WO2009037302A1

WO2009037302A1 - 5-substituted-1, 4-benz0diazepines as phosphodiesterase inhibitors

Info

Publication number: WO2009037302A1
Application number: PCT/EP2008/062425
Authority: WO
Inventors: Mustapha Abarghaz; Said Oumouch; Yan Lagouge
Original assignee: VIA Pharmaceuticals Inc
Current assignee: VIA Pharmaceuticals Inc
Priority date: 2007-09-18
Filing date: 2008-09-18
Publication date: 2009-03-26
Anticipated expiration: 2010-03-18

Abstract

Novel 7, 8 dialkoxy-5 - (amino alkyl phenyl) - 1, 4 -benzodiazepines of formula I with said amino being substituted or forming a nitrogen containing heterocyclic alkyl ring, which 1, 4- benzodiazepines are inhibitors of phosphordiesteraste type IV (PDE-4) making then active as anti- inflammatory agents.

Description

5-SUBSTITUTED-l , 4-BENZODIAZEPINES AS PHOSPHODIESTERASE INHIBITORS

FIELD OF THE INVENTION

The field of this invention relates to novel 5-(substituted alkylene-phenyl)-i,4- benzodiazepines which are inhibitors of phosphodiesterase type-IV (PDE-4) making them active as anti-inflammatory agents.

BACKGROUND OF THE INVENTION

Phosphodiesterase type-IV (PDE-4) belongs to a complex superfamily of at least 11 isozymes that regulates the intracellular level of cyclic adenosine-3',5'- monophosphate (cAMP) and/or cyclic guanylate-3',5'- monophosphate (cGMP) ubiquitous second messengers involved in regulating many cellular activities. PDE-4 is characterized by its selective, high affinity hydrolytic degradation of the second messenger cyclic nucleotide, adenosine 3',5'-cyclic monophosphate (cAMP), and by its sensitivity to inhibition by rolipram. Several isoforms of PDE-4 exist. They are derived from four distinct but related genes, 4A, 4B, 4Q and 4D which are differentially expressed in a wide variety of tissues and cell types including inflammatory cells, cardiovascular tissue and brain, heart, kidney, blood as well as in smooth muscle cells. The biology of PDE-4 is described in several recent reviews, see, for example, Houslay, Prog. Nucleic Acid Res. MoL Biol. 200i_; 69, 249-315; Souness et al., Immunopharmacol. 2000, 47, 127-162; or Conti and Jin, Prog. Nucleic Acid Res. MoI. Biol. 1999, 63, 1-38,

The involvement of PDE-4 iⁿ pathological conditions, diseases and disorders associated with these tissues suggests pharmacological intervention in a variety of disorders involving inflammatory states such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), vascular disorders, autoimmune pathology and neurological disorders such as depression, Parkinson's disease and Alzheimer's disease. Among drugs in development for the treatment of inflammatory airways diseases, such as COPD is Ariflo® (SB 207499, cilomilast, GlaxoSmithKline), which is a selective, prototypical PDE-4 inhibitor which improves lung function, symptom? and quality of life indicators among COPD patients. Among drugs which have shown promise in the treatment of depression, Rolipram® (ZK 62711, Schering AG) is active in the central nervous system and is suggested as an antidepressant. It was also found that this PDE-4 inhibitor improves memory in both long-term potential and contextual learning. Other examples of PDE-4 inhibitors include cipamfylline, arofyline, cilomilast, roflumilast, mesopram and pumafentrine.

PDE-4 inhibitors provide therapeutic potential through selective elevation of intracellular cAMP and therefore can be potent antidepressant, neuroprotective, neuroregenerative and anti-inflammatory agents. Several studies have demonstrated that inhibition of PDE-4 leads to an elevation of the intracellular cAMP and produces a variety of biological effects, including, for example :t he relaxation of airway smooth muscle, inhibition of the activation of inflammatory cells and modulation of the activity of pulmonary nerves. For references, see, for example, Torphy et al., Environ. Health Perspect. 102 Suppl. 10, 79-84, 1994; Duplantier et al., J. Med. Chem. 39 120-125, 1996; Schneider et al., Pharmacol. Biochem. Behav. 50 211-217, 1995; Banner and Page, Br. J. Pharmacol. 114 93-98, 1995; Barnette et al., J. Pharmacol Exp. Ther. 273 674-679, 1995; Wright et al. Can. J. Physiol. Pharmacol. 75 1001-1008, 1997; Manabe et al. Eur. J. Pharmacol. 332 97-107, 1997; and Ukita et al. J. Med. Chem. 42 1088-1099, 1999-

Accordingly, there continues to be considerable interest with regard to the discovery of further selective inhibitors of PDE-4. The international application WO 02/098865 describes i,4-benzodiazepin-2-one and 2,3-benzodiazepin-4-one as PDE-4 inhibitors.

The most frequent side -effects of the prototypical PDE-4 inhibitors such as Rolipram® and other PDE-4 inhibitors, are nausea and vomiting, effects which severely restrict their therapeutic utility. Thus PDE-4 inhibitors with an improved side effect profile will consequently have a much improved therapeutic utility. BRIEF SUMMARY QF THE INVENTION

In accordance with this invention, it has been discovered that novel 5- (substituted alkylene phenyl) -1,4-benzodiazepines of the formula I:

wherein Ri and R₂ are lower alkoxy; n is an integer from i to 5; R₃ is hydrogen or lower alkyl; R₄ is hydrogen or lower alkyl; R₅ is lower alkyl,

O

where ^- ^ is a ring selected from the group consisting of phenyl, a 3 to 10 membered cycloalkyl ring and a 4 to 7 membered heterocycloalkyl or a 5 or 6 membered heteroaromatic ring with said hetero rings containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen: or R₄ and R₅ can also be taken together with their attached nitrogen atom to form a nitrogen containing ring of the formula:

wherein the ri is a nitrogen containing 5 to 7

membered heterocycloaiicyi ring containing from 0 to 2 additional hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; Re is lower alkyl; R₇ is hydrogen, lower alley! , hydroxy, lower alkoxy, halogen or trifluoromethyl; Rg is hydrogen, hydroxy, lower alkoxy , halogen, trifluoromethyl or lower alkyl; R₉ is hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, trifluoromethyl,

or when Rs and R₉ are substituted on adjacent carbon atoms, they can also be taken together with said attached carbon atoms to form a ring selected from the group consisting of phenyl, cycloalkyl containing 5 to 10 carbon atoms, or a 4 to 7 membered heterocycloalkyl ring or a 5 or 6 membered heteroaromatic ring with said hetero rings containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; or when Rs and R₉ are substituted on the same carbon atom of said heterocycloalkyl ring, they can also form oxo or be taken together with their attached carbon atom to form a 5 to 10 membered cycloalkyl ring or a 4 to 7 membered heterocycloalkyl ring, with said hetero ring containing from 1 to 2 hetero atoms selected from the group oxygen, sulfur and nitrogen with said rings can being unsubstituted or substituted in 1 or 2 positions with substitutents selected from the group consisting phenyl, oxo, halogen, trifluoromethyl or lower alkyl;

is a ring selected from the group consisting of phenyl, a 3 to 10 membered cycloalkyl , a 4 to 7 membered heterocycloalkyl or a 5 or 6 membered heteroaromatic ring with said hetero ring containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; Rj₀ and R_u are individually hydrogen, hydroxy, lower alkoxy, halogen or trifluoromethyl or when Ri₀ and Rn are substituted on adjacent carbon atoms, they can be taken together with said attached carbon atoms to form a ring selected f/om the group consisting of a phenyl ring , a cycloalkyl ring containing from 5 to 10 carbon atoms, a 4 to 7 membered heterocycloalkyl ring, a 5 or 6 membered heteroaromatic ring with said hetero rings containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen and all of said rings being unsubstituted or substituted with lower alkyl, halogen, trifluoromethyl or lower alkoxy; Rj₂ is hydrogen or phenyl; Ri₃ is phenyl; x and v are integers from 0 to 1 and y is an integer from 0 to 6; or pharmaceutically acceptable salts thereof inhibit the activity of PDE-4 and are potential anti-inflammatory agents for use in therapeutic treatment, prevention or suppression of pathological conditions, diseases and disorders associated with PDE-4 activation. While the compounds of formula I above are potent and selective PDE-4 inhibitors, they have a reduced propensity to cause emetic side effect.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with this invention the compounds of formula I and its pharmaceutically-acceptable salts inhibit the activity of PDE-4. Therefore these compounds may be used in therapeutic treatment, prevention or suppression of pathological conditions, diseases and disorders associated with PDE-4 activation such as that produced by inflammation. The compounds and the compositions of the invention are of particular interest as anti-inflammatory agents for use in therapy, especially in the treatment of pathological conditions, diseases and disorder in the inhibition of inflammatory pathology of the central nervous system or neuroinflammation. Therefore the compounds of this invention may be useful in treating inflammatory conditions in various diseases which include asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), vascular disorders, autoimmune pathology and neurological disorders such as depression, Parkinson's disease and Alzheimer's disease.

As used herein the term halogen includes the four halogens chlorine, fluorine, bromine and iodine.

As used in the specification, the term "lower alkyl", alone or in combination, means a monovalent straight or branched-chain saturated hydrocarbon alkyl group containing from one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl and the like. The term "cycloalkyl", unless otherwise indicated, means a cycloalkyl substituent which is a monovalent unsubstituted 3- to 10-membered monocyclic bicyclic or tricyclic saturated carbocylic hydrocarbon ring. Among the preferred cycloalkyl substituents are cyclopropyl, cyclobutyl, cyclohexyl, adamantanyl. Where the cycloalkyl substituent forms the outer fused ring i,e. when Rs and R₉ taken together or when Ri₀ and R_n are taken together with their attached carbon atoms to form a cycloalkyl ring, the cycloalkyl ring so formed contains from 5 to 10 carbon atoms.

The term "lower alkoxy" means a straight-chain or branched- chain alkoxy group formed from lower alkyl containing from one to six carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like.

The term "heterocycloalkyl" refers to a monovalent 4 to 7 membered monocyclic saturated ring containing 3 to 5 carbon atoms and one or two hetero atoms selected from the group consisting of oxygen, sulfur or nitrogen. Among the preferred heterocyclic alkyl groups are included mopholinyl, piperidinyl, piperazinyl.

The term "heteroaromatic ring" refers to a monovalent 5 on 6 membered monocyclic heteroaromatic ring containing from 3 to 5 carbon atoms and from 1 to 2 hetero atoms selected from the group consisting of oxygen, nitrogen or sulfur. Among the preferred heteroaromatic groups are included pyridinyl, pyrimidinyl, furanyl, and the like.

The term "lower alkylene" designates a divalent saturated straight or branch chain hydrocarbon substituent containing from one to six carbon atoms.

Among the preferred embodiments of the compound of formula I-A are compounds of the formula;

wherein n, y, , R₁, R₂₁R₃,

and R₇ are as above; or pharmaceutically acceptable salts thereof; compounds of the formula:

wherein, n, Ri, R₂, R₃ are as above,

and R's and R'₉ are individually hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, trifluoromethyl, or when R's and R'₉ are substituted on adjacent carbon, atoms, they can also be taken together with said attached carbon atoms to form a ring selected from the group consisting of phenyl, cycloalkyl containing 5 to 10 carbon atoms, or a 4 to 7 membered heterocyclic or a 5 or 6 membered heteroaromatic ring, with said hetero rings containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; or when R's and R₉ are substituted on the same carbon atom of a heterocycloalkyl ring, they can also form oxo or be taken together with their attached carbon atom to form a ring selected from the group consisting of phenyl, a 5 to IO membered cycloalkyl ring or a 4 to 7 membered heterocycloalkyl ring with said hetero rings containing from 1 to 2 hetero atoms selected from the group oxygen, sulfur and nitrogen where all of said rings can be unsubstituted or substituted in 1 or 2 positions with substitutents selected from the group consisting phenyl, oxo, halogen, trifiuoromethyl or lower alkyl; or pharmaceutically acceptable salts thereof; compounds of the formula:

wherein Ri, R₂, R₃, Ri₀, Rπ_? n, v and y are as above

and R"s is hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen or trifloromethyl; or pharmaceutically acceptable salts thereof; or compounds of the formula:

wherein, n,x,Ri, R₂, R₃, R₄ and Re are as above; or pharmaceutically acceptable salts thereof.

Among the preferred compounds of Formula I are those compounds where n is an integer from 1-3 when R₄ and R₅ are taken together with their attached nitrogen atom form the nitrogen containing ring i.e. such as in the compounds of Formula IA- 1. On the other hand compounds of Formula I when n is an integer of from 1-5 are preferred in the case when R₄ and R₅ are other than being taken together with their attached nitrogen atom to form the nitrogen containing ring.

The term "pharmaceutically-acceptable salt" refers to a salt prepared from a base or acid which is acceptable for administration to a patient. Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically- acceptable inorganic or organic acids.

Salts derived from pharmaceutically-acceptable acids include acetic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic (i-hydroxy-2-naphthoic acid) and the like. Particularly preferred are salts derived from fumaric, hydrobromic, hydrochloric, acetic, sulfuric, phosphoric, methanesulfonic, p- toluenesulfonic, xinafoic, tartaric, citric, malic, maleic, succinic, and benzoic acids.

Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occuring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethyl enediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

The term pharmaceutically acceptable salt also comprises solvates.

The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, i.e. a compound of the invention or a pharmaceutically-acceptable salt thereof, and one or more molecules of a solvent. Such solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent. Representative solvents include by way of example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate.

In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

According to a preferred embodiment, R₂ and R₁ each independently represent an ethoxy or methoxy group, preferably both Ri and R₂ represent an ethoxy group.

The compounds of the invention may be prepared from commercially available starting materials, by using a sequence of chemical reactions known to those skilled in the art. A reaction scheme outlining the synthesis of the compounds of the invention from a common intermediate A is given below. The intermediate A is obtained from commercially available starting materials through benzoylation of 1,2-diethoxybenzene with the appropriate benzoyl chloride. Nitration followed by reduction of the nitro compound to the corresponding aniline and then acylation and reaction with ammonia gave the intermediate B which was transformed into the final products in the number of steps shown in the Scheme depending on the nature of the substituent X. Alternatively A (X = I) could be transformed into the final products in a nine step sequence.

X = CO₂CH₃ (Formula 1 , π = 1 } = (CH₂J₂Ci (Formula 1 , n =2) = I (Formula 1 , n =3-5)

Scheme

The following examples describe the synthetic routes of compounds represented ula (I). These methods for preparing compounds of formula (I) represent further objects of the present application.

It should be understood that other ways of producing these compounds may be designed by the skilled person, based on common general knowledge and following guidance contained in this application.

A further object of this invention relates to a pharmaceutical composition comprising at least one compound of formula (I), as defined above, and a pharmaceutically acceptable vehicle or support, optionally in association with another active agent.

The compounds and the compositions of the invention are of particular interest as active agents for use in therapy, especially in the treatment of pathological conditions, diseases and disorders associated with PDE-4 activation. In particular, the compounds are useful for the treatment of a pathological condition or disorder susceptible to amelioration by inhibition of PDE-4 such as treatment of an inflammatory pathology of the central nervous system or neuroinflammation.

The compounds and the pharmaceutical composition of the invention are more particularly intended to treat the inflammatory states in diseases such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), vascular disorders, autoimmune pathology and/or neurological disorders such as depression, Parkinson's disease, Alzheimer's disease, and also to improve memory in both long-term potential and contextual learning, or to treat obesity. The compounds may be formulated in various forms, including solid and liquid forms, such as tablets, gels, syrups, powders, aerosols, etc.

The compositions of this invention may contain physiologically acceptable diluents, fillers, lubricants, excipients, solvents, binders, stabilizers, and the like. Diluents that may be used in the compositions include but are not limited to dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar and for prolonged release tablet, hydroxypropyl methyl cellulose (HPMC). The binders that may be used in the compositions include but are not limited to starch, gelatin and fillers such as sucrose, glucose, dextrose and lactose. Natural and synthetic gums that may be used in the compositions include but are not limited to sodium alginate, ghatti gum, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone and veegum. Excipients that may be used in the compositions include but are not limited to microcrystalline cellulose, calcium sulfate, dicalcium phosphate, starch, magnesium stearate, lactose, and sucrose. Stabilizers that may be used include but are not limited to polysaccharides such as acacia, agar, alginic acid, guar gum and tragacanth, amphotsics such as gelatin and synthetic and semi-synthetic polymers such as carbomer resins, cellulose ethers and carboxymethyl chitin. Solvents that may be used include but are not limited to Ringers solution, water, distilled water, dimethyl sulfoxide to 50% in water, propylene glycol (neat or in water), phosphate buffered saline, balanced salt solution, glycol and other conventional fluids. The dosages and dosage regimen in which the compounds of formula (I) are administered will vary according to the dosage form, mode of administration, the condition being treated and particulars of the patient being treated. Accordingly, optimal therapeutic concentrations will be best determined at the time and place through experimentation.

The compounds according to the invention can be used enterally. For oral administration, suitable forms are, for example, tablets, gel, aerosols, pills, dragees, syrups, suspensions, emulsions, solutions, powders and granules; a preferred method of administration consists in using a suitable form containing from i mg to about 500 mg of active substance. The compounds according to the invention can also be administered parenterally, for instance in the form of solutions or suspensions for intravenous or intramuscular perfusions or injections.

Such compounds, compositions comprising the same, or treatment can be implemented alone or in combination with other active ingredients, compositions or treatments. Moreover, it can correspond to treatment of chronic or acute disorders. Further aspects and advantages of this invention will be disclosed in the following examples, which should be regarded as illustrative and not limiting the scope of this application.

EXAMPLE ANALYSIS

In the preparation of the examples given, unless otherwise stated: Proton Magnetic Resonance (¹H-NMR) spectra were recorded on a Bruker Avance DRX at 200, 300 and 400 MHz. Chemical shifts are reported in ppm downfield from Me₄Si, used as internal standard, and are assigned as singlets (s), doublets(d), doublets of doublets (dd), triplets (t), quartets (q) or multiplets (m). The chromatographic analysis conditions were: column Waters XTerra MS C18 (4.6 x 30mm, 5μm); flow rate l.omL/min with a mobile phase of an aqueous solution of 0,05% TFA (B) and acetonitrile.

The melting points were performed using a capillary melting point apparatus, 7SMP3-0 Bibby. PHARMACOLOGICAL ACTIVITY

PDE-4 activity was measured by a radio-enzymatic assay as described in Keravis TM, Wells JNand Hardman JG. "Cyclic nucleotide phosphodiesterase activities from pig coronary arteries:lackof interconvertibility of major forms";. Biochim. Biophys. Acta. 1980; 613: 116-129. The procedure is as follows: A. Isolation of phosphodiesterases from smooth muscle

A 3g segment of bovine aortic media cut into pieces λvith scissors was homogenized with an ultra-turrax then a potter glass/glass homogenizer in 7 volumes by weight of buffer A containing a protease inhibitor cocktail (20 mM Tris-HCI, G.25 M saccharose, 2 mM magnesium acetate, 1 mM dithiothreitol, 5 mM EGTA, 2000 U/ml aprotinin, 10 mg/1 leupeptin and 10 mg/i soya typsic inhibitor). The homogenate was centrifuged at 105,000 g for 1 hour. The supernatant was loaded on a DKAE-Sephacel column (15 x 1.6 cm) pre-equilibrated with buffer B (buffer A without the saccharose, EGTA and protease inhibitors). The column was washed until there was no detectable absorption at 280 nm, then eluted with a linear gradient of NaCl (0-0,5 M) in buffer B. 3-ml fractions were collected described hereinafter to localize the different enzymes PDEi, PDE3, PDE4 and PDE5, which were aliquoted and frozen at -80⁰C. (Lugnier et al., Biochem, PhamacoL, 35 (1986) 1746-1751). PDE2 was isolated from human platelets, provided by Etablissement Franςais du Sang-Alsace (French establishment of blood in Alsace). It was purified according to Kameni Tcheudji JF et al. {Kameni Tcheudji JF, Lebeau L, Virmaux N, Maftei CG, Cote RH, Lugnier C and S:hultz P. Molecular organisation of bovine rod cGMP-phosphodiesterase 6. J. MoI Biol. 2001; 3io:i8i-ygi.), and stored until use at -80⁰C in small aliquots.

B. Protocol for Measuring Phosphodiesterase Activity

Cyclic nucleotide phosphodiesterase activity was determined in vitro by a radio enzymatic assay as described by Lugnier et al., 1986. PDE2, PDEβ, PDE4 activities were measured at a substrate concentration of 1 μM of cyclic AMP in the presence of 15,000 cpm [sH]-cyclic AMP (as a tracer). PDEi and PDE5 activities were measured at a substrate concentration of 1 μM of cyclic GMP in the presence of 15,000 cpm [3B]-cyclic GMP (as a tracer).

The activity of the PDE enzyme was assessed by a two -step radio enzymatic assay by measuring the amount of radiolabeled 5 '-nucleotide product resulting from the hydrolysis of the radiolabelled substrate after separation from the non-hydrolysed substrate by an anion-exchange chromatography.

Phosphodiesterase enzymes were first incubated in the presence or in the absence of increasing concentrations of test substance. The reactions were stopped by the addition of Phosphodiesterase-stopping buffer. During this first step, both radiolabelled and non-radiolabelled cyclic nucleotides are hydrolyzed into nucleotide monophosphate. The second step performed in the presence of 1.5 mg/ml of 5'- nucleotidase snake venom results in the formation of nucleoside. The products resulting from the enzymatic reaction are separated by anion- exchange chromatography (QAE- sephadex A-25 column). Anion-exchange chromatography allows the separation of the dephosphorylated products (nucleoside) from the non-hydrolyzed cyclic nucleotide, Nucleoside radioactivity was determined by liquid scintillation counting. Enzymatic incubations were carried out under conditions allowing no more than 15% hydrolysis of the substrate, each point was performed in duplicate.

C. Determination of inhibition of PDE4

The concentration of substance which inhibits enzymatic activity by 50% (IC₅₀) at 1 μM cyclic AMP was calculated by nonlinear regressions (Prism, GraphPad).

The results obtained are presented in the Tables hereinafter and are expressed as the inhibition percentage of enzymatic activity produced by 10 μmol of the tested compound together with IC₅₀ values measured.

In carrying out this assay: cytosolic PDE4 was isolated from media layer of bovine aorta (Lugnier C, Schoeffter P₃ Le Bee A, Strouthou E and Stoclet JC. Selective inhibition of cyclic nucleotide phosphodiesterases of human, bovine and rat aorta. Biochem. Pharmacol. 1986; 35: 1743-1751). PDE activities were measured as described in section B. PDE assays were performed in the absence or in the presence of increasing concentrations of PDE inhibitor in order to determine the IC₅₀ for each PDE isoform. The PDE concentration is adjusted to hydrolyze less than 15 % of the total substrate.The concentration of drug that produced 50% inhibition of substrate hydrolysis (IC₅₀) values was calculated by non-linear regression analysis from concentration-response curves (Prism software).

The percentage of hydrolyzed cyclic nucleotide phosphate (CNP) in each sample is calculated as follows:

% CNP hydrolyzed = R_x-R₀/ RT-RO

R_x = cpm of sample

Ro = cpm of blank assay

RT = cpm of total radioactivity t = incubation time of the first enzymatic reaction in min

• The PDE activity of the sample is calculated as indicated:

PDE activity (mol/min) = (% CNP) (25OXIO-⁶) f IXiCr⁶M) t

• The % of PDE inhibition of the sample is calculated as indicated

% Inhibition = PDE activity in the presence of inhibitor (mol/min) X 100 PDE activity in the absence of inhibitor (mol/min)

Data are analyzed with Graph-Pad Prism 4 software by nonlinear regression.

1. The preparation of compounds of formula (I), wherein n =1, (1 carbon chain) is shown in Scheme 1 via the benzyl chloride (10) as the key intermediate.

Scheme i 4-Chlorocarbonyl-benzoic acid methyl ester (2).

To a mixture of Terephtalic acid monomethyl ester, compound 1 (lo.oog, 0.056 mol) and SOCl₂ (somL) was added a drop of DMF and the mixture was boiled at refluxed for 15I1. The excess SOCl₂ was removed in vacuo to afford compound 2 (io.57g) as a white solid in 95% yield. This compound was used for the next step without further purification.

4"(3-4"Diethoxy-benzoyl)-benzoic acid methyl ester (3).

To a mixture of diethoxybenzene (9-79-g, 1.05 mol) and compound 2 (io.57g, 0.053 mol) in CH2CI2 (3OmL) was added dropwise SnCl₄ (i.2eq, 7.44Ω1L). After stirring at 0⁰C for 30 minutes the mixture was boiled at reflux for 3h. Then the mixture was cooled and methanol was added until the blue colour disappeared. The solvent was evaporated in vacuo and the residue obtained was triturated with methanol and filtered and then dried to give compound 3 (i3.i7g) as a white solid in 73% yield. ¹H NMR (CDCl₃, 300 MHz): δ 8.17 ppm (d, 4/ = 8.47 Hz, 2 Har), δ 7.8 ppm (d, 4J= 8.48 Hz, 2 H_ar), 7-5 (s, H_ar), 7-35 (d,

J= 6.22 Hz, Har), 6.9 (d, J=8.48 Hz, Har), 4-2 (q, J= 7.02 HZ, 4H 2-0CH₂CH₃), 3-98 (S,

0-CH₃), 1.5 (m, 6H 2-0CH₂CH₃).

4-(4.5-Diethoxy-2-nitro-benzoyl)-benzoic acid methyl ester (4).

To compound 3 (13.175, o.039mol) was added DCM (8omL). The mixture was cooled to 0⁰C and then HNO₃ (3.6ml,) was added slowly. The solution was stirred at O⁰C for 30 minutes and then for 20 minutes at room temperature. The mixture was quenched with ice water and concentrated in vacuo to remove DCM. Then the solution was filtered and the residual solid was washed three times with water and once with ethanol to obtain I4.i3g of compound 4 as a yellow solid in 94% yield. ¹H NMR (CDCl₃, 300 MHz): 8 8.10 ppm (d, 4J = 8.16 Hz, 2 H_ar), 7-8 (d, J= 8.16 Hz, 2 H_ar), 7-73 (s, Har), 6.86 (s, H_ar), 4-2 (m, 4H 2-OCH₂CH3), 3.98 Cs, 0-CH₃), 1.5 (m, 6H 2-0CH₂CH₃).

4-(2-Ammo~4.5-dϊethoxy-benzoyl)-benzoic acid methyl ester (5).

To compound 4 was added Fe (i4g), ethanol (i4θmL) and then acetic acid (i4θmL). The solution was stirred and heated at 90⁰C for 4I1. The solution was then cooled and filtered through celite. Then the celite and residue was washed with ethyl acetate and the filtrate concentrated in vacuo. To the residue was added carefully a 10% aqueous solution of Na₂CO₃ and ethyl acetate. The organic layer was separated and the aquous layer was extracted with ethyl acetate and the combined organic layers were dried over Na₂SO₄. Then the solution was filtered and concentrated in vacuo to obtain n.og of compound 5 as an orange-yellow solid in 84% yield. ¹H NMR (CDCl₃, 300 MHz): 5 8.12 ppm (d, 4J = 8.16 HZ_; 2 Har), 7-6 (d, J= 8.16 HZ, 2 Har), 6.86 (S, H_ar)_; 6.28 (S, NH₂), 6.19

(s, H_ar), 4.12 (q, J=6.96 Hz, 2H OCH₂CH₃), 4 (s, 0-CH₃), 3.82 (q, J=6.96 Hz, 2H OCH₂CH₃), 1.5 (t, J=6-99, 3H 2-0CH₂CH₃), 1.32 (t, J=6.99, 3H 2-0CH₂CH₃).

4-[2-(2-Bromoacetylamino)-4.5-diethoxy-benzoyl]-benzoic acid methyl ester (6).

To compound 5 (ii.og, o.O3imol) was added DCM (5OmL) then bromoacetyl bromide (1.5 eq, 4-O7mL) dropwise at O⁰C. After complete addition, to the mixture was carefully added a 10% aqueous solution of Na₂CO₃ (somL). The mixture was stirred for a further 30 minutes at 0⁰C and then for 2h at room temperature. The organic layer was separated dried over Na₂SO₄, filtered and then concentrated in vacuo to give i3-6g of compound 6 as a yellow solid in 93% yield. ¹H NMR (CDCl₃, 300 MHz): δ 8.43 (s, H_ar), 8.17 ppm (d, J = 8.04 Hz, 2 Har), 7-73 (d, J= 8.64 Hz, 2 Har), 7-015 (s, Har), 4-27 Cq, J=6.α.6 Hz, 2H OCH₂CH₃), 3.94 (s, NH), 3.92 (s, 0-CH₃), 3.88 (q, J=6.g6 Hz, 2H OCH₂CH₃), 1.5 (t, J=6.99, 3H 2-OCH₂CH₃), 1.32 (t, J=6.99, 3H 2-0CH₂CH₃).

4-(7.8-Diethoxy-2-oxo-2.3-dihydro-iH-benzo[e] [1.4] diazepin-5-yl) -benzoic acid methyl ester (7).

To compound 6 (13.6g, o.029mol) was slowly added 23θmL of a solution of NH₃ in methanol (7N) while being cooled in an ice bath at O⁰C. The solution was stirred at O⁰C for a further 4I1 and then boiled at reflux for 15I1. The mixture was then concentrated in vacuo and the residue was mixed with iced water and filtered. The solid product was was dried in vacuo, and then crystallised from methanol to give compound 7 (9-55g) as a yellow solid in 87% yield. Η NMR (CDCl₃, 300 MHz): δ 8.43 (s, H_ar), 8.17 ppm (d, J = 8.04 Hz₅ 2 Har), 7-73 (d, J= 8.64 Hz, 2 H_ar)₅ 7-015 Cs, H₈₁), 4.27 (q, J=6.9ό Hz, 2H OCH₂CH₃), 3-94 Cs, NH), 3-92 (s, 0-CH₃), 3-88 (q, J=6-96 Hz, 2H OCH₂CH₃), 1.5 (t, J=6.99, 3H 2-0CH₂CH₃), 1.32 (t, 3=6.99, 3H 2-0CH₂CH₃).

4-(7,8-Diethoxy-2-oxo-2_?3-dihydro-iH-benzo[e][i,4]diazepin-5-yl)-benzoic acid (8).

To compound 7 (9.55g, 0.025mol) was added THF (20OmL), water (4OmL) and LiOH

(5⁶Q) 5-5g)- The resultant solution was stirred for 4I1 at room temperature and then concentrated in vacuo to remove THF and then acidified with HCl (iNj until a precipitate appeared. After precipitation was complete the mixture was then filtered and the solid obtained was dried in vacuo, to afford compound 8 (7-6g) as a yellow solid in 98% yield. ¹H NMR (DMSO, 300 MHz): δ 10.31 (s, OH), 7.97 PP^ (d, J = 8.28 Hz, 2 Har), 7.62 (d, J= 8.4 Hz, 2 Har), 6.81 (s, H_ar), 6.64 (s, Har), 4-12 (m, 4H: OCH₂CH₃ + NCH₂CO), 3-83 Cq, J=6.99 Hz, 2H OCH₂CH₃), 3-30 Cs, NH), 1.41 Ct, J=6.99, 3H 2- OCH₂CH₃), 1.22 Ct, J=6.99_; 3H 2-0CH₂CH₃).

7 , 8-Diethoxy- 5-(4-hydroxymethyl -phenyl) 1 , 3dihydr obenzo[e] [1,4] diazepin- 2~one (9).

The compound 8 (lg, 2.7mmoϊ) was dissolved in THF C2θmL). Then N-methyl- morpholine Co.3rnL, ieq) and isobutylchloroformate Co.37mL, l.ieq) were added. The mixture was cooled at O⁰C and then with stirring, NaBH₄ (o.6ig, 6eq) in water CiomL) was added to the mixture. After lh ethyl acetate (lOomL) was added and the organic layer was separated and then dried over Na₂SO₄. The mixture was filtered and the filtrate was concentrated in vacuo to give a crude product which was purified on silica to obtain compound 9 C348mg) as a white solid in 36% yield.¹H NMR CCDCl₃, 300 MHz): 6 10.31 Cs, OH), 7.97 ppm (d, J = 8.28 Hz, 2 Har), 7.62 (d, J= 8.4 Hz₃ 2 Har), 6.81 Cs, Har), 6.64 Cs, Har), 4-12 (m, 4H: OCH₂CH₃ + NCHaCO), 3.83 Cq, J=6.99 Hz, 2H OCH₂CH₃), 3.30 (s, NH), 1.41 Ct, J=6.99, 3H 2-0CH₂CH₃), 1.22 (t, J=6.99, 3H 2- OCH₂CH₃). 5- (4-Chloromethyl)~7, 8-diethoxyphenyl) 1,3 dihydrobenzo [e] [1,4] diazepin-2- one (10).

To compound 9 (3481Ug₅ g.83mmol) dissolved in DCM (smL) was added SOCl₂ (o.22mL, 3eq) dropwise.. The mixture was stirred for 3h at room temperature and then water (2OmL) was added. The mixture was extracted with DCM (3 x 2OmL).. The combined extracts were then dried over Na₂SO₄, filtered and the filtrate concentrated in vacuo to give compound 10 (35θmg) as a yellow solid in 94% yield. . ¹H NMR (CDCl₃, 300 MHz): δ 8.80 (m, NH), 7.62 ppm (d, J = 8.0 Hz, 2 H_ar), 7.44 (d, J= 8.0 Hz, 2 H₈₁), 6.71 (s, Har), 6.69 Cs, Har), 4-31 Cs, CH₂Cl), 4-20 (s, NCH₂CO), 4-15 Cq, J = 7-0 Hz , 2 H: OCH₂CH₃), 3-93 Cq, J = 7-0 Hz, 2 H OCH₂CH₃), 1.54 Ct, J = 7-0 Hz, 3 H OCH₂CH₃), 1.40 Ct, J = 7-O Hz, 3 H 2-0CH₂CH₃).

General procedure for the synthesis of compounds 11.

The compound 10 (35θmg, 9.4mmol) was dissolved in CH₃CN (lomL). An amine (seq) was added slowly to the mixture stirred at room temperature. The mixture was then heated to 50⁰C and stirred at this temperature for 4h. The mixture was then cooled and then concentrated in vacuo. The residue was purified by chromatography on silica to give compound 11.

Compounds synthesized by this method include:

2. The preparation of compounds of formula (I), wherein n = 2 (2 carbon chain) is shown in Scheme 2 via the phenethyl chloride (17) as the key intermediate: 0°C

Commercially available

HNO₃, DCM

Scheme 2

-3O- 4-(2-Chloroethyl)~benzoyl chloride (12).

Compound 12 was synthesized from commercially available 4-(2-chloroethyl)-benzoic acid in a similar manner to compound 2 (Scheme 1) and used without purification in the following step.

4-(2-Chloroethyl)-phenyl-(4-etlioxy-3-metlioxymethyl-phenyl)-nieth :inone

(13).

Compound 13 was synthesised from compound 12 using the same procedure as for compound 3 from compound 2 (Schemei) .

¹H NMR (CDCl₃, 300 MHz): δ 7.60 ppm (d, J = 7-8 Hz, 2 H_ar), 7-32 (d, J = 7-8 Hz, 2 H_ar),

7.02 (s, H_ar)_; 6.31 (s, H_ar), 4-13 Cq, J = 7-1 Hz, 2 H OCH₂CH₃), 3-87 Cq, J = 7-1 Hz, 2 H

OCH₂CH₃), 3.76 (t, J = 7-2 Hz, 2 H CH₂CH₂Cl), 3.18 (t, J = 7.2 Hz, 2 H CH₂CH₂CI),

4.15 Cq, J = 7-0 Hz, 2 H: OCH₂CH₃), 3-93 Cq, J = 7>o Hz, 2 H OCH₂CH₃), 1.50 (m, 6 H 2

OCH₂CH₃).

[4-(2-Chloro-ethyl)-phenyl3-(4-ethoxy-5-methoxyπiethyl-2-nitro-phenyI)- methanone (14).

Compound 14 was synthesized using the same procedure as for compound 4 (Scheme 1) ¹H NMR (CDCl₃, 300 MHz): δ 7.70 ppm (d_} J = 8.1 Hz, 2 Har), 7.30 (d, J = 8.iHz, 2 H_ar)_? 6.83 Cs, Har), 6.31 (s, Har), 4-24 (m, 4H 2-0CH₂CH₃), 3.76 Ct, J = 7-1 Hz, 2 H CH₂CH₂Cl)₅ 3.15 Ct, J = 7.1HZ, 2 H CH₂CH₂Cl), 1.50 (m, 6 H 2-OCH₂CH₃). (2-Ainmo-4-etlιoxy-5-methoxyinethyl-pheiiyI)-[4'-(2-chloro-ethyl)-pheiiyI]- methanone (15).

Compound 15 was synthesized using the same procedure as for compound 5 (Scheme

1).

.¹H NMR (CDCl₃, 300 MHz): δ 7.58 ppm (d, J = 7-7Hz₅ 2 H_ar), 7.33 (4 J = 7-7Hz, 2 H_ar),

7.00 (s, Har), 6.20 Cs, H_ar), 4-13 Cm, OCH₂CH₃), 3-8o (q, J = 7-3 Hz, OCH₂CH₃), 375 (t, J = 7-2 Hz, 2 H CH₂CH₂Cl), 3.18 (t, J = 7-2 Hz, 2 H CH₃CH₂Cl), 1.52 (q, J = 7-0 Hz, 2 H OCH₂CH₃), 1-35 (m, 6 H 2OCH₂CH₃).

2-Bromo-N-{2-[4-(2-chloro-ethyl)-benzoyl]-5-ethoxy-4-inethoxymethyl- phenyl}-acetamide (16).

Compound 16 was synthesized using the same procedure as for compound 6 (Scheme

1).

¹H NMR (CDCl₃, 300 MHz): δ 8.38 ppm (s, Har), 7-67 (d, J = δ.iHz, 2 H_ar), 7.37 (d, J =

8.1 Hz, 2 Har), 7.11 (s, Har), 4-26 (q, J = 7.1 Hz, 2 H OCH₂CH₃), 3.94 (s, OCH₂Br), 3.90 (q, J = 7.1 Hz, 2 H OCH₂CH₃), 3.79 (t, J = 7.2 Hz, 2 H CH₂CH₂Cl), 3.18 (t, J = 7-2 Hz₅ 2 H CH₂CH₂Cl), 4-15 Cq, J = 7-0 2 H: OCH₂CH₃), 1.53 (q, J = 7.0 Hz, 3 H OCH₂CH₃), 1.37 Cm, 3 H OCH₂CH₃).

5- [4-(2-Chloro-ethyl)-phenyl] -β-ethoxy-y-methoxymethyl-i.3.9.9a- tetrahydro-benzo[e] [i,4]diazepin-2-cme (17) .

To compound 16 (o.35g, 9.8mmol) dissolved in DCM (smL) was added SOCl₂ (o.22mL_; 3eq) dropwise.. The mixture was stirred for 3I1 at room temperature and then water

(2OmL) was added. The mixture was extracted with DCM (3 x 2OmL).. The combined extracts were then dried over Na₂SO₄, filtered and the filtrate concentrated in vacuo to give compound 17 (35θmg) as a yellow solid in 94% yield. . ¹H NMR (CDCl₃, 300 MHz): δ 8.80 (m, NH), 7.65 ppm (d, J = 8.0 Hz, 2 Har), 7-32 (d, J= 8.0 Hz, 2 Har), 6.86 (s, H_ar), 6.67 Cs₁ Har), 3-63 Cm, CH₂Cl), 3-23 Cm, CH₂CH₂Cl), 4.23 (s, NCH₂CO)₅ 4.18 (q, J = 7-0 Hz , 2 H: OCH₂CH₃), 3.94 (q, J = 7.0 Hz, 2 H OCH₂CH₃), 1.51 (t, J = 7-0 Hz, 3 H OCH₂CH₃), 1.35 Ct, J = 7-0 Hz, 3 H 2-0CH₂CH₃).

General procedure for the synthesis of compounds 18.

The compound 17 (35θmg, 94mmol) was dissolved in CH₃CN (lomL). An amine (seq) was added slowly to the mixture stirred at room temperature. The mixture was then heated to 50⁰C and stirred at this temperature for 4I1. The mixture was then cooled and then concentrated in vacuo. The residue was purified by chromatography on silica to give compounds 18.

Compounds 19: C7_J8-Diethoxy-5-[4-(2-morpholin-4-yl-ethyl)-phenyl]-i-propyI-i,3- dihydro-benzo[e][i,4]diazepm-2-one hydrochloride and 7_J8-Diethoxy-5-(4-{2-[4-(3- methoxy-phenyl)-piperazin-i-yl]-ethyl}-phenyl)-i-propyl-i,3-dihydro- benzo[e][i,4]dizepin-2-one hydrochloride) are obtained by alkylation of compounds 18.

Compounds synthesized by this method include:

3. The preparation of compounds of formula (I), wherein n = 3 (3 carbon chain) via the key mesyl intermediate ( 28 ) is shown in Scheme 3:

SnCI,,. CH₂CI₂

15h, reflux

Ih, 70⁰C

Scheme 3 (3 ,4-Diethoxy-phenyl) -(4-iodo-phenyl) -methanone (20) .

To a solution of diethoxybenzene (31.0 g, 0.188 mol) in dichloromethane (1901Ϊ1L) under an argon atmosphere, was added 4-iodobenzoyl chloride (50.0 g, 0.188 mol). The mixture was then cooled to 0⁰C, and tin^IV chloride (2όmL, 0.225 mol) was added drop wise maintaining the temperature between 0 and 10⁰C with iced- water bath external cooling. The resultant solution was stirred at room temperature for 30 minutes and then boiled at reflux for 1.5L The reaction mixture was then quenched with methanol (to destroy excess of tin™ chloride) at 0⁰C and stirred at room temperature for 10 min. After evaporation to dryness in vacuo the product was triturated with methanol, filtered and dried in vacuo to afford the title compound (66.7 g) as a green solid in 90% yield. Η-NMR (CDCl₃, 300MHz) : δ 7.29-7.33 (dd, IHAΓO, 7.80-7.86 (dd, 2H Ar-), 7-44- 7.50 (m, 3H ArO, 6.86-6.90 Cd, IH AΓ.), 4.13-4.20 (m, 4H, 2 OCH₂), 1.44-1-54 (m, 6H, 2 CH₃)TLC: Rf = 0.50 (EtOAc / cyclohexane: 1/4).

(2-Nitro-4,5-diethoxy-phenyl)-(4-iodo-phenyl)-methanone (21). Fuming nitric acid (14111L, 0.337 mol) was slowly added to an ice-cold stirred solution of compound 20 (66.7 g, 0.168 mol) in dichloromethane (23OmL)₁ After complete addition the solution was then stirred at room temperature for ih. Then ice-cold water (20OmL) was added and the organic layer was separated and concentrated in vacuo. The product was purified by crystallization from water, filtered, washed with cold water (4 x lOOmL) and then with cold ethanol (1 x lOOmL) to give the title compound (73.7 g) as beige solid in 99% yield.¹H-NMR (CDCl₃, 300MHz) : δ 7.82-7.86 Cm, 2H Ar) 7.74 Cs, iH Ar), 7-45" 749 Cm, 2H AT), 6.84 Cs, iH AT), 4.15-4.32 (m, 4H, 2 OCH₂), 1.49-1.61 (m, 6H, 2 CH₃). TLC: Rf = 0.50 (EtOAc / cyclohexane: 1/4)

(4,5-Diethoxy-2-nitro-phenyl)-[4-(3-hydroxy-prop-i-ynyl)-plienyl3- methanone (22).

To a solution of compound 21 (40.0 g, 0.090 rnol) in dry acetonitrile C870111L) and triethylamine (24omL) under argon was successively added PdCl₂(PPh₃)2 (3.2 g, 0.0045 mol) copper iodide (863 mg, 0.0045 mol) and propargyl alcohol Cu ml, 0.181 mol). The reaction mixture was stirred at 70⁰C for lh. The reaction mixture was then cook d and water (soomL) was added. The aqueous layer was extracted with dichloromethane (3 x 15OmL)) and the combined organic layers were then then washed with brine (3 x 50OmL) and then dried over sodium sulfate, filtered and and the filtrate concentrated in vacuo. The product was chromatographed on silica gel using a gradient eluent CEtOAc/cyclohexane : 1/2 then 100% EtOAc) followed by crystallization from diethyl ether to afford the title compound (27.3 g) as a beige solid in 82% yield.¹H-NMR (CDCl₃, 300MHz): δ 7.72-7.68 (m, 2H AT), 7-71 (s, iH Ar), 7-50-7-47 (m, 2H Ar), 6.83 (s, iH AT), 4.53 (s, 2H HOCH₂), 4.26-4.17 Cm, 4H, 2 OCH₂), 1.58-1.48 Cm, 6H, 2 CH₃). TLC: Rf = 0.38 (EtOAc / cyclohexane: 3/7).

{4-[3-(tert-Butyl-dimethyl-silanyloxy)-prop-i-yπyl]-phenyl}-(4,5-diethoxy- 2-mtro-phenyI)-methanone (23).

To a solution of compound 22 (27.3 g, 0.074 ^m°l) in dimethylformarnide (22OmL) was added imidazole (7.5 g, 0.111 mol) and the mixture was stirred at room temperature for lh. t-Butyldimethylsilyl chloride (14.5 g, 0.096 raol) was then slowly added and the reaction mixture was stirred under argon at room temperature for a furtherih. Ice-cold water (soomL) was then added to the mixture and the aqueous layer was separated and then extracted with diethyl ether (2 x 20OmL)). The combined organic layers were then dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was triturated with a mixture of pentane/di ethyl ether to furnish the title compound (33-3 g) as a beige solid in 93% yield.¹H-NMR (CDCl₃₅ 300MHz): δ 7.72-7.68 (m, 2H Ar), 7.70 (s, lH Ar.), 7-49-7-46 (m, 2H Ar), 6-82 (s, iH Ar), 4-56 (s, 2H HOCH₂), 4.26-4.17 (m, 4H, 2 OCH₂), 1.58-1.48 (m, 6H, 2 CH₃), 0.95 (s, 9H 3 CH₃), 0.18 (s, 6H 2 CH₃). TLC: Rf = 0.27 (EtOAc / cyclohexane: 1/3).

(2-Ajnino-4,5-diethoxy-phenyI)-{4-[3-(tert-biityl-diinethyl-silanyloxy)- propyl] ~phenyl}~methanone (24).

The compound 23 (33.3 g, 0.069 ^m°0 dissolved in ethyl acetate (40OmL) was charged with 10% Pd/C (3.4 g) and hydrogenated with H₂ at atmospheric pressure at room temperature for 24L The reaction mixture was then filtered through a celite pad which was washed with methanol. The filtrate was concentrated in vaccuo to give an oily residue partially reduced. The residue was again dissolved in ethyl acetate (400 ml), charged with fresh 10% Pd/C (3.4 g) and hydrogenated at atmospheric atmosphere for an additional 24Ϊ1 for complete reaction. The reaction mixture was filtered over a celite pad which was rinsed with methanol. After evaporation of the filtrate to dryness in vacuo, trituration with diethyl ether afforded the title compound (28.8 g) as a yellow solid in 91% yield. ¹H-NMR (CDCl₃, 300MHz): 6 7.57-7.54 (m, 2H Ar), 7.29-7.26 (m, 2H Ar), 7-03 Cs, iH Ai)₅ 6.20 (s, lH Ai), 6.10 (s, 2H NH₂), 4.16-3.65 Cm, 6H, 3 OCH₂), 2.79- 2.74 (m, 4H, 2 CH_a), 1.93-1.84 Cm, 2H, CH₂), 1.52-1.31 Cm, 6H, 2 CH₃), 0.93 Cs, 9H, 3 CH₃), 0.08 (s, 6H, 2 CH₃). TLC: Rf = 0.55 CEtOAc / cyclohexane: 1/1).

2-Bromo-N-(2-{4-[3-(tert-butyl-dimethyl-silanyloxy)-propyI]-benzoyI>-4,5- diethoxy-phenyl)-acetamide (25).

To an ice-cold stirred solution of the compound 24 (28.8 g, 0.063 mol) in dichloromethane (200 ml) was added a 10% aqueous solution of sodium carbonate (90 ml) followed by the dropwise addition of bromoacetyl bromide (7.1 ml, 0.082 mol). The reaction mixture was stirred at room temperature for ih. The phases were separated and the aqueous layer was extracted with dichloromethane (3 x loomL). The combined organic layers were washed with water (2 x 15OmL)₁ dried over sodium sulfate, filtered and the filtrate concentrated in vacuo to afford the title compound as a crude brown oil. ¹H-NMR CCDCl₃, 300MHz): δ 11.94 Cs, iH NH), 8.37 Cs, iH Ar), 7.65-7-62 Cm₁ 2H Ar), 7-33-7-28 (m, 2H AT), 7-i3Cs, lH Ar)₃ 4-27-4-03 Cm₅ 2H, OCH₂), 3.97 (s, 2H CH₂), 3.94- 3.64 Cm, 4H, 2 CH₂), 2.81-2.76 Cm, 2H, CH₂), 1.94-1.84 Cm, 2H, CH₂), 1.55-1.3Q Cm, 6H₇ 2 CH₃), 0.93 Cs, 9H 3 CH₃), 0.08 (s, 6H 2 CH₃). TLC: Rf = 0.75 CEtOAc / cyclohexane: 1/1). The crude product was used in the subsequent step without further purification.

5"{4-[3-(tert-ButyI-dimethyl-siIaπyIoxy)-propyl]-phenyI}-7,8-diethoxy-i,3- dihydro-benzo[e] [i,4]diazepm-2-one (26).

To an ice-cold stirred solution of crude compound 25 (ca. o.oόmol) in dichloroethane

C46 mL) was added a solution of 7N ammonia in methanol (ca. 2θθmL). The reaction mixture was stirred at 0⁰C for ih, at room temperature for 2h and then heated to 70⁰C for 15L The reaction mixture was concentrated in vacuo and then the residue was dissolved in DCM (20OmL) and washed with water (2 x loomL)) and then dried over sodium sulfate, filtered and the filtrate concentrated in vacuo to furnish the title compound as a crude brown oil. ¹H-NMR (CDCl₃, 300MHz): δ 8.91 (s, iH NH), 7.55-

7.53 (m, 2H Ar), 7-26-7-23 (m, 2H Ar), 6.74 (S, lH Ar), 6.67(5, lH Ar), 4-29 (S, 2H CH₂),

4.21-3.63 (m, 6H, 3 OCH₂), 2.76-2,71 (m, 2H, CH₂), 1.91-1.82 (m, 2H, CH₂), 1.55-1-35 (m, 6H, 2 CH₃), 0.92 (s, 9H 3 CH₃), 0.07 (s, 6H 2 CH₃). TLC: Rf = 0.10 (EtOAc / cyclohexane: 1/1).

The crude product was used in the subsequent step without further purification 7,8-Diethoxy-5-[4"(3-hydroxy-propyl)-phenyl]-i,3-dihydro- benzo[e] [i,4]diazepin-2-one (27) .

To a stirred solution of crude compound 26 (ca. 0.06 mol) in dichloromethane (50 mL) was added a solution of 4N hydrogen chloride in dioxane (somL). The reaction mixture was stirred at room temperature for 15b.. A few drops of 12N hydrochloric acid were then added and stirring continued for a further 8h. The reaction mixture was then concentrated in vacuo dissolved in DCM (loomL) and a saturated aqueous solution of sodium hydrogencarbonate (loomL) was added carefully. The phases were separated and the aqueous layer was extracted with dichloromethane (3 x 50111L)). The combined organic phases were dried over sodium sulfate, filtered and the filtrate concentr Λted in vacuo to afford the title compound (24 g) as a yellow solid in quantitative yield.¹H-NMR (CDCl₃, 300MHz): 5 8.84 (s, lH NH), 7.52-749 Cm, 2H Ar), 7-23-7-21 Cm, 2H Ar), 6.74 (s, iH AT), 6.61(S, IH AT), 4-30 (s, 2H CH₂), 4-20-3.66 (m, 6H, 3 OCH₂), 2.78-2.73 (m, 2H, CH₂), 1.91-1.86 (m, 2H, CH₂), 1.54-1-35 (m, 6H, 2 CH₃).

_(Z)-3-(4-(7,8-diethoxy-2-oxo-2,3-dihydro-iH-benzo[e][i,4]diazepm-3- yl)phenyl)propyl methanesulfonate (28).

To a stirred solution of compound 27 (5.0 g, 13.1 mmol) in dry dichloromethane (150 mL) was successively added methaiiesulfonic anhydride (4.6 g, 26.2 mmol) and 4- dimethylaminopyridine (1.8 g, 14.4 mmol) at room temperature. The reaction mixture was heated at reflux for 6oh. After the removal of volatiles in vacuo, the residue was purified by chromatography on silica gel (eluent: CH₂Cl₂ / MeOH: 95/5) and after crystallization from diethyl ether the title compound (4.44 g) was obtained as a yellow solid in 73% yield. ¹H-NMR (CDCl₃, 300MHz): δ 9-54 (s, iH NH)₁7.63-7.60 (m, 2H Ar), 7.31-7.28 (m, 2H AT), 6.81 (s, iH AT), 6.68 (s, iH Ar), 4-28 (s, 2H CH₂), 4.26-3.91 (m, 6H, 3 OCH₂), 3-02 (s, 3H CH₃), 2.86-2.81 (m, 2H, CH₂), 2.15-2.10 (m, 2H, CH,), i.M-i-35 (m, 6H, 2 CH₃).

7,8-Diethoxy-5-[4-(3-morpholin-4-yI-propyl)-phenyl3-i,3~dihydro- benzo[e][i,4]diazepin-2-one (R₄R₅NH = morpholine) (29).

To a stirred solution of compound 28 (400 mg, 0.87 mmol) in dry acetonitrile (5 mL) was successively added triethylamine (120 μl, 0.87 mmol) and morpholine (227 μl, 2.61 mmol) at room temperature. The reaction mixture w^ras heated at 80⁰C for 15b and then water (10 mL) was added. The aqueous layer was extracted with dichloromethane (3 x lOmL) The combined organic layers were dried over sodium sulfate and filtered. After concentration of the filtrate in vacuo, the residue was purified by chromatography on silica gel (eluent: CH₂Cl₂ / MeOH: 95/5). Crystallization from a mixture of diethyl ether and pentane furnished the title compound (265 mg) as a beige solid in 67% yield.

The following compounds were sysnthesised in a similar manner:

¹I 5-{4-{3-[4-(3,4-Dichlσro 97 ύ phenyl)-pιperazιn-1 -yl]- propyl}-phenyl)-7,8-dsethoxy-

1 ,3-dιhydro- benzo[e][1 ,4]dιazepιn-2-one

W v*v^N-f 5-{4-[3-(4-Benzoth)azol-2-yl- 98 v pιpeπdin-1»yl)-propy[]» phenyl}-?, δ-dιethoxy-1 ,3-

CC dihydro- benzo[e][1 ,4]dιazeptn-2-one

7,8-Dιethoxy-5-{4-[3-(4- 97 0 19 hydroxy-pφeπdin-i -yl)- propyl}-phenyl}-1 ,3-dιhydro- benzo[e][1 ,4]dιazepin-2-one

7,δ-Dιethoxy-5-{4-[3-(4-oxo- 99 0 046 pjpertdιn-1 -yl}-ρropyl|- pheny!}-1 ,3-dihydro- benzo[e][1 ,4]dιazepιn-2-one

5"[4-(3-Dιιsopropylamιno- 98 0 13 propyl)-phenyl]-7,8-dιethoxy-

1 ,3-dιhydro- beπzo[e][1 ,4]dιazepιn-2-one

4« The preparation of compounds of formula (I), where in the chain (CHa)_nNR₄R₅, N is not part of a ring, is shown in Scheme 4 via the key iodo intermediate (33).

Fe, AoOH EtOH

84%

>

, CuI ELN, CH₃CN, 1h, 70°

Scheme 4

Compounds synthesized by this method include;

Claims

1. A benzodiazepine consisting essentially of a compound of the formula

wherein R_x and R₂ are lower alkoxy; n is an integer of from i to 5; R₃ is hydrogen or lower alkyl; R₄ is hydrogen or lower alkyl; R₅ is lower alkyl, or

-(O), R₆ or (CH ^> ₂₂)> . y. - f P R,

O

where (^~ P ) is a ring selected from the group consisting of phenyl, cycloalkyl ring containing from 3 to 10 carbon atoms, or a 4 to 7 membered heterocycloalkyl or a 5 or 6 membered heteroaromatic ring with said hetero rings containing from 1 to 2 hetero atoms being selected from the group consisting of oxygen, sulfur and nitrogen; or R₄ and R₅ can also be taken together with their attached nitrogen atom to form a nitrogen containing ring of the formula:

wherein the ring _/"^N\ is ^a nitrogen containing 4 to 7 member ed

heterocycloalkyl ring containing from 0 to 2 additional hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; Re is or lower alkyl; R₇ is hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen or trifluoromethyl; Rs hydrogen, hydroxy, lower alkoxy, halogen, trifluoromethyl or lower alkyl; R₉ is hydrogen, hydroxy, lower alkyl_} loweralkoxy, halogen, trifluoromethyl,

or when Rs and R₉ are substituted on adjacent carbon atoms, they can also be taken together with said attached carbon atoms to form a ring selected from the group consisting of phenyl, cycloalkyl containing 5 to IO carbon atoms, or a 4 to 7 membered heterocycloalkyl or a 5 or 6 member ed hetero aromatic ring, with said formed hetero rings containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; or when Rs and R₉ are substituted on the same carbon atom of a heterocycloalkyl ring they can also be taken together to form oxo or taken together with their attached carbon atom to form a 5 to 10 membered cycloalkyl ring or a 4 to 7 membered heterocycloalkyl ring containing from 1 to 2 hetero atoms selected from the group oxygen, sulfur and nitrogen with all of said rings defined by Rs and R₉ being unsubstituted or substituted in 1 or 2 positions with substitutents selected from the group consisting phenyl, oxo, halogen, trifluoromethyl or lower

alkyl; is a ring selected from the group

consisting of phenyl, cycloalkyl containing 3 to 10 carbon atoms, or a 4 to 7 membered heterocycloalkyl or a 5 to 6 membered heteroaromatic ring with said hetero rings containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; Ri₀ and R_u are individually hydrogen, hydroxy, lower alkoxy, halogen or trifluoromethyl or when Ri₀ and Rn are substituted on adjacent carbon atoms, they can be taken together with said attached carbon atoms to form a ring selected from the group consisting of a phenyl ring, a 5 to 10 membered cycloalkyl ring containing from 3 to 10 carbon atoms or a 4 to 7 membered heterocycloalkyl or a 6 to 7 membered heteroaromatic ring with said hetero rings containing from 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur which rings defined by R_i0 and Rn being unsubstituted or substituted with lower alkyl, halogen, trifluoromethyl or lower alkoxy; R12 is hydrogen or phenyl; R₁₃ is a phenyl; x and v are integers from 0 to 1 and y is an integer from 0 to 6; or pharmaceutically acceptable salts thereof.

2. The benzodiazepine of claim 1 wherein said compound has the formula:

R , - N- (C H ₂i)' y R y

■ ,^■R₄ and R₇ are as above;

3. The benzodiazepine of claim 2 wherein -4- p J is a phenyl ring.

4. The benzodiazepine of claim 3 wherein said compound is 5-[4-(3-benzylamino- propyl)-phenyl]-7,8-diethoxy-i,3-dihydro-benzo[e][i_j4]diazepin-2-one.

5. The benzodiazepine of claim 3 wherein said compound is 5-{4-[3-G)enzyl-methyl- amino)-propyl]-phenyl}"7,8-diethoxy-i,3-dihydro-benzo[e][i_;4]diazepin-2-one.

6. The benzodiazepine of claim 3 wherein said compound is 5-{4-[3~(benzyl-ethyl~ amino)-propyl]-phenyl}-7,8-diethoxy-i,3~dihydro-benzo[e][i,4]diazepin-2-one.

7. The benzodiazepine of claim 3 wherein said compound is 7,

8-diethoxy-5-(4-[3- Cmethyl-phenethyl-amino)-propyl]-phenyl}-i,3-dihydro-benzo[e][i,4]diazepin-2-one.

The benzodiazepine of claim 2 wherein

is a heteroaromatic ring.

9. The benzodiazepine of claim 8 wherein said compound is 7,8-diethoxy-5-{4-[3- (pyrimidin-2-ylamino)-propyl]-phenyl}-i,3-dihydro-benzo[e][i,4]diazepin-2-oϊie.

10. The benzodiazepine of claim 8 wherein said compound is 5-(4-[3~(6-chloro- pyrazin-2-ylamino)-propyl3-phenyl}-7,8-diethoxy-i,3-dihydro-benzo[e][i,4]diazepin-2- one.

11. The benzodiazepine of claim 2 wherein _\i ^PJ is a cycloalkyl ring.

12. The benzodiazepine of claim 11 wherein said compound is 5-{4~[3-(adamantan-i- yl-methyl-amino)-propyl]-phenyl}-7,8-diethoxy-i,3~dihydro-benzo[e][i,4]diazepin-2- one.

13. The benzodiazepine of claim 1 wherein said compound has the formula:

wherein Ri, R₂, R₃, R₄, Re, n and x are as above.

14. The benzodiazepine of claim 13 wherein said compound is {3-[4-(7,8-diethoxy-2- oxo-2,3-dihydro-iH-benzo[e] [i,4]diazepin-5-yl)-phenyl]-propyl}-carbamic acid tert- butyl ester.

15. The benzodiazepine of claim 13 wherein said compound is N-{3-[4-(7,8-diethoxy- 2-oxo-2,3-dihydro-iH-benzo[e][i,4]diazepin-5™yl)-phenyl]-propyl}-acetamide.

16. The benzodiazepine of claim 13 wherein said compound is {3-[4-(i- cycIopropylmethyl-7_f8-diethoxy-2-oxo-2,3-dihydro-iH-benzo[e][i,4]diazepm-5-yl)- phenyl]-propyl}-carbamic acid tert-butyl ester.

17. The benzodiazepine of claim 1 wherein said compound has the formula

wherein, n, Ri, R₂, R₃ are as above,

and R's and R'_g are individually hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, trifluoromethyl, or when R^'s and R^' ₉ are substituted on adjacent carbon atoms, they can also be taken together with said attached carbon atoms to form a ring selected from the group consisting of phenyl, cycloalkyϊ containing 5 to IO carbon atoms, a 4 to 7 membered heterocycloalkyl ring or a 5 or 6 membered heteraromatic ring with said hetero rings containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; or when R's and R₉ are substituted on the same carbon atom of said heterocycloalkyl ring, they can also form oxo or be taken together with their attached carbon atom to form a ring selected from the group consisting of phenyl, a 5 to 10 membered cycloalkyl ring or a 4 to 7 membered heterocycloalkyl ring containing from i to 2 hetero atoms selected from the group oxygen, sulfur and nitrogen with said rings being unsubstituted or substituted in 1 or 2 positions with substitutents selected from the group consisting phenyl, oxo, halogen, trifluoromethyl or lower alkyl.

18. The benzodiazepine of claim 17 wherein said is a heterocycloalkyl ring.

19. The benzodiazepine of claim 18 wherein R'g, and R'₉ are hydrogen, hydroxy, halogen, lower alkoxy or trifluoromethyl.

20. The benzodiazepine of claim 19 wherein said compound is 7,8-diethoxy-5-(4- morpholin-4-ylmethyl-phenyl)-i-propyI-i_J3-dihydro-benzo[e][i,43diazepm-2-one.

21. The benzodiazepine of claim 19 wherein said compound is 7,8-diethoxy-5-[4-(2- morpholm-4-yl-ethyl)-phenyl]-i,3-dihydro-benzo[e][i,4]diazepin-2-one.

22. The benzodiazepine of claim 19 wherein said compound is 7,8-diethoxy-5-[4-(2- morpholin-4-yl-ethyl)-phenyl]-i-propyl-i,3-dihydro-benzo[e][i,4]diazepin-2-one hydrochloride.

23. The benzodiazepine of claim 19 wherein said compound is 7,8-diethoxy-5-[4-(3- piperidin-i-yl-propyl)-phenyl]-i,3-dihydro-benzo[e][i,4]diazepin-2-one.

24. The benzodiazepine of claim 19 wherein said compound is 7,8-diethoxy-5-[4-(3- morpholin-4~yl-propyl)-phenyl]-i₎3-dihydro-benzo[e][i,4]diazepin-2-one.

25. The benzodiazepine of claim 19 wherein said compound is 7,8-diethoxy-5-{4-[3- (4-methyl-piperazin-i-yl)-propyl]-phenyl}-i,3-dihydro-benzo[e3[i_}4]diazepin-2-one.

26. The benzodiazepine of claim 19 wherein said compound is 7,8-diethoxy~5-[4-(3- pyrrolidin-i-yl-propyl)-phenyl]-i,3-dihydro-benzo[e]ti,4]diazepin-2~one.

27. The benzodiazepine of claim 18 wherein R¹S, and R'₉ are substituted on the same carbon atom of said heterocycloalkyl ring and are taken together form oxo .

28. The benzodiazepine of claim 27 wherein said compound is 7,8-diethoxy-- ;-{4-[3- (4-oxo-piperidin-i-yl)-propyl]-phenyl}-i,3-dihydro-benzo[e][i,4]diazepin-2-one.

29. The benzodiazepine of claim 18 wherein R's, and R'₉ are substituted on adjacent carbon atoms and are taken together with their attached carbon atoms to form a ring selected from the group consisting of phenyl, cycloalkyl containing from 5 to 10 carbon atoms, a 4 to 7 membered heterocycloalkyl or 5 or 6 membered heteroaromatic ring with said hetero rings containing from one to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen.

30. The benzodiazepine of claim 29 wherein said compound is 5-[4-(3,4-dihydro-iH- isoquinolin-2-ylmethyl)-phenyl]-7,8-diethoxy-i,3-dihydro~benzo[e][i,4]diazepin-2-one.

31. The benzodiazepine of claim 18 wherein Rs' and R₉' are substitiuted on the same carbon atom of a heterocycloalkyl ring and are taken together with their attached carbon atom form a cycloalkyl ring or heterocycloalkyl ring containing from 1 to 2 hetero atoms selected from the group oxygen, sulfur and nitrogen where said rings can be unsubstituted or substituted in 1 or 2 positions with substitutents selected from the group consisting of phenyl, oxo, trifluormethyl ,lower alkyl and halogen.

32. The compound of Claim 31 wherein said compound is 7,8-diethoxy-5-(4-[3-(4- oxo-i-phenyl-i,3,8-triaza-spiro[4.5]dec-8-yl)-propyl]-phenyl}-i,3-dihydro- benzo[e][i,4]diazepin-2-one.

33. The benzodiazepine of claim I wherein said compound has the formula

wherei

n ' Ri, R₂, R₃, Ri₀, Rn, n, v and y are as above and R"g is hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen or trifloromethyl; or pharmaceutically acceptable salts thereof;

34. The benzodiazepine of claim 33 wherein v and y are o.

35. The benzodiazepine of claim 34 wherein Ri₀ and Rn are hydrogen, hydroxy, lower alkoxy, halogen, lower alkyl or trifhioromethyl.

36. The benzodiazepine of the claim 34 wherein T " 4 J is phenyl.

37. The benzodiazepine of claim 36 wherein one of Rj₀ and Rn is hydrogen, halogen or trifluoromethyl and the other is halogen or trifluoromethyl.

38. The benzodiazepine of claim 37 wherein said compound is 5-{4-[4-(4-chloro- phenyl)-piperazin-i-yImethyl]-phenyl}-7,8-diethoxy-i,3-dihydro-benzo[e][i,4]diazepin- 2-0 ne.

39. The benzodiazepine of claim 37 wherein said compound is 7,8-diethoxy-5-(4-{3- [4-(4-fluoro-phenyl)-piperazin-i-yl]-propyl}~phenyl)-i,3-dihydro- benzo[e][i,4]diazepin-2-one.

40. The benzodiazepine of claim 37 wherein said compound is 5-(4-{3-[4-(4-chloro- phenyl)-4-hydroxy-piperidin-i-yl]-propyl}-phenyl)-7,8-diethoxy-i₎3-dihydro- benzo [e] [1,4] diazepin-2-one.

41. The benzodiazepine of claim 37 wherein said compound is 7,8-diethoxy-5-(4-{3- [4-C4-trifluoromethyl-phenyl)-piperazin-i-yl]-propyl}-phenyl)-i_J3-dihydro- benzo[e] [1,4] diazepin-2-one.

42. The benzodiazepine of claim 36 wherein Ri₀ and Rn are lower alkyl, lower alkoxy or hydrogen.

43. The benzodiazepine of claim 42 wherein said compound is 7,8-diethoxy-5-(4-{2- [4-(3-methoxy-phenyl)-piperazin-i-yl]-ethyl}-phenyl)-i-propyl-i,3-dihydro- benzo[e][i,4]dizepin-2-one hydrochloride.

44. The benzodiazepine of claim 41 wherein said compound is 7,8-diethoxy~5~{4-[3- (4-phenyl-piperazin-i-yl)-propyl]-phenyl}-i,3-dihydro-benzo[e][i,4]diazepin-2-one.

45. The benzodiazepine of claim 42 wherein said compound is 7,8-diethoxy-5-(4-{2- [4-(3-methoxy-phenyl)-piperazin-i-yl]-ethyl}-phenyl)-i-propyl-i,3-dihydro- benzo[e][i,4]dizepin-2~one hydrochloride.

46. The benzodiazepine of claim 42 compound is 7,8-diethoxy-5-(4-{3-[4-(4~ methoxy-phenyl) -pip erazin- i-yl] -propyl}-phenyl) -1,3 -dihy dro-benzo [e] [ 1 ,4] diazepin-2 - one.

47. The benzodiazepine of claim 34 wherein ( P ) is ring selected from the group consisting of a heteroaromatic ring, cycloalkyl ring or heterocycloalkyl ring.

48. The benzodiazepine of claim 47 wherein said ring is cycloalkyl ring.

49. The benzodiazepine of claim 48 wherein said compound is 5-{4-[3-(4- cyclopentyl-piperazin-i-y^-propyy-phenyll-y^-dietboxy-ijS-dihydro- benzo[e][i,4]diazepin-2-one.

50. The benzodiazepine of claim 47 wherein said ring is a heterocycloalkyl or heteroaromatic ring.

51. The benzodiazepine of claim 50 wherein said compound is 7,8~diethoxy-5-{4-[3- (4-thiazol-2-yl-piperazin-i-yl)-propyi]-phenyl}-i,3-dihydro-benzo[e][i,4]diazepin-2- one.

52. The benzodiazepine of claim 50 wherein said compound is 7,8-diethoxy~5-{4-[3- (4-pyrimidin-2-yl-piperazin-i-yl)-propyl]-phenyl}-i,3-dihydro-benzo[e3[i,4]diazepin-2- one.

53. The benzodiazepine of claim 50 wherein said compound is 5-(4-{3-[4-(3,5- dichloro-pyridm-4-yl)-piperazm-i-yl]-propyl}-phenyl)-7_}8-diethoxy-i,3-dihydro- benzo[e][i,4]diazepin-2-one.

54. The benzodiazepine of claim 50 wherein said compound is 7,8-diethoxy-5-(4-[3- C5-trifluoromethyl piperidin-2-yl)--piperazin-i-yl]-propyl]-phenyl}-i_;i3-dihydro- benzo[e] [ 1,4] diazepin-2-one.

55. The benzodiazepine of claim 33 wherein Rio and Rn are substituted on adjacent carbon atoms and are taken together with their with their attached carbon atom to form a ring selected from the group consisting of a phenyl ring, a cycloalkyl ring, a heterocycloalkyl or a heteroaromatic ring which rings can be unsubstituted or substituted with lower alkyl, halogen, trifluoromethyl or lower alkoxy.

56. The benzodiazepine of claim 55 wherein said compound is 5-{4-[3~(4- benzothiazol-2-yl-piperazin-i-yl)-propyl]-phenyl}~7,8-diethoxy-i,3-dihydro- benzo[e][l,4]diazepin-2-one.

57. The benzodiazepine of claim 55 wherein said compound is 7j8-diethoxy~5-{4-[3- (4-indan-i-yl-piperazin-i-yl)-propyl]-phenyl}-i,3-dihydro-benzo[e][i,4]diazepin-2-one.

58. The benzodiazepine of claim 55 wherein said compound is 7,8-diethoxy-5-(4-{3- [4-(iH-indol— yl)-piperidin-i-yl]-propyl}-phenyl)~i,3-dihydro-benzo[e][i,4]diazepin-2- one.

59. The benzodiazepine of claim 55 wherein said compound is 5~(4-[3-(4- benzothiazol-2-yl-piperidin-i-yl)-propyl]-phenyl}-7,8-diethoxy-i,3-dihydro- benzo[e][i,4]diazepin-2-one.

60. The benzodiazepine of claim 55 wherein said compound is 5-(4-{3-[4-(5-chloro- benzofuran-2-yl)-piperidin-i-yl]-propyl}-phenyl)-7,8-diethoxy-i,3-dihydro- benzo[e] [1,4] diazepin2-one.

61. The benzodiazepine of claim 33 wherein v is 0 and y is 1.

62. The benzodiazepine of claim 61 wherein said compound is 7,8-diethoxy-5-(4-(3- [4-(6-methyl-benzothiazol-2-ylmethyl)-piperazin-i~yl]-propyl}-phenyl)-i,3~dihydro- benzo[e][i,4]diazepin-2-one.

63. The benzodiazepine of claim 61 wherein said compound is 5-{4-[3-(4-benzyl-4~ hydroxy-piperidin-i-yl)-propyl]~phenyl}-7,8-diethoxy-i,3-dihydro- benzo[e][i,4]diazepm~2-one.

64. The benzodiazepine of claim 61 wherein said compound is 7_}8-diethoxy-5-{4-[3- (4-phenethyl-piperazin-i-yl)-propyl]-phenyl}-i,3-dihydro-benzo[e][i_J4]diazepin-2-one.

65. The benzodiazepine of claim 34 wherein y is 0 and v is 1.

66. The benzodiazepine of claim 65 wherein said compound is 7,8-diethoxy-5-(4-{3- [4-(furan-2-carbonyl)-piperazin-i-yl]-propyl}-phenyl)-i,3-dihydro- benzo[e][i,4]diazepin-2-one.

67. The benzodiazepine of claim 65 wherein said compound is 7,8-diethoxy-.ς-(4-{3- [4-(4-fluoro-benzoyl)-piperidin-i-yl]-propyl}-phenyl)-i,3-dihydro- benzo [e] [ 1,4] diazepin- 2-one .

68. The benzodiazepine of claim 65 wherein said compound is 5-(4-{3-[4~(4-chloro- benzoyl)-piperidin-i-yl]-propyl}-phenyl)-7,8-diethoxy-i,3-dihydro- benzo[e][i,4]diazepin-2-one.

69. The benzodiazepine of claim 1 wherein R₄ and R₅ form the ring

R

R₈ and R₉ is ' ; and Ri₂ and Ri₃ are as above.

" C H

R 1 3

70. The benzodiazepine of claim 69 wherein said compound is 5-{4-[3-(4- benzhydryl-piperazin-i-yl)-propyl]-pb.enyl}-7_j8-diethoxy-i,3-dihydro" benzo [e] [1,4] diazepin-2-one .