-one

A solution of 7-bromo-3(R,S)-tert-butoxycarbonyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-

1 -benzazepine-2-one (50 mg, 0.126 mmol) in TFA (1 mL) was stirred at room temperature

for 30 min. After this reaction period the reaction mixture was evaporated under reduced

pressure to remove the excess of TFA. Thus obtained product was washed with n-hexane and

dried in vacuum. The desired compound was obtained as a white powder (43 mg, 100%).

M.P.: 188-189°C (decomp).

C₁₄H₁₆BrNO₄ (342.2); MS (FAB, NBA) m/e 343 (M+ H) ⁺

This product was also analyzed by Η and ^,3C NMR. The corresponding NMR spectra were

consistent with the structure of the anticipated product.

Example 18:

3(R,S)-tert-Butoxycarbonyl-l-ethyl-8-methoxy-7-(piperazin-l-yl)-2,3,4,5-tetrahydro-lH-

1 -benzazepine-2-one

An oven-dried flask, charged with 7-bromo-3(R,S)-tert-butoxycarbonyl-l-ethyl-8-methoxy-

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (48 mg, 0.121 mmol), piperazine (12.64 mg, 0.145 mmol), Pd(OAc)₂ (2.72 mg, 0.0121 mmol, 10 mol%), BINAP (11.65 mg, 0.0182

mmol) was purged with argon for 5 min. After addition of anhydrous toluene (1 mL) through

a syringe followed by sodium tert-butoxide (16.78 mg, 0.169 mmol) in one portion, the flask

was purged with argon, vigorously stirred and heated at 80°C for 22 hrs. The course of the

reaction was monitored by TLC. The reaction mixture was diluted with DCM (20 mL),

percolated through a short column of Celite and evaporated to dryness. Purification of a crude

product using preparative silica TLC developed with MeOH/DCM (1 :4) provided the desired

compound (8.0 mg, 16%) as a white crystalline product.

M.P.: 165°C (decomp).

C₂₂H₃₃N₃O₄ (403.52); MS (FAB) m/e 404 (M+l)⁺.

consistent with the structure of the anticipated product.

Example 19:

l,4-Di-[(3(R,S)-tert-butoxycarbonyl-l-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-lH-l-

benzazepine)-7-yl] -piperazine

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (300 mg, 0.75 mmol), piperazine (78.6 mg, 0.90

mmol), Pd(OAc)₂ (16.8 mg, 0.075 mmol, 10 mol %), BINAP (70.1 mg, 0.1125 mmol) was

purged with argon for 5 min and anhydrous toluene (1 mL) was added through a syringe.

After addition of Cs₂CO₃ (0.342 g, 1.05 mmol) in one portion, the reaction mixture was

purged with argon for 3 min, vigorously stirred and heated at 100°C for 22 hrs. The reaction

mixture was diluted with DCM (20 mL), percolated through a short column of Celite and evaporated to dryness. Purification of the crude product by flash chromatography on silica gel

column eluted with MeOH/DCM (1 :9), provided the desired compound (40 mg, 7%) as a

white crystalline product.

M.P.: 146 - 149°C.

C₄₀H₅₆N₄O₈ (720.91); MS (FAB) m/e 721 (M+l)⁺

This product was also analyzed by 'H and ¹³C NMR. The coπesponding NMR spectra were

consistent with the structure of the anticipated product.

Example 20:

l,4-Di-[(3(R,S)-carboxyl-l-ethyI-8-methoxy-2-oxo-2,3,4,5-tetrahydro-lH-l-

b enzazepin e)-7-yl] -piperazine

A solution of l,4-di-[(3(R,S)-tert-butoxycarbonyl-l-ethyl-8-methoxy-2-oxo-2,3,4,5-

tetrahydro-lH-l-benzazepine)-7-yl]-piperazine (6 mg, 0.008 mmol) in TFA (1 mL) was

stiπed at room temperature for 30 min. The reaction mixture was then evaporated to dryness

under reduced pressure to remove excess of TFA. After washing the solid product with n-

hexane and drying in vacuum the desired compound was obtained as a yellowish powder (5

mg, 75%).

M.P.: 149-152°C

C₃₂H₄₀N₄O₈ (608.69); MS (FAB, NBA) m/e 609 (M+ H) ⁺

consistent with the structure of the anticipated product. Example 21:

7- [(4-tert-butoxycarbonylpiperazin)-l-yl] -1 -ethyl-8-methoxy-2,3,4,5-tetrahydro-l H-l -

benzazepine-2-one

An oven-dried flask, charged with 7-bromo-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one (268 mg, 0.90 mmol), benzyl 1-piperazinecarboxylate (201 mg, 1.08

mmol), Pd(OAc)₂ (20.16 mg, 0.09 mmol, 10 mol %), BINAP (84.12 mg, 0.134 mmol) was

purged with argon for 5 min. Anhydrous toluene (1.5 mL) was added via syringe. The flask

was opened and sodium tert-butoxide (120.0 mg, 1.26 mmol) was added in one portion. After

purging with argon for 3 min, the reaction mixture was stiπed and heated at 100°C for 2 hrs.

TLC indicated that the starting material has been consumed. The reaction mixture was

allowed to cool to ambient temperature, poured into water, extracted with ethyl acetate, dried

over Na_jSO^ filtered and evaporated to dryness. Purification of the crude product by flash

chromatography on silica gel column eluted with MeOH/DCM (10% of MeOH in DCM)

gave the title compound as brownish foam (266 mg, 73%).

M.P.: amoφhous compound

MS (FAB): calcd for C₂₂H₃₃N₃O₄ 403.52; found m/e 404 (M+l)⁺.

consistent with the structure of the anticipated product.

Example 22:

l-ethyl-8-methoxy-7-(piperazin-l-yl)-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

hydrochloride

7-[(4-tert-Butoxycarbonyl)-piperazin- 1 -yl)- 1 -ethyl-8-methoxy-2,3 ,4,5-tetrahydro- IH- 1 -

benzazepine-2-one (150 mg, 0.372 mmol) was added portionwise into 4 M solution of HCl in 1,4-dioxane (4 mL) at 0°C. After stirring at room temperature for 3 hrs, the reaction mixture

was cooled in ice-water bath and a final product precipitated by addition of anhydrous ether

(15 mL). The precipitate was collected by filtration, washed with anhydrous ether and dried

in high vacuum. The title compound was obtained as a white foam (135 mg, 96%).

M.P.: amoφhous compound

MS (FAB): calcd for C₁₇H₂₅N₃O₂ 303.41; found m/e 304 (M+l)⁺.

consistent with the structure of the anticipated product.

Example 23:

l-tert-Butoxycarbonyl-3(R,S)-ϊ'erι'-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one

l-tert-Butoxycarbonyl-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one was obtained as a by -product in a synthesis of 3-tert-butoxycarbonyl-8-

methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one. The experimental procedure for a

preparation of 3-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

was repeated with 8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (lO.OOg, 52.26

mmol) as a starting compound. During purification of the reaction mixture by flash

chromatography fractions running faster than those containing 3-tert-butoxycarbonyl-8-

methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one were collected and evaporated to

dryness. The residue was further purified on silica gel column eluted with ethyl acetate/n-

hexane (30% ethyl acetate in n-hexane). Crystallization of the crude product from chloroform/n-hexane (30% chloroform in n-hexane), gave the title compound as a white

crystalline product (2.5 g, 12%).

M.P.: 91-92°C. MS (FAB): calcd for C₂₁H₂₉NO₆ 391.46; found m/e 392 (M+l)⁺.

consistent with the structure of the anticipated product.

Example 24:

7-Bromo-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

A suspension of 8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (100 mg, 0.52

mmol), NBS (103 mg, 0.57 mmol) and BPO (ca. 5 mg) in carbon tetrachloride (1.5 mL) was

heated at reflux for 3 hrs. The reaction mixture was allowed to cool to room temperature,

diluted with DCM (20 mL), washed with water and dried over Na₂SO₄. Filtration and

evaporation of the organic layer provided a solid residue, which was washed with n-hexane

and dried in high vacuum. The title compound was obtained as a white crystalline product

(140 mg, 100%).

M.P.:180-182°C. MS (FAB): calcd for C„H₁₂BrNO₂ 270.11; found m e 271 (M+l)⁺.

consistent with the structure of the anticipated product.

Example 25:

benzazepine-2-one

A suspension of 3-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-

one (2.0 g, 6.86 mmol), 3-fluorobenzyl bromide (1.68 mL, 13.72 mmol) and Cs₂CO₃ (4.48 g, 13.72 mmol) in acetonitrile (20 mL) was stiπed at room temperature for 16 hours. The

DCM. The organic layer was washed with water, dried over Na^O^ filtered and evaporated

to dryness. Thus obtained crude product was purified by flash chromatography on silica gel

column eluted with ethyl acetate/n-hexane (30%o of ethyl acetate in n-hexane). The title

compound (2.10 g, 77%) was obtained as a colorless foam.

M.P.: amoφhous compound

MS (FAB): calcd for C₂₃H₂₆FNO₄ 399.46; found m/e 399 (M)⁺.

consistent with the structure of the anticipated product.

Example 26:

7-[(4-benzyloxycarbonyl)-piperazin-l-yl]-3(R,S)-terι'-butoxycarbonyI-l-ethyl-8-methoxy-

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

An oven-dried flask, charged with 7-bromo-3-tert-butoxycarbonyl-l-ethyl-8-methoxy-

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (240 mg, 0.60 mmol), benzyl 1-

piperazinecarboxylate (159 mg, 0.72 mmol), Pd(OAc)₂ (14.0 mg, 0.06 mmol, 10 mol %>),

BINAP (56 mg, 0.09 mmol) was purged with argon for 5 min. Anhydrous toluene (1.5 mL)

was added via syringe. The flask was opened and sodium tert-butoxide (80.0 mg, 0.84 mmol)

was added in one portion. After purging with argon for 3 min, the reaction mixture was

stiπed and heated at 100°C for 2 hrs. Then, the reaction mixture was poured into water,

extracted with ethyl acetate and dried over Na^ ,, filtered and evaporated to dryness.

Purification of the crude product by flash chromatography on silica gel column eluted with MeOH/DCM (10% of MeOH in DCM) afforded the title compound as brownish foam (150

mg, 46%).

M.P.: amoφhous compound

MS (FAB): calcd for C₃₀H₃₉N₃O₆ 537.66; found m/e 538 (M+l)⁺.

consistent with the structure of the anticipated product.

Examples 27 and 28:

3,7-dibromo-l-ethyl-3(R,S)-methoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l- benzazepine-2-one and

7-bromo-l-ethyl-3(R,S)-methoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one

A mixture of 7-bromo-3(R,S)-tert-butoxycarbonyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-

l-benzazepine-2-one (lOOmg, 0.25 mmol), Br₂(300 mg, 1.88 mmol) and MeOH (5mL) was

stiπed at ambient temperature for 24 hours. Then, the reaction mixture was evaporated under

reduced pressure to dryness and the residue dried under low vacuum at 50°C for two hours.

Thus obtained crude product was dissolved in MeOH (200mL) and carbon decolorizing was

added. After stirring the suspension at ambient temperature for an hour, the reaction mixture

was filtrated through a celite pad and the filtrate evaporated to dryness. The residue was

dissolved in cold water and extracted with chloroform. The combined extracts were washed

with saturated NaHCO₃ and brine and dried over MgSO₄. TLC (ethyl acetate/: n-hexane, 3:7)

of the crude product revealed two new formed products which were separated by flash

chromatography with ethyl acetate/ n-hexane, 1:1 as an eluent. 45 mg (41%) of 3,7-dibromo-

3(R,S)-methoxycarbonyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-l-benzazepine-2-one was obtained as a white crystalline product. In addition, 36 mg (40%>) of 7-bromo-3(R,S)-

methoxycarbonyl- 1 -ethyl- 8-methoxy-2 ,3,4,5 -tetrahydro- 1 H- 1 -benzazepine-2-one was

isolated as a white amoφhous product.

3,7-dibromo-l-ethyl-3(R,S)-methoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one:

M.P.: 71-73°C (decomp).

C₁₈H₂₅BrN₂O₃ (397.31); MS (FAB) m/e 436 (M+l)⁺

This product was also analyzed by 'H NMR. The coπesponding NMR spectra were

consistent with the structure of the anticipated product.

7-bromo-l-ethyl-3(R,S)-methoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one:

M.P.: amoφhous product

C₁₅H₁₇BrNO₄ (355.21); MS (FAB) m/e 356 (M+l)⁺

This product was also analyzed by 'H NMR. The corresponding NMR spectra were

consistent with the structure of the anticipated product.

Example 29:

7-bromo-3(R,S)-N-(tert-butyl)aminocarbonyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-

l-benzazepine-2-one

A mixture of 7-bromo-3(R,S)-carboxyl-l-ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one (200 mg, 0.58 mmol), l-[3-dimethylamino]propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (134 mg, 0.70 mmol), and HOBT (108 mg , 0.80 mmol) in anhydrous

THF (15mL) was stiπed at room temperature for 30 min. To this solution was added

dropwise triethylamine (250 μL) as a neat liquid and the reaction mixture stiπed at room

temperature for 1.5 hour and subsequently tert-butylamine (46 mg, 0.63 mmol, 100 μL)

added as a neat liquid. After the reaction mixture was stirred at ambient temperature for 20

hours, the solvent was evaporated under reduced pressure and the residue was dissolved in

ethyl acetate (100 ml), washed with saturated aqueous NaHCO₃ and dried over Flash

chromatography of the crude mixture on silica gel column and elution with n-hexane/ethyl

acetate, 1 : 1 afforded the title compound. Trituration of the chromatographed product with n-

pentane gave 131 mg (56%) of an off- white crystalline product.

C₁₈H₂₅BrN₂O₃ (397.31); MS (El) m/e 397 (M)⁺.

consistent with the structure of the anticipated product.

Example 30:

7-Bromo-3(R,S)-tert-butoxycarbonyl-l-(3-fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-

1 H-l -benzazepine-2-one

A suspension of 3-tert-butoxycarbonyl-l-(3-fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-lH-

l-benzazepine-2-one (l.OOg, 2.503 mmol) and NBS (0.49 g, 2.754 mmol) in acetic acid (0.8

mL) and chloroform (8 mL) was heated at reflux for 4 hrs. The reaction mixture was allowed

to cool to room temperature, diluted with DCM (30 mL), washed with saturated aqueous

sodium bicarbonate solution, dried over Filtration and evaporation of the organic

layer gave a solid residue, which was purified by flash chromatography on silica column eluted with ethyl acetate/n-hexane (25%) of ethyl acetate in n-hexane). The title compound

was obtained as a white powder (0.400 g, 33%).

M.P.: 146-148°C

MS (FAB): calcd for C₂₃H₂₅FBrNO₄ 478.36; found m/e 478 (M)⁺.

consistent with the structure of the anticipated product.

Example 31:

7-[(4-Benzyloxycarbonyl)piperazin-l-yl]-3(R,S)-te/*j'-butoxycarbonyl-l-(3-fluorobenzyl)-

8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

An oven-dried flask, charged with 7-bromo-3-tert-butoxycarbonyl-l-(3-fluorobenzyl)-8-

methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (150 mg, 0.314 mmol), benzyl 1-

piperazinecarboxylate (83 mg, 0.376 mmol), Pd(OAc)₂ (7.0 mg, 0.03 mmol, 10 mol %),

BINAP (28 mg, 0.045 mmol) was purged with argon for 5 min. Anhydrous toluene (1.5 mL)

was added via syringe. The flask was opened and sodium tert-butoxide (42.0 mg, 0.44 mmol)

was added in one portion as a dry powder. After purging with argon for 3 min, the reaction

mixture was stiπed and heated at 100°C for 1.5 hrs. The reaction mixture was cooled to

ambient temperature, poured into water, extracted with ethyl acetate, dried over Na^O^

filtered and evaporated to dryness. Purification of the crude product by flash chromatography

on silica gel column eluted with ethyl acetate/n-hexane (50% of ethyl acetate in n-hexane)

provided the title compound as brownish foam (60 mg, 32%).

M.P.: amoφhous compound

MS (FAB): calcd for C₃₅H₄₀FN₂O₆ 617.72; found m/e 618 (M+l)⁺. This product was also analyzed by ^!H and ¹³C NMR. The coπesponding NMR spectra were

consistent with the structure of the anticipated product.

Example 32:

7-Bromo-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-

one

A suspension of 3-tert-butoxycarbonyl-8-methoxy-2,3 ,4,5 -tetrahydro- 1 H- 1 -benzazepine-2-

one (l.OOg, 3.43 mmol) and NBS (0.672g, 3.78 mmol) in acetic acid (0.8 mL) and chloroform

(8 mL) was heated at reflux for 3 hrs. Then, the reaction mixture was diluted with DCM (30

mL), washed with water, dried over Na_jSO^ filtered and evaporated. The crude residue was

purified by flash chromatography on silica column using gradient elution with EtOAc/DCM

(from 5%) ethyl acetate in DCM to 10%> ethyl acetate in DCM). The title compound was

obtained as a white powder (0.689g, 54%).

M.P.: 207-208°C

MS (FAB): calcd for C₁₆H₂₀BrNO₄ 370.24; found m e 371 (M+l)⁺.

consistent with the structure of the anticipated product.

Example 33:

8-Hydroxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

To a solution of 8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (l.OOg, 5.23 mmol)

in DCM (5 mL) was added dropwise IM solution of BBr₃ in DCM (5.23 mL ). After stirring

at room temperature for 30 min, the reaction mixture was heated at reflux for 5 hrs, allowed to cool to ambient temperature and poured into ice-water. The aqueous layer was extracted

with DCM (5X1 OmL), dried over Na₂SO₄, filtered and evaporated. The solid residue was

washed with n-hexane and dried in high vacuum. The title compound was obtained as a white

powder (705 mg, 76%). M.P.: 226-227°C; MS (FAB): calcd for C,oH„NO₂ 177.2; found m/e

178 (M+l)⁺.

consistent with the structure of the anticipated product.

Table I contains additional embodiments of the invention according to Formula I or Formula II, wherein a and b are single bonds.

TABLE I

Table II contains additional prefeπed embodiments of this invention.

TABLE II: Compounds of the formula I

wherein: a and b are a single bond unless noted as a double (dbl) bond in the table below and:

Table II

Example 175:

8-Hydroxy-7-nitro-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

To a stiπed suspension of 8-hydroxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (645 mg,

3.642 mmol) in acetic anhydride (15 mL) cooled on ice-water bath was added dropwise 90%

nitric acid (0.26 mL, 5.463 mmol) by syringe. After being stirred for 20 minutes, the

yellowish suspension was poured into water and stiπed for another 30 minutes. The aqueous

mixture was neutralized with saturated aqueous sodium bicarbonate and filtered. The solid

residue was washed with water and dried in vacuum. The title compound (301 mg, 37%) was

obtained as yellowish crystal.

M.P.: 239 - 240oC

C10H10N2O4 (222.19); MS (FAB, NBA) m/e 223 (M+l)+

This product was also analyzed by IH and 13C NMR. The corresponding NMR spectra were

consistent with the structure of the anticipated product.

Example 176:

3(R,S)-tert-Butoxycarbonyl-7-[(ethoxycarbonylamino)thiocarbonyl)]amino-8-methoxy-

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Ethyl isothiocyanato formate (200 Dl ,1.7 mmol) was added dropwise , as a neat liquid, to a

solution of 306 mg (1 mmol) of 7- amino -3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-

tetrahydro-lH-l-benzazepine-2-one in 5ml of anhydrous THF. The reaction mixture was

stiπed at room temperature for an hour under argon and then evaporated under reduced pressure to dryness to give an orange semi-solid crude product. After drying under high

vacuum for two hours the crude product was purified by flash chromatography on SiO₂(32-

63, 60 A) using AcOEt 3 : CHC1₃ 7 as a mobile phase. Recrystallization of the

chromatographed product from CHCl₃ -n-hexane(l:l) afforded 371 mg( 85 %) of the desired

product as an off-white crystalline solid.

M.P.: 174-176 °C

C₂₀H₂₇N₃O₆ S (437.52); MS (El) m/e 437 (M)⁺

consistent with the structure of the anticipated product.

Example 177:

8-Phenoxy-2,3,4,5-tetrahydro-l H-l -benzazepine-2-one

Example 178:

3(R,S)-tert-Butoxycarbonyl-l-ethyl-8-hydroxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-

one

To a solution of 3(R,S)-tert-butoxycarbonyl-8-(tert)-butyldi(methyl)silyloxy-l -ethyl -2,3,4,5-

tetrahydro-lH-l-benzazepine-2-one (389 mg, 0.93 mmol) in dichloromefhane was added

dropwise 1 M solution of tetrabutylammonium fluoride (1.2 mL, 1.20 mmol) in THF at 0°C.

After being stirred for 5 minutes, the mixture was poured into water and extracted with

dichloromethane. The organic layer was washed with water and dried over anhydrous

N _jS ,. The crude residue was purified by flash chromatography on silica column eluted with AcOEt/dichloromethane (30%). The title compound (105 mg, 37%) was obtained as

white crystal.

M.P.: 154 - 156°C

C₁₇H₂₃NO₄ (305.36); MS (FAB, NBA) m/e 306 (M+l)⁺

consistent with the structure of the anticipated product.

Example 179:

3(R,S)-tert-Butoxycarbonyl-8-tert-Butyldimethylsilyloxy-l-ethyl-2,3,4,5-tetrahydro-lH-

1 -benzazepine-2-one

Step l

8-(tert)-Butyldi(methyl)silyloxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

To a solution of 8-hydroxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one (3.50 g, 19.75 mmol),

triethylamine (4.12 mL, 29.63 mmol) and 4-dimethylaminopyridine (20 mg) in DMF (30 mL)

was added (tert)-butyldimethylsilyl chloride (3.573 g, 29.63 mmol). After being stirred at

room temperature overnight, the mixture was poured into water and extracted with

dichloromethane. The organic layer was washed with water, dried over anhydrous Na^O^

filtered and evaporated. The residue was purified by flash chromatography on silica column

with AcOEt/hexane (25%) as eluent. The title compound (4.60 g, 80%) was obtained as white

crystal, with partial recovery of starting material (0.31 g).

M.P.: 138 - 140°C C₁₆H₂₅SiNO₂ (291.45); MS (El) m/e 291(M⁺)

This product was also analyzed by 'H and ^,3C NMR. The coπesponding NMR spectra were

consistent with the structure of the anticipated product.

Step 2

3(R,S)-tert-Butoxycarbonyl 8-(tert)-butyldi(methyl)silyloxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one

A oven-dried flask was charged with 8-(tert)-butyldi(methyl)silyloxy-2,3,4,5-tetrahydro-lH-

l-benzazepine-2-one (2.50 g, 8.58 mmol) and anhydrous THF. 2.0 M LDA in

heptane/THF/ethylbenzene (10.28 mL, 20.56 mmol) was added dropwise at -78°C under

argon. The reaction mixture was then allowed to warm up to room temperature, stiπed for 30

minutes and cooled down to -78°C again. A solution of di-(tert)-butyl dicarbonate (2.04 g,

9.35 mmol) in anhydrous THF ( mL) was added dropwise via syringe. After being stiπed for

4 hours at -78°C, the mixture was warmed up to room temperature, quenched with saturated

aqueous NH₄C1 (5 mL) and evaporated to remove THF. The crude residue was dissolved into

dichloromethane (50 mL), washed with water and dried over anhydrous NajSO,,. Flash

chromatography on silica column, eluting with AcOEt/DCM (5 - 7 %) provided the title

compound (0.92 g, 27%) as white foam.

M.P.: amoφhous compound

C₂₁H₃₃SiNO₄ (391.56); MS (El) m/e 391 (M⁺)

consistent with the structure of the anticipated product. Step 3

A suspension of 3(R,S)-tert-butoxycarbonyl-8-(tert)-butyldi(methyl)silyloxy-2,3,4,5-

tetrahydro-lH-l-benzazepine-2-one (0.570g, 1.59 mmol), cesium carbonate (2.00g, 6.14

mmol), ethyl iodide (0.5 mL, 6.25 mmol) in acetonitrile (5 mL) was stiπed at room

temperature for three hours. The reaction mixture was poured into water, extracted with

dichloromethane, dried over anhydrous Na^O^ filtered and evaporated. The residue was

chromatographed on silica column eluted with ethyl acetate hexane (20%). The title

compound (412 mg, 62%) was obtained as oil.

C₂₃H₃₇SiNO₄ (419.62); MS (FAB, NBA) m/e 420 (M+l)⁺

consistent with the structure of the anticipated product.

Example 180:

8-Ethoxy-3(R,S)-tert-butoxycarbonyl-l-ethyl-2,3,4,5-tetrahydro-lH-l-benzazepine-2-

one

Example 181:

8-Nitro-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 182: 8-Nitro-l-ethyl-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 183:

l,3(RjS)-Di(tert-butoxycarbonyl)-8-hydroxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 184:

3(R,S)-carboxyl-l-(3-fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-

one

Example 185:

7-Methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 186:

6-Methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 187:

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 188:

6-Hydroxy-2,3)4,5-tetrahydro-lH-l-benzazepine-2-one

Example 189:

7-Hydroxy-2,3,4,5-tetrahydro-l H-l -benzazepine-2-one Example 190:

8-Amino-l-ethyl-2,3_»4,5-tetrahydro-lH-l-benzazepine-2-one

Example 191:

8-Bromo-l-ethyl-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 192:

3(R,S)-carboxyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 193:

3-Benzyloxyaminocarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

To a suspension of 3(R,S)-carboxyl-8-methoxy -2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

(500 mg, 2.13 mmol) and 1-hyroxybenzotriazole (316 mg, 2.34 mmol) in chloroform (5 mL)

was added l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (449 mg, 2.34

mmol) and the mixture was stiπed at room temperature for 30 minutes. O-benzyl

hydroxylamine hydrochloride (407 mg, 2.55 mmol) and subsequently triethylamine were

added. After being refluxed overnight, the reaction mixture was diluted with dichloromethane

(20 mL), washed with water, dried over anhydrous Na^O^ filtered and evaporated. The

residue was further purified by flash chromatography on silica column eluted with

MeOH/DCM (10%). The title compound (474 mg, 65%) was obtained as white powder. M.P.: 162 - 164°C

C₁₉H₂₀N₂O₄ (340.36); MS (FAB, NBA) m/e 341 (M+l)⁺

consistent with the structure of the anticipated product.

Example 194:

3-(3-dimethylaminopropyl)aminocarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one

Example 195:

l,3(R,S)-Di(tert-butoxycarbonyl)-8-methoxy-7-nitro-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one

To a solution of l,3(R,S)-di(tert-butoxycarbonyl)-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one (1.00 g, 2.55 mmol) in acetic anhydride (7 mL) cooled on ice-water bath

was added 90% nitric acid (0.18 mL, 3.83 mmol). After being stirred for 30 minutes at room

temperature, the reaction mixture was poured into ice-water and stirred for another one hour.

The reaction mixture was then extracted with dichloromethane, dried over anhydrous Na^O^

eluted with AcOEt/hexane (25%), giving the title compound (300 mg, 27%) as yellowish

solid.

M.P.: 142 - 144°C (Decomp.) C₂₁H₂₈N₂O₈ (436.44); MS (FAB, NBA) m/e 437 (M+l)⁺

This product was also analyzed by Η and ^l3C NMR. The coπesponding NMR spectra were

consistent with the structure of the anticipated product.

Example 196:

3(R,S)-tert-Butoxycarbonyl-l-cyanomethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one

A suspension of 3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one (500 mg, 1.72 mmol), cesium carbonate (841 mg, 2.58 mmol) and

iodoacetonitrile (0.249 mL, 3.44 mmol) in acetonitrile (5 mL) was stirred at room

temperature overnight. The reaction mixture was poured into water, extracted with

dichloromethane, dried over anhydrous NajSO,, filtered and evaporated. The crude residue

was purified by flash chromatography on silica column eluted with AcOEt/hexane (25%).

The title compound (525 mg, 92%) was obtained as colorless oil.

C₁₈H₂₂N₂O₄ (330.37); MS (FAB, NBA) m/e 331 (M+l)⁺

consistent with the structure of the anticipated product.

Example 197: 3-Hydoxyaminocarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 198:

3(R,S)-tert-Butoxycarbonyl-8-methoxy-7-nitro-2,3_>4,5-tetrahydro-lH-l-benzazepine-2-

one

Example 199:

7-Amino-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-

2-one

Example 200:

l-(tert-Butoxycarbonyl)methyl-3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-

tetrahydro-1 H-l -benzazepine-2-one

Example 201:

l-(Aminocarbonyl)methyl-3(R,S)-tert-butyloxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-

1 H-l -benzazepine-2-one

Example 202:

l-Carboxylmethyl-3(R,S)-carboxyl -8-methoxy-2,3_>4,5-tetrahydro-lH-l-benzazepine-2-

one

Example 203: 3(R,S)-Carboxyl -8-methoxy-7-nitro-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 204:

3(R,S)-tert-Butoxycarbonyl-7-di(ethoxycabonylaminocarbonyl)amino-8-methoxy-

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 205:

8-Hydroxy-7-nitro-3-carboxyl-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 206:

8-Hydroxy-3-carboxyl-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 207:

7-(4-Benzyloxycarbonyl)piperazinyl-3(R,S)-carboxyl-l-ethyl-8-methoxy-2,3,4,5-

tetrahydro-lH-l-benzazepine-2-one

Example 208:

7-Amino-3(R,S)-carboxyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 209:

3(R,S)-Carboxyl-7-[(ethoxycarbonylamino)thiocarbonyl)]amino-8-methoxy-2,3,4,5-

tetrahydro-lH-l-benzazepine-2-one Example 210:

3(R,S)-Carboxyl-7-[(ethoxycarbonylamino)carbonyl)]amino-8-methoxy-2,3,4,5-

tetrahydro-lH-l-benzazepine-2-one

Example 211:

7-Amino-3(R,S)-carboxyl-8-hydroxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 212:

3(R,S)-tert-Butoxycarboxyl-7-[(ethoxycarbonylamino)carbonyl)]amino-8-methoxy-

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 213:

3(R,S)-tert-Butoxycarboxyl-8-methoxy-l-[2-(4-morpholinyl)]ethyl-2,3,4,5-tetrahydro-

lH-l-benzazepine-2-one

Example 214:

l-Amidinomethyl-3(R,S)-Carboxyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-benzazepine-2-

one

Example 215:

3(R,S)-tert-Butoxycarbonyl-7-[(ethoxycarbonylamino)thiocarbonyl)]amino-8-hydroxyl

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one Example 216:

3(R,S)-Carboxyl-7-[(ethoxycarbonylamino)thiocarbonyl)]amino-8-hydroxyl -2,3,4,5-

tetrahydro-lH-l-benzazepine-2-one

Example 217:

3(R,S)-Carboxyl-7-[(ethoxycarbonylamino)carbonyl)]amino-8-hydroxyl -2,3,4,5-

tetrahydro-lH-l-benzazepine-2-one

Example 218:

3(R,S)-tert-Butoxycarbonyl-7-[(ethoxycarbonylamino)carbonyl)]amino-8-hydroxyl -

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 219:

7-Amino-3(R,S)-tert-butoxycarbonyl-8-hydroxyl -2,3,4,5-tetrahydro-lH-l-benzazepine-

2-one

Example 220:

3(R,S)-tert-Butoxycarbonyl-8-hydroxyl-7-nitro-2,3,4,5-tetrahydro-lH-l-benzazepine-2-

one

To a stiπed solution of 3(R,S)-tert-butoxycarbonyl-8-hydroxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one (500 mg, 1.803 mmol) in acetic anhydride (5 mL) was added dropwise

90% nitric acid (0.128 mL, 2.73 mmol) by syringe. After being stirred at 0°C for 20 minutes, the yellowish suspension was poured into water and stiπed for one hour, extracted with

dichloromethane, dried over anhydrous Na_jSO^ filtered and evaporated. The yellowish solid

was further washed with DCM/hexane (20%) and dried in vacuum. The title compound (130

mg, 22%) was obtained as yellowish crystal.

M.P.: 189 - 191°C (Decomp.)

C₁₅H₁₈N₂O₆ (322.30); MS (FAB, NBA) m/e 267 (M+1-C₄H₈)⁺

consistent with the structure of the anticipated product.

Example 221:

3(R,S)-tert-Butoxycarbonyl-8-methoxy-l-[2-(tetrahydro-2H-pyran-2-yl)oxyethyl]-

2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

Example 222:

3(R,S)-tert-Butoxycarbonyl-l-(2-hydroxy)ethyl-8-methoxy-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one

Example 223:

3(R,S)-tert-Butoxycarbonyl-8-methoxy-l-[2-(l,3-dioxolan-2-yl)ethyl]-2,3,4,5-tetrahydro-

1 H-l -benzazepine-2-one

Example 224:

3(R,S)-tert-ButoxycarbonyI-8-methoxy-7-nitro-l-[2-(tetrahydro-2H-pyran-2- yloxy)]ethyl-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one

A suspension of 3(R,S)-tert-butoxycarbonyl-8-methoxy-7-nitro-2,3,4,5-tetrahydro-lH-l-

benzazepine-2-one (300 mg, 1.03 mmol), tetrabutylammonium iodide (10 mg), cesium

carbonate (671 mg, 2.06 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran(0.311 mL, 2.06

mmol) in acetonitrile (3 mL) was stirred at room temperature overnight. The reaction mixture

was poured into water, extracted with dichloromethane, dried over anhydrous Na₂SO₄, filtered

and evaporated. The crude residue was passed through a short silica column eluted with

AcOEt/hexane (5%). The title compound (360 mg, 83%) was obtained as white solid.

M.P.: 80 - 82°C

C₂₃Η₃₃NO₆ (419.50); MS (El) m/e 419 (M)⁺

consistent with the structure of the anticipated product.

Example 225:

3(R,S)-tert-Butoxycarbonyl-8-methoxy-7-nitro-l-(2-hydroxyethyl)-2,3,4,5-tetrahydro-

1 H-l -benzazepine-2-one

Ex. 300

Ex. 310 Ex. 311

Ex. 341

Ex. 340

Ex. 342

Ex. 345 Ex. 346

EX. 356

Ex. 386

Ex.403 Ex.404

Ex. 424

Ex. 430

Ex. 431

Ex. 447

Ex. 448 Dosage and Formulation

The compounds of this invention can be administered as treatment for

bacterial, viral or fungal infections by any means that produces contact of the active agent

with the agent's site of action, the bacteria, virus or fungus in the body of an animal or plant

or on the surface of nonliving objects. They can be administered by any conventional means

available for use in conjunction with pharmaceuticals, either as individual therapeutic agents

or in a combination of therapeutic agents.

They can be administered alone, but generally administered with a pharmaceutical

carrier selected on the basis of the chosen route of administration and standard

pharmaceutical practice.

They are of course given by forms suitable for each administration route. For example,

they are administered in drops, tablets or capsule form, by injection, inhalation, eye lotion,

ointment, suppository, etc. administration by injection, infusion, inhalation, topically or

rectally. Oral or mucosal administration is preferred. The compounds of the invention are

useful for the treatment of infections in hosts, especially mammals, including humans, in

particular in humans and domesticated animals (including but not limited to equines, cattle,

swine, sheep, poultry, feline, canine and pets in general) and plants. The compounds may be

used, for example, for the treatment of infections of, inter alia, the respiratory tract, the

urinary/reproductive tract, and soft tissues, bone, and blood, especially in humans.

The compounds may be used in combination with one or more therapeutic partners for

the treatment of infections. The term "therapeutic partner" or "therapeutic agent" as used

herein and in the claims includes but is not limited to antibiotics (for example, tobramycin, cephalosporin), steroids, vaccines, anti-oxidants, non-steroidal anti-inflammatories, antacids,

antibodies, interferons, or cytokines. Examples of therapeutic partners that may be co-

administered with the compounds according to the invention include, but are not limited to

ascorbic acid, ascorbate, dextran sulfate, histamine H2 receptor antagonist, metronidazole,

tetracycline imipenem, meropenem, biapenem, aztreonam, latamoxef (MOXALACTAM™),

and other known beta-lactam antibiotics, benzylpeniciUin, phenoxymethylpenicillin,

carbenicillin, azidocillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin, cyclacillin,

pirbenicillin, azlocillin, mezlocillin, sulbenicillin, piperacillin, and other known penicillins.

The penicillins may be used in the form of pro-drugs thereof, for example as in vivo

hydrolysable esters, for example the acetoxymethyl, pivaloyloxymethyl, alpha-

ethoxycarbonyloxyethyl and phthalidyl esters of ampicillin, benzylpeniciUin and amoxycillin;

as aldehyde or ketone adducts of penicillins containing a 6-alpha-aminoacetamido side chain

(for example hetacillin, metampicillin and analogous derivatives of amoxycillin); and as

alpha-esters of carbenicillin and ticarcillin, for example the phenyl and indanyl alpha-esters.

Cephalosporins that may be therapeutic partners with the compounds according to the

invention include, but are not limited to, cefatrizine, cephaloridine, cephalothin, cefazolin,

cephalexin, cephacetrile, cephapirin, cephamandole nafate, cephradine, 4-hydroxycephalexin,

cephaloglycin, cefoperazone, cefsulodin, ceftazidime, cefuroxime, cefinetazole, cefotaxime,

ceftriaxone, and other known cephalosporins. All of therapeutic partners may be used in the

form of pro-drugs thereof.

When the compounds of the invention are co-administered with a therapeutic

partner, the ratio of the amount of the compound according to the invention to the amount of

the therapeutic partner may vary within a wide range. The said ratio may, for example, be from 100:1 to 1 :100; more particularly, it may, for example, be from 2:1 to 1:30. The amount

of the therapeutic will normally be approximately similar to the amount in which it is

conventionally used per se, for example from about 50 mg, advantageously from about 62.5

mg, to about 3000 mg per unit dose, more usually about 125, 250, 500 or 1000 mg per unit

dose.

It is generally advantageous to use a compound according to the invention in

admixture or conjunction with a therapeutic partner that can result in an additive or

synergistic effects. The compound of the invention can be administered separately or in the

form of a single composition containing both active ingredients. The compound of the

invention and the therapeutic partner may be administered simultaneously or sequentially.

Examples of simultaneous administration include where two or more compounds,

compositions, or vaccines which may be the same or different, are administered in the same

or different formulation or are administered separately, e.g. in a different or the same

formulation but within a short time (such as minutes or hours) of each other. Examples of

sequential administration include where two or more compounds, compositions or vaccines

which may be the same or different are not administered together within a short time of each

other, but may be administered separately at intervals of for example days, weeks, months or

years.

Formulations of the present invention include those suitable for oral, nasal,

topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration. The

formulations may conveniently be presented in unit dosage form and may be prepared by any

methods well known in the art of pharmacy. The amount of active ingredient which can be

combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred

per cent, this amount will range from about 1 per cent to about ninety-nine percent of active

ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about

10 per cent to about 30 per cent.

Methods of preparing these formulations or compositions include the step of

bringing into association a compound of the present invention with the carrier and,

optionally, one or more accessory ingredients. In general, the formulations are prepared by

uniformly and intimately bringing into association a compound of the present invention with

liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the

product.

Formulations of the invention suitable for oral administration may be in the

form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and

acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or

non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or

syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia)

and/or as mouth washes and the like, each containing a predetermined amount of a compound

of the present invention as an active ingredient. A compound of the present invention may

also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration (capsules,

tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed

with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium

phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose,

glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol;

disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic

acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin;

absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as,

for example, cetyl alcohol and glycerol monostearate; absorbents, such as kaolin and

bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid

polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, and coloring agents. In the

case of capsules, tablets and pills, the pharmaceutical compositions may also comprise

buffering agents. Solid compositions of a similar type may also be employed as fillers in soft

and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as

high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more

accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin

or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for

example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-

active or dispersing agent. Molded tablets may be made by molding in a suitable machine a

mixture of the powdered compound moistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceutical compositions of

the present invention, such as dragees, capsules, pills and granules, may optionally be scored

or prepared with coatings and shells, such as enteric coatings and other coatings well known

in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or

controlled release of the active ingredient therein using, for example, hydroxypropylmethyl

cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a

bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid

compositions which can be dissolved in sterile water, or some other sterile injectable medium

immediately before use. These compositions may also optionally contain opacifying agents

and may be of a composition that they release the active ingredient(s) only, or preferentially,

in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of

embedding compositions which can be used include polymeric substances and waxes. The

active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of

the above-described excipients.

Liquid dosage forms for oral administration of the compounds of the invention

include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions,

syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain

inert diluents commonly used in the art, such as, for example, water or other solvents,

solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,

ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in

particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol,

tetrahydro furyl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures

thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as

wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring,

perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents as,

for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar,

bismuth,and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions of the invention for rectal or vaginal

administration may be presented as a suppository, which may be prepared by mixing one or

more compounds of the invention with one or more suitable nonirritating excipients or

carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a

salicylate, and which is solid at room temperature, but liquid at body temperature and,

therefore, will melt in the rectum or vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginal

administration also include pessaries, tampons, creams, gels, pastes, foams or spray

formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration of a compound of this

invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches

and inhalants. The active compound may be mixed under sterile conditions with a

pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which

may be required.

The ointments, pastes, creams and gels may contain, in addition to an active

compound of this invention, excipients, such as animal and vegetable fats, oils,

waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones,

bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of this invention,

excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates

and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted

hydrocarbons, such as butane and propane.

Transdermal patches have the added advantage of providing controlled delivery of a

compound of the present invention to the body. Such dosage forms can be made by

dissolving or dispersing the compound in the proper medium. Absorption enhancers can also

be used to increase the flux of the compound across the skin. The rate of such flux can be

controlled by either providing a rate controlling membrane or dispersing the active compound

in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like, are also

contemplated as being within the scope of this invention.

For administration by inhalation, the compounds for use according to the

present invention are conveniently delivered in the form of an aerosol spray presentation from

pressurized packs or a nebulizer, with the use of a suitable propellant, e.g.,

dichlorodifiuoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide

or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined

by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for

use in an inhaler or insufflator may be formulated containing a powder mix of the compound

and a suitable powder base such as lactose or starch.

Pharmaceutical compositions of this invention suitable for parenteral administration

comprise one or more compounds of the invention in combination with one or more

pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions,

suspensions or emulsions, or sterile powders which may be reconstituted into sterile

injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended

recipient or suspending or thickening agents.

These compositions may also contain adjuvants such as preservatives, wetting agents,

emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be

ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben,

chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic

agents, such as sugars, sodium chloride, and the like into the compositions. In addition,

prolonged absorption of the injectable pharmaceutical form may be brought about by the

inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirable to slow the

absorption of the drug from subcutaneous or intramuscular injection. This may be

accomplished by the use of a liquid suspension of crystalline or amorphous material having

poor water solubility. The rate of absorption of the drug then depends upon its rate of

dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively,

delayed absorption of a parenterally-administered drug form is accomplished by dissolving or

suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the subject

compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the

ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug

release can be controlled. Examples of other biodegradable polymers include

poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by

entrapping the drug in liposomes or microemulsions which are compatible with body tissue.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active

ingredient which is effective to achieve the desired therapeutic response for a particular

patient, composition, and mode of administration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factors including the activity

of the particular compound of the present invention employed, or the ester,

salt or amide thereof, the route of administration, the time of administration, the rate of

excretion of the particular compound being employed, the duration of the treatment, other

drugs, compounds and/or materials used in combination with the particular compound

employed, the age, sex, weight, condition, general health and prior medical history of the

patient being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readily determine and

prescribe the effective amount of the pharmaceutical composition required. For example, the

physician or veterinarian could start doses of the compounds of the invention employed in the

pharmaceutical composition at levels lower than that required in order to achieve the desired

therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will be that amount of

the compound which is the lowest dose effective to produce a therapeutic effect. Such an

effective dose will generally depend upon the factors described above. Generally,

intravenous and subcutaneous doses of the compounds of this invention for a patient, when

used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per

kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per

day, and still more preferably from about 1.0 to about 100 mg per kg per day, preferably from

5 to 500 mg. Each unit dose may be, for example, 5, 10, 25, 50, 100, 125, 150, 200 or 250 mg of a compound according to the invention. If desired, the effective daily dose of the active

compound may be administered as two, three, four, five, six or more sub-doses administered

separately at appropriate intervals throughout the day, optionally, in unit dosage forms

For use in agricultural applications, the compound or compositions of the invention is

suspended in an agriculturally acceptable diluent, including but not limited to water or a

fertilizer solution. To assure better adhesion of the liquid for example, in the case when the

suspension is applied to the plant surface, glycerin can be added to the final diluted liquid

formulation. The compounds or compositions of the invention is mixed as a dry ingredient(s)

with an inert agriculturally acceptable particulate dry carrier or diluent which provides a fine

powdery formulation. The agriculturally acceptable diluent is one that serves as a carrier for

the low concentrations of compounds or compositions of the invention. Preferably the dry

diluent is one which readily suspends in suitable diluents for administration to plants, such as

water.

The formulation is applied to the plant by any of a variety of art-recognized means.

For example, the formulation can be applied to the plant surface by spraying. Alternatively,

the solution can be introduced by injection into a plant, for example, with a syringe, applied

as a solid fertilized-like preparation for absorption by the roots at the base of a plant or a

solution can be distributed at the base of a plant for root absorption. The formulation can be

applied as soon as symptoms appear or prophylactically before symptoms appear.

Application can be repeated.

Utility

The present invention is the result of the unexpected discovery that substituted 1- benzazepines and analogs thereof defined by Formula I and II inhibit growth and/ or the life

of bacteria. The compounds of this invention can be administered as treatment for bacterial,

protozoan, viral , or fungal infections or colonization by any means that produces contact of

the active agent with the agent's site of action, the bacteria, protozoa, algae, virus or fungus in

the body of an animal or plant or on the surface of animal carcass or nonliving objects.

Accordingly, pharmaceutical compositions containing the compounds of structural Formula I

and II inhibit microbial agents and are useful as pharmaceutical agents for animals, especially

mammals, including humans, for the treatment of microbial diseases. In one embodiment of

the invention diseases are those caused by or associated with infection by microorganisms

including, but are not limited to, Streptococcus spp., Staphylococcus spp., Clostridium spp.,

Borrelia spp., Bacillus spp., Enterococcus spp., Propionibacterium spp, and

Peptostreptococcus spp. Haemophilus spp., Pseudomonas spp., Neisseria spp., Bacillus spp.

Yersinia spp., Francisella spp., Coxiella spp., Shigella spp., Campylobacter spp.,

Corynebacterium spp., Enter ococcae spp., E. coli spp., Helicobacter spp., Klebsiella spp.,

Moraxella spp., Chlamydia spp., Trichophyton spp., retrovirus spp., Microsporum spp,

Mycobacteria spp. Trichomonas spp, Candida spp, Aspergillus spp. and Coccidioides spp.

Toxocara spp., Trichophyton spp., Giardia spp., Epidermophyton spp.

More preferred are infections caused by Streptococcus pyogenes, Staphylococcus

aureus, methicillin resistant Staphylococcus aureus ("MRSA"), Staphylococcus epidermidis,

Bacillus anthraci, s Neisseria gonorrhoeae, Neisseria meningitidis Mycobacteria

tuberculosis, vancomycin resistant Enterococcae ("VRE"), Helicobacter pylori, Chlamydia

pneumoniae, Chlamydia trachomatis, Campylobacter jejuni, Propionibacterium acnes,

Pseudomonas aeruginosa, Haemophilus influenzae, Candida albicans, Candida atropicalis, Francisella tularensis, Yersinia pestis, Trichophyton rubrum, Trichophyton tonsurans,

Trichophyton mentagrophytes, Trichophyton violaceum, Trichophyton cutaneum,

Epidermophyton floccosum, Pityrosporum orbicularae, Aspergillus funigatus, Aspergillus

flavus, Aspergillus niger, Coccidioides immitis, Trichomonas hominis, Trichomonas tenax,

Trichomonas vaginalis, Giardia lamblia, Streptococcus pneumoniae, Entercococcus faecalis,

Escherichia coli, Corynebacterium diphtheria, Morazella catarrhalis, Haemophilus

influenzae, Bacillus cerius, HIV and Toxocara canis.

The present invention is also useful in a method directed to treating infections

in a host in need of such treatment, which method comprises administering a therapeutically

effective amount of compounds represented by general Formula I and II. In one embodiment,

the infected hosts are animals, preferably mammals, most preferably human, especially

immunologically compromised individuals. In another embodiment, the infected host is a

plant.

Optionally, nonliving material such as but not limited to soil, surfaces, etc.,

may be usefully treated with the instant compounds to kill bacteria.

The present invention is also useful in a method of treating neoplastic disorders,

proliferative disease, psoriasis, lichen planus, verruca vulgaris, verruca plana juvenile,

osteoporosis, osteomyelitis, seborrheic keratosis, central nervous system disorders,

psychosis, depression, pain, cardiovascular disorders, ulcers, neurodegenerative disorders,

stroke, phlebitis, pulmonary emboli, renal disorders, diseases of the ear, inflammatory

disease, transplantation rejection, graft versus host disease, and autoimmune disease in a

host in need of such treatment, which method comprises administering a therapeutically

effective amount of compounds represented by general Formula I and II. The present invention also relates to benoazepines which are useful as vasodilators, vasopressin

antagonists, vasopressin agonist, oxytocin antagonist, anti-hypotensive agents, anti-

arrhythmic, anti-fibrillatory, diuretics, platelet aggregation inhibitors, anti-coagulants,

immunomodulatory agent, or agents that promote release of growth hormone. The present

invention is also useful in the a method of treating neurofibromatosis, rheumatoid arthritis,

asthma, myocardial infarction, human papilloma viral infection, Kaposi's sarcoma, otis

media, cystic fibrosis, scleroderma. In one embodiment, the infected hosts are animals,

preferably mammals, most preferably human.

The compositions of the instant invention can also be used in a wide variety of

agriculturally beneficial species such as tobacco, vegetables including cucumber, the

Cruciferae, pea, and corn, beans such as soy beans, grains including cotton, rice, alfalfa, oat

and other cereals, fruits, including apple, pear, peach, plum, tomato, banana, prune and citrus

fruits, tubers and bulbs including potatoes and onions, nuts including walnut, grasses

including sugar cane and the like.

The compositions of the instant invention also are beneficial in the treatment of nursery plants

and ornamental plants such as flowers, including chrysanthemum, begonia, gladiolus,

geranium, carnations and gardenias.

The compositions of the instant invention also find use in the treatment of

shade trees, forest trees, annual field crops and biannual field crops. Other plant species in

which the compositions of the invention can be used are Espinas, Cotoneaster,

Phyrachanthas, Stranvaesis, Fraxinus, Pyrus, Malus, Capsicum, Cydonia, Crataegus and

Soreus.

Besides their use as medicaments in human, veterinary or plant therapy, the compounds of the invention can also be used as animal growth promoters. For this purpose, a

compound of the invention is administered orally in a suitable feed. The exact concentration

employed is that which is required to provide for the active agent in a growth promotant

effective amount when normal amounts of feed are consumed.

The addition of the active compound of the invention to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration. Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed. The way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as such as "Applied Animal Nutrition", W.H. Freedman and CO., S. Francisco, USA, 1969 or "Livestock Feeds and Feeding" O and B books, Corvallis, Oreg., USA, 1977).

Antibacterial activity can be determined by several standard methods well known by those skilled in the art, including disc diffusions methods, broth dilution minimal inhibitory concentration (MIC) methods, etc., including the detailed method outlined below and as defined by the National Committee of Clinical Laboratory Standards in the United States.

Anti-fungal activity can be determined by several standard methods well known by those skilled in the art (see for instance, U.S. 5,885,782), including disc diffusion methods, broth dilution minimal inhibitory concentration (MIC) methods and microplate growth assay.

MIC, broth dilution method

A. Starting culture

Cultures of bacteria are initially brought up from the freezer stocks onto chocolate agar plates by streaking a loop-full, then incubated for 18 hours at 35-37°C in a 5% CO2 incubator.

B. First subculture

Five to 10 colonies are picked from the chocolate agar plate for subculture to Brain- Heart Infusion (BHI) broth or Mueller Hinton broth or BHI containing 4% serum and incubated as described. C. Final culture

Evaluate the optical density of the organisms in the wells of a 96 well microtiter plate with and without the test compound. The optical density of the organisms in the presence of an active compound will be less than the optical density of the same organism untreated. The activity of the compounds is described as either negative or the lowest concentration inhibiting growth. The results are depicted in Table III, where +/- represents the least activity and ++++ represents the greatest activity. In Table IV, the results are depicted where MIC represents the lowest concentration of antibiotic that inhibits bacterial growth.

Table III: Antibacterial activity:

TABLE IV: ANTIBACTERIAL ACTIVITY

Example Antibacterial Example Antibacterial

# Activity # Activity (micrograms/ml) (micrograms/ml)

Campylobacter Helicobacter Campylobacter Helicobacter jejuni pylori jejuni pylori

2 50 >200 22 >200 >200

3 100 50-100 23 200 50

4 50 125-250 24 >200 100

5 >200 100 25 >200 12.5

6 50 12.5 26 125 12.5

7 >200 100 27 >200 12.5

8 50 >200 28 >200 25

9 >200 100 29 >200 >200

10 >200 >200 30 >200 1.56

11 100-200 50 31 >200 0.78

12 >200 50 32 >200 0.78

13 >200 6.25-12.5 33 >200 0.78

14 >200 50 34 >200 12.5

15 >200 >200 35 >200 12.5

16 >200 >6.25 36 >200 6.25

17 >200 200 37 50 50

18 >200 50 38 125 250

20 >200 100 175 30 1

21 >200 12.5-25 176 >250 4

Table V

Antibacterial Activity

Table V (cont.)

Antibacterial Activity

EXAMPLES FOR ANTIBIOTIC EVALUATION

Example : Helicobacter Colonization Model

The Helicobacter gastric colonization model, using methods generally known

to those skilled in the art, is employed to evaluate the antibiotic activity against H. pylori or

H.felis in vivo. For example, groups of female Balb/C mice (~6 weeks of age or 18-22g ) are

colonized by oral gavage for a suitable period of time to detect an antibiotic effect ( for

example 4-14 days) , then treated with test compound (for example, 7-12 days later).

Following a period of time, half of the stomach from mice are scraped and plated onto

bacterial culture medium, for instance BHI agar containing antibiotics and horse serum. The

plates are incubated and colonies counted to determine whether any bacteria can be recovered

from the gastrointestinal tract after treatment. Additionally, urease enzymatic assay, using

methods generally known to those skilled in the art, is used to determine whether urease

activity from Helicobacter is present. The absence of or reduction of bacteria on the culture

plate or urease activity from treated mice, compared to that from non-treated mice, indicates

the test substance is effective as an antibiotic against H. pylori or H. felis.

Example: Sepsis Model

The sepsis model, using methods generally known by those skilled in the art,

is used to evaluate the prophylactic antibiotic efficacy of test compounds against a number of

bacteria. Basic methods include, for example, challenging mice intraperitoneally with a

lethal amount of one or more bacteria, for example Staphylococcus aureus, and 7% mucin.

Approximately 1 hr after challenge, the mice are treated by any route of administration, for

example, subcutaneously, orally or intraperitoneally, with various concentrations of test

compound. Vancomycin or another antibiotic is administered to a group of mice as the positive control and the placebo group of mice is administered the vehicle alone. Mortality is

monitored for 96 hr. A reduction of the comparative mortalities or an increase in survival

time in the various experimental groups provides evidence of efficacy of the test compound.

Example: Wound Infection Model

The wound healing model, using methods generally known by those skilled in

the art, is used to measure the efficacy of topically applied compounds against any bacteria,

for example, Staphylococcus aureus. Basic methods include, for example, inserting a suture

impregnated with S. aureus subcutaneously on the shaved backs of mice. An incision is made

along the cord. After 24 hours, topical therapy with the test compound, placebo ointment or

neomycin-polymyxin-B-bacitracin topical ointment (as control) (twice daily) is initiated.

Ninety-six hours post-infection, the wound is sampled for microbial burden.

Alternatively, the backs of mice or rabbits are shaved. Gently scraping the

skin, a superficial wound is created. About 10 (5)- 10(6) cfu/20ul of any bacteria, for

example, S aureus, is applied to the wound. The latter is occluded with a sterile plastic film

and secured with an adhesive tape. Topical therapy is employed approximately 24 hours later

using the above-mentioned treatment regimen. After a suitable period of time ( for example

24-38 hours), the wound is swabbed to determine the microbial load. A reduction is bacterial

load in the wound is evidence that the compound is efficacious.

Example: Shigella Wasting Model

Using methods well known to those skilled in the art, the Shigella sublethal

wasting model is used to evaluate the antibiotic activity against Shigella flexneri or Shigella

sonnei. For example, groups of mice are challenged intranasally with a sublethal wasting dose (~lθ5 cfu) of either live Shigella βexneri or Shigella sonnei. Immediately before and at

1, 2, 5 and 7 days following challenge animals are weighed and the mean group weight

determined. Approximately 1 hour after challenge, the mice are treated by any route of

administration, for example, subcutaneously, orally or intravenously, with various

concentrations of test compound. A suitable antibiotic is administered to a group of mice as

the positive control and the placebo group of mice is administered vehicle alone. Antibiotic

activity is measured by a reduction of weight loss.

Example: Campylobacter jejun Lethality Model

Using methods well known to those skilled in the art, the C. jejuni mortality

model is used to evaluate the antibiotic activity against Campylobacter jejuni. For example,

groups of mice are challenged with a single lethal dose of live C. jejuni (~10^ cfu) mixed

with iron dextran in endotoxin free PBS delivered intraperitoneally. Approximately 1 hour

after challenge, the animals are treated by any route of administration, for example,

subcutaneously, orally or intraperitoneally, with various concentrations of test compound. A

suitable antibiotic is administered to a group of animals as the positive control and the

placebo group of animals is administered vehicle alone. Antibiotic activity is measured by a

reduction in mortality.

Example: Campylobacter jejuni Fecal Shedding Model

Using methods well known to those skilled in the art, the C. jejuni fecal

shedding model is used to evaluate the antibiotic activity against Campylobacter jejuni. For example, BALB/c mice are challenged nasally or orally with 10°^* C. jejuni. Approximately 1

hour after challenge, the mice are treated by any route of administration, for example,

suitable antibiotic is administered to a group of mice as the positive control and the placebo

group of mice is administered vehicle alone. The duration of fecal shedding is determined by

monitoring over a 9 day period. Antibiotic activity is measured by a reduction in numbers of

bacteria shed.

Example: Chlamydia pneumoniae lung model

Using methods well known to those skilled in the art, the Chlamydia

pneumoniae lung model is used to evaluate the antibiotic activity against Chlamydia

pneumoniae. For example, BALB/c are inoculated intranasally with approximately 5 X 10^

IFU of C. pneumoniae, strain AR39 in 100 μl of SPG buffer. Approximately 1 hour after

challenge, the mice are treated by any route of administration, for example, subcutaneously,

orally or intravenously, with various concentrations of test compound. A suitable antibiotic is

administered to a group of mice as the positive control and the placebo group of mice is

administered vehicle alone.

Lungs are taken from mice at days 5 and 9 post-challenge and immediately

homogenized in SPG buffer (7.5% sucrose, 5mM glutamate, 12.5 mM phosphate pH 7.5).

The homogenate is stored frozen at -70°C until assay. Dilutions of the homogenate are

assayed for the presence of infectious Chlamydia by inoculation onto monolayers of

susceptible cells (for example HL cells). The inoculum is centrifuged .onto the cells and the

cells are incubated for three days at 35°C in the presence of 1 μg/ml cycloheximide. After incubation the monolayers are fixed with formalin and methanol then immunoperoxidase

stained for the presence of Chlamydial inclusions using convalescent sera from rabbits

infected with C. pneumoniae and metal-enhanced DAB as a peroxidase substrate. Antibiotic

activity is measured by a reduction in numbers of Chlamydia.

Example: Chlamydia trachomatis infertility model

Using methods well known to those skilled in the art, the Chlamydia

trachomatis infertility model is used to evaluate the antibiotic activity against Chlamydia

trachomatis. Female C3HeOuJ mice are administered a single intraperitoneal dose of

progesterone (2.5 mg in pyrogen-free PBS, Depo-Provera, Upjohn) to stabilize the uterine

epithelium. One week later, animals are infected by bilateral intraoviduct inoculation with

approximately 5 X 10^ inclusion forming units (IFU) of C. trachomatis (including but not

limited to serovar F, strain Nil) in 100 μl of sucrose phosphate glutamate buffer (SPG). At

the appropriate time (for example, approximately 1 hour or 1 week after challenge), the mice

are treated by any route of administration, for example, subcutaneously, orally or

intravenously, with various concentrations of test compound. A suitable antibiotic is

administered vehicle alone. At week 3, females from each group are caged with 8-10 week

old

male C3H mice for a 2 month breeding period to assess fertility (1 male for every 2 females

per cage with weekly rotation of the males within each group, animals from different

experimental groups were not mixed). Palpation and periodic weighing are used to determine

when animals in each pair become pregnant. The parameters used to estimate group fertility are: F, the number of mice which littered at least once during the mating period divided by

the total number of mice in that study group; M, the number of newborn mice (born dead or

alive) divided by the number of litters produced in that group during the mating period; and

N, the number of newborn mice (born dead or alive) divided by the total number of mice in

that group. Antibiotic activity is measured by an increase in fertility.

Example: Neisseria gonorrhoeae lethality model

Using methods well known to those skilled in the art, the N gonorrhoeae

mortality model is used to evaluate the antibiotic activity against Neisseria gonorrhoeae. For

example, groups of mice are challenged with a single lethal dose of live N gonorrhoeae

(-10°^" cfu) and 7% mucin in endotoxin free PBS delivered intraperitoneally. Approximately

1 hour after challenge, the animals are treated by any route of administration, for example,

reduction in mortality.

Example: Neisseria gonorrhoeae vaginal challenge model

Using methods well known to those skilled in the art, the N. gonorrhoeae

vaginal infection model is used to evaluate the antibiotic activity against Neisseria

gonorrhoeae. For example, groups of mice are vaginally challenged with a dose of live N.

gonorrhoeae in endotoxin free PBS. Approximately 1 hour after challenge, the animals are

treated by any route of administration, for example, subcutaneously, orally or intraperitoneally, with various concentrations of test compound. A suitable antibiotic is

administered to a group of animals as the positive control and the placebo group of animals is

administered vehicle alone. Vaginal clearance rates are determined for each group by daily

sampling (swab) and cultivation of vaginal secretions. Antibiotic activity is measured by a

reduction in the number of N gonorrhoeae.

While the preferred embodiments of the invention have been illustrated and

described, it will be appreciated that various changes can be made therein without departing

from the spirit and scope of the invention.

Claims

WHAT IS CLAIMED IS:

Claim 1. A compound of the following Formula II

wherein:

R¹ is H, with the proviso that if R is H R⁴ and R⁵ are not both H, substituted or

unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted

or unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mC(=O)R, -(CH₂)_nCN,

(CH₂)_mC(=Q)OR, -C(=O)N(R)₂, -OR, -SO₂R, -C(=O)N(H)(NHR), -(CH₂)„(OAr),

-(CH₂)_n(OR), -(CH₂)_mC(=NH)NH₂, , -(CH₂)_nNHAr or a functional group of the

following structure:

wherein R is N,N-dimethylethylenediamino, 2-methoxyethylamino,

benzylamino, 3-trifluormethylbenzylamino, cyclopropylamino, propylamino,

allylamino, 3-methoxybenzylamino, 2-(4-methoxyphenyl)ethylamino, cyclohexanemethylamino, 2,4-dichlorophenethylamino,

3-diehylaminopropyldiamino, 3-ethoxypropylamino,

N,N-di-N-butylethylenediamino, 1 -(2-aminoethyl)piperidine,

1 -(3-aminopropyl)imidazole, 4-(2-aminnoethyl)morpholine, 2-(aminomethyl)- 1 -

ethyl-pyrrolidine, 2-(2-aminoethyl)pyridine or 3-(aminomethyl)pyridine;

R² and R³ are independently H, halogen, -N₃, -CN, substituted or unsubstituted,

straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or

unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mN(R)₂, -(CH₂)_mNH(Aa),

-(CH₂)_mNC(=O)R, -(CH₂)_mC(=O)NHOR, -(CH₂)_mC(=O)OR, -

(CH₂)_mC(=O)NH(Aa), -(CH₂)_mC(=O)N(R)₂, and (CH₂)_nC(=O)NH(Aa),

or a functional group of the following structure:

R⁴ and R⁵ are independently H, halogen, -NO₂, -CN, substituted or unsubstituted, straight

chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted -Ar

or -(CH₂)_nAr, substituted or unsubstituted primary amine or secondary amine,

-NHC(=O)R, -NHC(=Q)NHC(=O)OR, -NH(C=Q)NHR, -QR, -OC(=O)N(R₂),

-C(=O)OR, -OSi(R)₃> -C(=O)N(R ), NH-SO₂- R⁷> where R⁷ is

2,4-difluorophenyl, 2-fluorophenyl, 4-isopropylphenyl,

2,5-dimethoxyphenyl, 3,4 -dichlorophenyl, 2,3,5,6-tetramethylphenyl, 2-chlorophenyl, 3-nitrophenyl, 4-acetylphenyl, 4-methyl-3-nitrophenyl,

4-butylphenyl, 4-nitrophenyl, 4-propylphenyl, 5-fluoro-2-methylphenyl,

4-chloro-2, 5 -dimethylphenyl,

or R⁴ and R⁵ are independently a functional group of the following structure:

with the proviso that R⁴ and R⁵ cannot both be H;

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 (CH₂)_nAr;

Ar is, aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic, heterocyclyl, or heteroaryl;

Aa is an amino acid;

Q is O or S;

Z is O or S; m is 0, 1 or 2; n is 1, 2 or 3; and pharmaceutically acceptable acid addition salts, base addition salts or prodrug forms thereof.
Claim 2. A pharmaceutical composition comprising a compound of Formula II

wherein:

R¹ is H, with the proviso that if R! is H R⁴ and R⁵ are not both H, substituted or

unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted

or unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mC(=O)R, -(CH₂)_nCN,

(CH₂)_mC(=Q)OR, -C(=O)N(R)₂, -OR, -SO₂R, -C(=O)N(H)(NHR), -(CH₂)_n(OAr),

-(CH₂)_n(OR), -(CH₂)_mC(=NH)NH₂, , -(CH₂)_nNHAr or a functional group of the

following structure:

wherein R is N,N-dimethylethylenediamino, 2-methoxyethylamino,

benzylamino, 3-trifluormethylbenzylamino, cyclopropylamino, propylamino,

allylamino, 3-methoxybenzylamino, 2-(4-methoxyphenyl)ethylamino,

cyclohexanemethylamino, 2,4-dichlorophenethylamino, 3-

diehylaminopropyldiamino, 3-ethoxypropylamino, N,N-di-N- butylethylenediamino, 1 -(2-aminoethyl)piperidine,

l-(3-aminopropyl)imidazole, 4-(2-aminnoethyl)morpholine, 2-(aminomethyl)-l -

ethyl-pyrrolidine, 2-(2-aminoethyl)pyridine or 3-(aminomethyl)pyridine;

R² and R³ are independently H, halogen, -N₃, -CN, substituted or unsubstituted,

straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or

unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mN(R)₂, -(CH₂)_mNH(Aa), -

(CH₂)_mNC(=O)R, -(CH₂)_mC(=O)NHOR, -(CH₂)_mC(=O)OR, -

(CH₂)_mC(=O)NH(Aa), -(CH₂)_mC(=O)N(R)₂, and (CH₂)_nC(=O)NH(Aa),

or a functional group of the following structure:

R⁴ and R ) 5⁵ are independently H, halogen, -NO₂, -CN, substituted or unsubstituted, straight

chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted -Ar

or -(CH₂)_nAr, substituted or unsubstituted primary amine or secondary amine,

-NHC(=O)R, -NHC(=Q)NHC(=O)OR, -NH(C=Q)NHR, -QR, -OC(=O)N(R₂),

-C(=O)OR, -OSi(R)₃> -C(=O)N(R ), NH-SO₂- R⁷> where R⁷ is

2,4-difluorophenyl, 2-fluorophenyl, 4-isopropylphenyl,

2,5-dimethoxyphenyl, 3,4 -dichlorophenyl, 2,3,5,6-tetramethylphenyl,

2-chlorophenyl, 3-nitrophenyl, 4-acetylphenyl, 4-methyl-3-nitrophenyl,

4-butylphenyl, 4-nitrophenyl, 4-propylphenyl, 5-fluoro-2-methylphenyl,

4-chloro-2,5-dimethylphenyl, or R⁴ and R are independently a functional group of the following structure:

with the proviso that R⁴ and R⁵ cannot both be H;

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 (CH₂)_nAr;

Ar is, aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic, heterocyclyl, or heteroaryl;

Aa is an amino acid;

Q is O or S;

Z is O or S; m is 0, 1 or 2; n is 1, 2 or 3; and pharmaceutically acceptable acid addition salts, base additional salts or prodrug forms thereof: and pharmaceutically acceptable carriers or excipients.
Claim 3. A compound of the following Formula (I):

wherein:

R¹ is H, with the proviso that if R* is H R⁴ and R⁵ are not both H, substituted or unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mC(=O)R, -(CH₂)_nCN, (CH₂)_mC(=Q)OR, -C(=O)N(R)₂, -OR, -SO₂R, -C(=O)N(H)(NHR), -(CH₂)_n(OAr), -(CH₂)_n(OR), -(CH₂)_mC(=NH)NH₂, -(CH₂)_nNHAr or

wherein R is N,N-dimethylethylenediamino, 2-methoxyethylamino,

benzylamino, 3-trifluormethylbenzylamino, cyclopropylamino, propylamino,

allylamino, 3-methoxybenzylamino, 2-(4-methoxyphenyl)ethylamino,

cyclohexanemethylamino, 2,4-dichlorophenethylamino, 3-

diehylaminopropyldiamino, 3-ethoxypropylamino, N,N-di-N-

butylethylenediamino, 1 -(2-aminoethyl)piperidine,

l-(3-aminopropyl)imidazole, 4-(2-aminnoethyl)morpholine, 2-(amino methyl)- 1

ethyl-pyrrolidine, 2-(2-aminoethyl)pyridine or 3-(aminomethyl)pyridine

R² and R³ are independently H, halogen, -N₃, -CN, substituted or unsubstituted, straight

chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted

Ar or -(CH₂)_nAr, -(CH₂)_mN(R)₂, -(CH₂)_mNH(Aa), -(CH₂)_mNC(=O)R,

-(CH₂)_mC(=O)NHOR, -(CH₂)_mC(=O)OR, -(CH₂)_mC(=O)NH(Aa),

-(CH₂)_mC(=O)N(R)₂, -(CH₂)_nC(=O)NH(Aa), and

with the proviso that R² and R³ cannot both be H;

R⁴ and R⁵ are independently H, halogen, -NO₂, -CN, substituted or unsubstituted, straight

chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted -Ar

or -(CH₂)_nAr, substituted or unsubstituted primary amine or secondary amine,

-NHC(=O)R, -NHC(=Q)NHC(=O)OR, -NH(C=Q)NHR, -QR, -OC(=O)N(R₂),

-C(=O)OR, and -OSi(R)₃> -C(=O)N(R₂), NH-SO₂-R⁷ wherein R⁷ is

2,4-difluorophenyl, 2-fluorophenyl, 4-isopropylphenyl,

2,5-dimethoxyphenyl, 3,4 -dichlorophenyl, 2,3,5,6-tetramethylphenyl,

2-chlorophenyl, 3-nitrophenyl, 4-acetylphenyl, 4-methyl-3-nitrophenyl,

4-butylphenyl, 4-nitrophenyl, 4-propylphenyl, 5-fluoro-2-methylphenyl,

4-chloro-2,5-dimethylphenyl,

or R⁴ and R⁵ are independently a functional group of the following structure:

with the proviso that R and R cannot both be H;

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 (CH₂)_nAr; Ar is, aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic, heterocyclyl, or heteroaryl;

Aa is an amino acid;

Q is O or S;

Z is O or S; a and b are a single or double bond and when a is a double bond only R and R are present; m is 0, 1 or 2; n is 1, 2 or 3; and pharmaceutically acceptable acid addition salts, base addition salts or prodrug forms

thereof.
Claim 4. A pharmaceutical composition compounds of the following Formula (I):

wherein:

R¹ is H, with the proviso that if R! is H R⁴ and R⁵ are not both H, substituted or

unsubstituted, straight chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted

or unsubstituted -Ar or -(CH₂)_nAr, -(CH₂)_mC(=O)R, -(CH₂)_nCN,

(CH₂)_mC(=Q)OR, -C(=O)N(R)₂, -OR, -SO₂R, -C(=O)N(H)(NHR), -(CH₂)_n(OAr), -(CH₂)_n(OR), -(CH₂)_mC(=NH)NH₂, -(CH₂)_nNHAr or

wherein R is N,N-dimethylethylenediamino, 2-methoxyethylamino,

benzylamino, 3-trifluormethylbenzylamino, cyclopropylamino, propylamino,

allylamino, 3-methoxybenzylamino, 2-(4-methoxyphenyl)ethylamino,

cyclohexanemethylamino, 2,4-dichlorophenethylamino, 3-

diehylaminopropyldiamino, 3-ethoxypropylamino, N,N-di-N-

butylethylenediamino, 1 -(2-aminoethyl)piperidine,

l-(3-aminopropyl)imidazole, 4-(2-aminnoethyl)moφholine, 2-(amino methyl)- 1

ethyl-pyrrolidine, 2-(2-aminoethyl)pyridine or 3-(aminomethyl)pyridine

R² and R³ are independently H, halogen, -N₃, -CN, substituted or unsubstituted, straight

chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted

-Ar or -(CH₂)_nAr, -(CH₂)_mN(R)₂, -(CH₂)_mNH(Aa), -(CH₂)_mNC(=O)R,

-(CH₂)_mC(=O)NHOR, -(CH₂)_mC(=O)OR, -(CH₂)_mC(=O)NH(Aa),

-(CH₂)_mC(=O)N(R)₂, -(CH₂)_nC(=O)NH(Aa), and

with the proviso that R² and R³ cannot both be H; R⁴ and R⁵ are independently H, halogen, -NO₂, -CN, substituted or unsubstituted, straight

chain, branched or cyclic, alkyl, alkenyl, or alkynyl, substituted or unsubstituted -Ar

or -(CH₂)_nAr, substituted or unsubstituted primary amine or secondary amine,

-NHC(=O)R, -NHC(=Q)NHC(=O)OR, -NH(C=Q)NHR, -QR, -OC(=O)N(R₂),

-C(=O)OR, and -OSi(R)₃» -C(=O)N(R₂), NH-SO₂-R⁷ wherein R⁷ is

2,4-difluorophenyl, 2-fluorophenyl, 4-isopropylphenyl,

2,5-dimethoxyphenyl, 3,4 -dichlorophenyl, 2,3,5,6-tetramethylphenyl,

2-chlorophenyl, 3-nitrophenyl, 4-acetylphenyl, 4-methyl-3-nitrophenyl,

4-butylphenyl, 4-nitrophenyl, 4-propylphenyl, 5-fluoro-2-methylphenyl,

4-chloro-2 , 5 -dimethylphenyl,

or R⁴ and R⁵ are independently a functional group of the following structure:

with the proviso that R⁴ and R⁵ cannot both be H;

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 (CH₂)_nAr;

Ar is, aryl, arylalkyl, heterocycle, heterocyclic group, heterocyclic, heterocyclyl, or heteroaryl;

Aa is an amino acid;

Q is O or S;

Z is O or S; a and b are a single or double bond and when a is a double bond only R² and R³ are present; m is 0, 1 or 2; n is 1, 2 or 3; and pharmaceutically acceptable acid addition salts, base additional salts or prodrug

forms thereof: and pharmaceutically acceptable carriers or excipients.
Claim 5. A method for the treatment of bacterial infections which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula II in accordance with claim 1.
Claim 6. A method for the treatment of bacterial infections which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula I in accordance with claim 3.
Claim 7. A method of killing bacteria on an inert surface or sanitizing said surface comprising applying a compound of Formula II in accordance with claim 1.
Claim 8. A method of killing bacteria on an inert surface or sanitizing said surface comprising applying a compound of Formula I in accordance with claim 3.
Claim 9. The method of claims 5 and 6, wherein the host is an animal.
Claim 10. The method of claim 9 wherein said host is a mammal.
Claim 11. The method of claim 9 wherein the host is a bird.
Claim 12. The method of claim 10 wherein the mammal is a human.
Claim 13. The method of claim 9 wherein the animal is further administered a therapeutic partner.
Claim 14. The method of claim 13 wherein the therapeutic partner is selected from the group consisting of antibiotics steroids, vaccines, anti-oxidants, non-steroidal anti-inflammatories, antacids, antibodies, interferons, or cytokines.
Claim 15. The method of claim 14 wherein the compound of the Formula I or Formula II and the therapeutic partner are administered simultaneously.
Claim 16 The method of claim 13 wherein the compound of the Formula I or Formula II and the therapeutic partner are administered sequentially.
Claim 17 The method of treating a host comprising administering to a host in need of such

treatment a therapeutically effective amount of a compound of a composition in accordance

with claim 2 wherein the host has one or more disorders selected from the group consisting

of neoplastic disorders, proliferative disease, psoriasis, lichen planus, verruca vulgaris,

verruca plana juvenile, osteoporosis, osteomyelitis, seborrheic keratosis, central nervous

system disorders, psychosis, depression, pain, cardiovascular disorders, neurodegenerative

disorders, stroke, phlebitis, pulmonary emboli, renal disorders, diseases of the ear, inflammatory disease, transplantation rejection, graft versus host disease and autoimmune

disease .
Claim 18. A compound of Formula II or a pharmaceutically acceptable salt or prodrug

wherein R¹ is
R² is H , R³ is H, R⁴ is -NH-SO₂R⁷, R⁵ is OR wherein R⁷ is in accordance with claim 1.
Claim 19 A compound of Formula I or a pharmaceutically acceptable salt or prodrug

wherein, R³ is

wherein R¹ is a unsubstituted straight chain alkyl, R² is H, R³ is (CH₂)_m CO₂R, m=0, R⁴ is substituted secondary amine, R^ is QR, Q =O.
Claim 21. A compound of Formula I or Formula II wherein R⁴ is at position 7 and R^ is at position 8.
Claim 22. A compound of Formula I or Formula II wherein R^ is at position 8 and is H or NH(C=Q)NR .
Claim 23. A compound of Formula I or Formula II wherein R! is 3-flurobenzyl or CH₂CN and R³ is H or CO₂But.
Claim 24. A method for the treatment of bacterial infections which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of any one of claims 18 -23.
Claim 25. A method of killing bacteria on an inert surface or sanitizing said surface comprising applying a compound of any one of claims 18-23.
Claim 26. The method of claim 24 wherein the host is an animal.
Claim 27 The method of claim 26 wherein said host is a mammal.
Claim 28. The method of claim 26 wherein the host is a bird.
Claim 29. The method of claim 27 wherein the mammal is a human.
Claim 30. The method of claim 24 wherein the animal is further administered a therapeutic partner.
Claim 31. The method of claim 30 wherein the therapeutic partner is selected from the group consisting of antibiotics steroids, vaccines, anti-oxidants, non-steroidal anti-inflammatories, antacids, antibodies, interferons, or cytokines..
Claim 32. The method of claim 30 wherein the compound of the Formula I or Formula II and the therapeutic partner are administered simultaneously.
Claim 33 The method of claim 30 wherein the compound of the Formula I or Formula II and the therapeutic partner are administered sequentially.
Claim 34 The method of treating a host comprising administering to a host in need of such

treatment a therapeutically effective amount of a compound of a composition in accordance

with claim 2, 4 or 18-23 wherein the host has one or more disorders selected from the group

consisting of neoplastic disorders, proliferative disease, psoriasis, lichen planus, verruca

vulgaris, verruca plana juvenile, osteoporosis, osteomyelitis, seborrheic keratosis, central

nervous system disorders, psychosis, depression, pain, cardiovascular disorders, ulcers,

neurodegenerative disorders, stroke, phlebitis, pulmonary emboli, renal disorders, diseases of

the ear, inflammatory disease, transplantation rejection, graft versus host disease and

autoimmune disease.
Claim 35. The method of claim 34 wherein the host is an animal .
Claim 36 The method of claim 34 wherein said host is a mammal.
Claim 37. The method of claim 34 wherein the host is a bird.
Claim 38. The method of claim 36 wherein the mammal is a human.
Claim 39. The method of claims 34 wherein the animal is further administered a therapeutic partner.
Claim 40. The method of claim 39 wherein the therapeutic partner is selected from the group consisting of antibiotics steroids, vaccines, anti-oxidants, non-steroidal anti-inflammatories, antacids, antibodies, interferons, or cytokines.
Claim 41. The method of claim 39 wherein the compound of the Formula I or Formula II and the therapeutic partner are administered simultaneously.
Claim 42 The method of claim 39 wherein the compound of the Formula I or Formula II and the therapeutic partner are administered sequentially.
Claim 43. A process for making the compound according to claim 1 as depicted in Scheme 1.
Claim 44. A process for making the compound according to claim 1 as depicted in Scheme 4.
Claim 45. A process for making the compound according to claim 3 as depicted in Scheme 1.
Claim 46. A process for making the compound according to claim 3 as depicted in Scheme 4.