WO2013068592A1 - Inhibitors of cystathionine beta synthase to reduce the neurotoxic overproduction of endogenous hydrogen sulfide - Google Patents

Inhibitors of cystathionine beta synthase to reduce the neurotoxic overproduction of endogenous hydrogen sulfide Download PDF

Info

Publication number
WO2013068592A1
WO2013068592A1 PCT/EP2012/072410 EP2012072410W WO2013068592A1 WO 2013068592 A1 WO2013068592 A1 WO 2013068592A1 EP 2012072410 W EP2012072410 W EP 2012072410W WO 2013068592 A1 WO2013068592 A1 WO 2013068592A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
methoxy
dibenzo
hexahydro
diazepin
Prior art date
Application number
PCT/EP2012/072410
Other languages
French (fr)
Inventor
Damien Charre
Henri Blehaut
François Bellamy
Original Assignee
Fondation Jerome Lejeune
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fondation Jerome Lejeune filed Critical Fondation Jerome Lejeune
Publication of WO2013068592A1 publication Critical patent/WO2013068592A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the invention relates to inhibitors of cystathionine beta synthase (CBS), in particular EC 4.2.1.22, for treatment of Down syndrome, in particular for treatment and/or prevention of cognitive disorders in Down syndrome.
  • CBS cystathionine beta synthase
  • Down syndrome or trisomy 21 is the most common genetic cause of mental retardation. It is a chromosomal condition characterized by the presence of an extra copy of genetic material on the 21st chromosome, either in whole (trisomy 21) or part (such as due to translocations). The gene encoding the cystathionine beta synthase enzyme is located on chromosome 21 and is overexpressed in children with Down syndrome, or trisomy 21.
  • An enrichment in CBS in the brain, an excess of CBS activity and endogenous hydrogen sulfide (3 ⁇ 4S) overproduction have all been found in Down Syndrome [LEJEUNE Jerome. Commentarii vol. III. n° 9, pages 1-12; ICHINOHE et al.
  • CBS catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine and is the only enzyme of the brain that produces H 2 S. It has been proposed that 3 ⁇ 4S may function as a neuro-modulator or transmitter in the brain (KIMURA, Hideo.
  • the object of the invention is to provide new methods and compounds that inhibit the activity of CBS and consequently regulate overproduction of hydrogen sulfide (H 2 S) in trisomic 21 patients due to an overexpression of CBS.
  • Benzodiazepines are known for their therapeutic activities, such as sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, muscle relaxant and amnesic action, and also for treating Hepatitis C Virus infection.
  • benzodiazepine derivatives for treating Down syndrome by inhibiting CBS activity, in particular for preventing or treating cognitive disorders in Down syndrome has neither been described nor suggested.
  • the present invention relates to a compound having the formula (I) :
  • R 2 and R 3 represent independently H, an halogen atom, -Ra, -ORa, -NHRa, or - NRaRb, with
  • Ra and Rb representing independently H, (Ci-C 6 )alkyl, -CO(CrC 6 )alkyl, or o Ra and Rb represent together a 5- or 6-membered cycle, in particular comprising
  • Rdi representing a (Ci-C 3 )alkyl, in particular -CH 3 , -C 2 H 5 , and
  • Rd 2 representing a (Ci-C 4 )alkyl, in particular -CH 3 , -C 2 H 5 , - CH(CH 3 ) 2 and -C3 ⁇ 4-CH(CH 3 ) 2 , or an aryl, in particular a phenyl, a benzyl radical, a substituted benzyl radical,
  • Rd 3 representing a (Ci-C 3 )alkyl, in particular -CH 3 , -C 2 H 5 and -CH(CH 3 ) 2, or -CH 2 -CH 2 -0-CH 3
  • Rd 4 representing a (Ci-C 3 )alkyl, in particular -CH 3 , -C 2 H 5 , and -CH(CH 3 ) 2
  • Rd 3 representing a (Ci-C 3 )alkyl, in particular -CH 3 , -C 2 H 5 and -CH(CH 3 ) 2
  • Rd 4 representing a (Ci-C 3 )alkyl, in particular -CH 3 , -C 2 H 5 , and -CH(CH 3 ) 2
  • R 5 represents (C,-C 6 )alkyl, -ORe, -NHRe, -N(Re) 2 or -NReRf, with
  • o Re and Rf representing independently a (C 2 -C 3 )alkyl or -CO(C r C 2 )alkyl, or o Re and Rf representing together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, i.e. a pyrrolidine or a piperidine, said pyrrolidine and piperidine may be alpha (di-)substituted, in particular as alpha methylated or alpha dimethylated,
  • R 6 represents H, methyl, ethyl, -ORh, with Rh representing H, (Ci-C6)alkyl, or - CO(d-C 6 ) alkyl,
  • R 7 represents H or a (C 2 -C 6 )alkyl
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as disclosed herein.
  • the terms "compound(s) according to the invention” or “compound(s) of the invention” designate compounds of formula I as described herein below and their enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof.
  • inhibitor of cystathionine beta synthase refers to a compound that inhibits the enzymatic activity of cystathionine beta synthase (EC 4.2.1.22) or that inhibits condensation of serine with homocysteine to form cystathionine and hydrogen sulfide (H 2 S) or that inhibits condensation of cysteine with homocysteine to form cystathionine and water. Inhibition of the enzymatic activity may be assessed according to the method published by Chen (Chen et al., J. Biol. Chem, 2004, 279) and disclosed in WO 2010/072807.
  • halogen refers to the elements fluorine, chlorine, bromine and iodine.
  • saturated heterocyclic group refers to a saturated cyclic alkyl radical in which one or more carbon atoms (and any associated hydrogen atoms) is replaced with the same or different heteroatom.
  • heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc.
  • saturated heterocyclic groups include, but are not limited to, groups derived from epoxides, morpholine, piperazine, piperidine, pyrrolidine,pyranyl.
  • aryl refers to a functional group derived from an aromatic ring.
  • aryl include, but are not limited to, phenyl, benzyl, naphtyl, tolyl, thienyl, xylil.
  • the aryl group may be substituted.
  • substituents include C1-C6 alkyl, C1-C6 alkoxy (for instance, methoxy, ethoxy), halogens.
  • substituted aryl group include substituted phenyl or substituted benzyl, such as p-methoxybenzyl.
  • the present invention relates to inhibitors of cystathionine beta synthase (CBS). These compounds are useful in the treatment of Down syndrome, in particular in the treatment and/or prevention of cognitive disorders in Down syndrome. Cognitive disorders include but are not limited to memory troubles, learning troubles and social relationship troubles.
  • a compound useful in the treatment of Down syndrome is of formula (I):
  • R 2 and R 3 represent independently H, an halogen atom, -Ra, -ORa, -NHRa, or - NRaRb, with
  • Ra and Rb representing independently H, (Ci-C 6 )alkyl, -CO(CrC 6 )alkyl, or o Ra and Rb represent together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring and optionally an oxygen atom in the ring, i.e. a morpholin,
  • o -CORdi with Rdi representing a (Ci-C 3 )alkyl, in particular -CH 3 , -C 2 H 5 , and -CH(CH 3 ) 2 , a saturated heterocyclic group or -CX 3 with X representing a halogen
  • o -COORd 2 with Rd 2 representing a (Ci-C 4 )alkyl, in particular -CH 3 , -C 2 H 5 , - CH(CH 3 ) 2 and -CH 2 -CH(CH 3 ) 2 , an aryl, in particular a phenyl, a benzyl radical or a substituted benzyl radical,
  • Rd 3 representing a (Ci-C 3 )alkyl, in particular -CH 3 , -C 2 H5 and -CH(CH 3 ) 2, or -C3 ⁇ 4-CH 2 -0-CH 3 , or
  • Rd 4 representing a (C r C 3 )alkyl, in particular -CH 3 , -C 2 H 5 , and -CH(CH 3 ) 2 ,
  • R 5 represents (C C 6 )alkyl, -ORe, -NHRe, -N(Re) 2 or -NReRf, with
  • o Re and Rf representing independently a (C 2 -C 3 )alkyl or -CO(Ci-C 2 )alkyl, or o Re and Rf representing together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, i.e. a pyrrolidine or a piperidine, said pyrrolidine and piperidine may be alpha (di-)substituted, in particular as alpha methylated or alpha dimethylated,
  • R 6 represents H, methyl, ethyl, -ORh, with Rh representing H, (Ci-C 6 )alkyl, or - CO(Ci-C 6 ) alkyl,
  • R 7 represents H, (C -C 6 )alkyl
  • R 2 and R 3 represent H, while Rj represents H, an halogen atom, -Ra, - ORa, -NHRa, or -NRaRb, with Ra and Rb representing independently H, (CrC 6 )alkyl, - CO(Ci-C )alkyl, or Ra and Rb represent together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, and optionally an oxygen atom in the ring, i.e. a morpholin, in particular Ri represents H, CI, Me, Et, -OH, -OMe, -OAc, -NMe 2 or morpholin, more particularly the morpholin is linked to the aromatic cycle through the nitrogen.
  • Rj represents H, an halogen atom, -Ra, - ORa, -NHRa, or -NRaRb
  • Ra and Rb representing independently H, (CrC 6 )alkyl, - CO(Ci-C
  • R 3 represents H
  • Ri and R 2 represent independently an halogen atom, -Ra, -ORa, -NHRa, or -NRaRb, with Ra and Rb representing independently H, (C C 6 )alkyl, -CO(Ci-C 6 )alkyl, or Ra and Rb represent together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, i.e. a pyrrolidine or a piperidine.
  • Ri and R 2 represent respectively -OMe, -OMe ; and -OH, -OH.
  • Ri and R 2 represent H
  • R 3 represent an halogen atom, -Ra, - ORa, -NHRa, or -NRaRb
  • Ra and Rb representing independently H, (Ci-C 6 )alkyl, - CO(Ci-C 6 )alkyl, or Ra and Rb represent together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, i.e. a pyrrolidine or a piperidine.
  • R 3 represents -OH, -OMe or morpholine.
  • R 5 represents iPr, tBu, -OiPr, -NHCOMe, -NEt 2 , -NiPr 2 , -N(Et)iPr, - NEt(CH 2 CH 2 OH), -NEt(CH 2 CH 2 OAc), alpha-methylated pyrrolidine, piperidine, alpha- methylated piperidine, or alpha-dimethylated piperidine.
  • R 6 represents H, Me, -OH, -OMe, -OiPr, -OCH(Me)Et, or -OAc.
  • R 7 represents H or iPr.
  • the compound may in particular present a 3S and/or a 11R configuration, in particular a 3S,1 1R configuration.
  • the carbon number 3 corresponding to the carbon bearing - Ph(Ri)(R 2 )(R 3 ) and the carbon number 1 1 to the carbon bearing -Ph(R 5 )(R 6 )(R 7 ).
  • the compound has the formula (I) with:
  • R 5 representing a branched (C 3 -C )alkyl, -ORe, -N(Re) 2 or -NReRf, with
  • o Re and Rf representing independently a (C 2 -C 3 )alkyl or -CO(Ci-C 2 )alkyl, or o Re and Rf representing together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, i.e. a pyrrolidine or a piperidine, said pyrrolidine and piperidine may be alpha (di-)substituted, in particular as alpha methylated or alpha dimethylated, and
  • Ri representing an halogen atom, -Ra, -ORa, -NHRa, or -NRaRb, with
  • Ra and Rb representing independently (Ci-C 6 )alkyl, -CO(Ci-C 6 )alkyl, or o Ra and Rb represent together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, i.e. a pyrrolidine or a piperidine, said pyrrolidine and piperidine may be alpha (di-)substituted, in particular as alpha methylated or alpha dimethylated,
  • Rd b Rd 2 , Rd 3 and Rd 4 representing a (C C 3 )alkyl, in particular Me, and more particularly R 4 is -COCH 3 .
  • the compound has the formula (I) wherein:
  • R ls R 2 and R 3 represents an halogen atom, (Ci-C 6 )alkyl, -0(Cr C 6 )alkyl, -NH(Ci-C 6 )alkyl or -N((Ci-C 6 )alkyl) 2 , in particular the alkyl is a branched alkyl,
  • - P4 is H, -CO(C C 3 )alkyl, -COO(C C 3 )alkyl or -CONH(C C 3 )alkyl
  • - R 5 represents a sterically hindered group such as -N(C 2 -C 3 )alkyl, in particular - N(Et) 2 or N(iPr) 2 , or -N is part of a 5- or 6-membered cycle , in particular such as pyrrolidine or piperidine, and - R 6 represents a methyl group, an ethyl group, -0(Ci-C 6 )alkyl, -OCO(Ci-C 6 ) alkyl.
  • the compound has the formula (I) wherein:
  • R h R 2 and R 3 represents a (Ci-C 6 )alkyl, -0(C 1 -C 6 )alkyl, -NH(C r C 6 )alkyl or -N((C
  • - R4 is H, -CO(Ci-C 3 )alkyl, -COO(C C 3 )alkyl or -CONH(C r C 3 )alkyl, in particular - CO(Ci-C 3 )alkyl, more particularly an acetyl group,
  • - R 5 represents a sterically hindered group such as -N(C 2 -C 3 )alkyl, in particular - N(Et) 2 or N(iPr) 2 , or -N is part of a 5- or 6-membered cycle , in particular such as pyrrolidine or piperidine, and
  • - R 6 is representing -0(Ci-C6)alkyl, in particular a methoxy group.
  • a compound of the invention is of Formula (I) wherein Ri is -OH or -OMe, R 2 and R 3 each represent H, R4 is Ac, R 5 is -N(iPr) 2 , R 6 is - OMe and R 7 is H.
  • a compound of the invention is of formula (I) wherein:
  • Rdi representing -CF 3
  • Rdi representing -CF 3
  • a tetrahydropyranyl group or o -COORd 2 with Rd 2 representing -CH 3 ,-CH(CH 3 ) 2 and -CH 2 -CH(CH 3 ) 2 , - phenyl, benzyl, p-methoxybenzyl , or
  • Rd 3 representing a (C 1 -C 3 )alkyl, in particular -CH 3 , -C 2 H 5 and ⁇ CH(CH 3 ) 2 , -CH 2 -CH 2 -0-CH 3 , or
  • - R 5 is -N(iPr) 2 ,
  • the compound of formula (I) may be chosen from the list consisting of:
  • the invention is related to a compound of formula (I) wherein R 5 is H and Ri, R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and R 9 are as disclosed above.
  • R 7 may be iPr or tBu.
  • the compounds may be chosen from the list consisting of:
  • the present invention further relates to pharmaceutical compositions comprising an effective amount of a compound according to the invention and a pharmaceutically acceptable carrier.
  • an effective amount refers to the amount of a compound that, when administered to a subject for treating a disease or disorder, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment of the disease, disorder, or symptom.
  • the "effective amount” may vary depending, for example, on the compound, its formulation, the age, weight, and/or health of the patient to be treated, and the judgment of the prescribing physician. An appropriate amount in any given instance may be readily ascertained by those skilled in the art or capable of determination by routine experimentation.
  • pharmaceutically acceptable carriers includes any and all solvents, dispersion media, coatings, and the like that are physiologically compatible.
  • compositions of the invention may be in a variety of forms. These include for example liquid, semi-solid, and solid dosage forms, but the preferred form depends on the intended mode of administration and therapeutic application.
  • compositions are preferably for systemic administration such as oral, subcutaneous, percutaneous and parenteral administration.
  • the carrier will usually comprises sterile water, at least in large part, though other ingredients, for example, to aid solubility and/or to increase stability, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprise saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin.
  • the compound of the present invention may be orally administered.
  • solid compositions for oral administration tablets, pills, powders (gelatine capsules, sachets) or granules may be used.
  • the active ingredient according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon stream.
  • inert diluents such as starch, cellulose, sucrose, lactose or silica
  • These compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a coloring, a coating (sugar-coated tablet) or a glaze.
  • compositions for oral administration there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil.
  • inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil.
  • These compositions may comprise substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
  • the doses depend on the desired effect, the duration of the treatment and the route of administration used.
  • the invention also relates to the use of a compound according to the invention for the manufacture of a medicament for the treatment of Down syndrome, in particular for the prevention and/or treatment of cognitive disorders in Down syndrome.
  • the compounds of formula I are inhibitors of the CBS and may be useful in the treatment of diseases associated with CBS activity, in particular Down syndrome.
  • the present invention also provides a method for inhibiting CBS in a patient, in particular a patient with Down syndrome, comprising administering to a patient in need thereof an amount of a compound of the present invention or of a pharmaceutical composition, effective to inhibit CBS.
  • the invention is directed to methods for preventing or treating cognitive disorders, which include administering an effective amount of a compound or a pharmaceutical composition according to the invention to a human or a patient in need thereof.
  • the invention is directed to methods for treating patients with Down syndrome, in particular for preventing or treating cognitive disorders in Down syndrome, which include administering an effective amount of a compound or a pharmaceutical composition according to the invention to a patient in need thereof.
  • the present invention further relates to compounds as described herein for use as a medicament.
  • Exemplary compounds of the present invention can be readily prepared according to the methods of scheme 1 using readily available starting materials, reagents and conventional synthetic procedures. It is also possible to make use of variants of these process steps, which in themselves are known to and well within the preparatory skill of the medicinal chemist.
  • the cyclohexenone (I) can be converted into its corresponding chloro derivative (II) by use of an appropriate chlorinating agent such as oxalyl chloride.
  • This intermediate can be reacted with 1 ,2-phenylenediamine in ethanol to afford the diamine (III).
  • a range of substituted aldehyde can then made to react with diamine (III) to give the benzodiazepine (IV).
  • the benzodiazepine core (IV) can be converted into its acetyl derivative via use of anhydride acetic in pyridine and DCM.
  • Example 1 Preparation of 10- Acetyl- 11 -(4-Diethylamino-phenyl)-3-(4-methoxy-phenyl)- 2,3 , 4,5 , 10,11 -hexahvdro-dibenzo [b,e] ⁇ 1 ,4 " ]diazepin- 1 -one 5-(4-methoxy-phenyl)-cyclohex-2-enone
  • Example 2 Preparation of 10- Acetyl- 1 l-(4-di ethyl amino-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5, 10, 11 -hexahvdro-dibenzo
  • Crystals were collected from the compound purified and analysed by X-ray, with an Oxford-Diffraction Gemini diffractometer using a copper source. Data were collected and analysed with the software CrysalisPro, and the structure was resolved by direct methods with the software Sir97.
  • Example 3 preparation of 10- Acetyl- 1 l-(4-di ethylamino-phenyl)-3 -(4-chloro-phenyl)- 2,3,4,5, 10, 11 -hexahydro-dibenzo b,e1 [ 1 ,4]diazepin- 1 -one
  • Example 4 preparation of 1 l-(4-diethylamino-phenyl)-3-phenyl-2,3,4,5,10,l 1 -hexahvdro- dibenzo[b,e] l ,4]diazepin-l -one
  • Example 5 preparation of 10-Acetyl-l l-(4-diethylamino-phenyl)-3-phenyl-2,3,4,5, 10,11- hexahydro-dibenzo b,e] l ,4]diazepin-l -one
  • Example 6 preparation of 10- Acetyl- 11 -(4-Diethylamino-phenyl)-3 -(4-ethyl-phenyl)- 2,3 ,4,5 , 10, 11 -hexahydro-dibenzo[b,e1 1 ,4 " ]diazepin- 1 -one
  • Example 7 10-Acetyl-l l-(4-Diethylamino-phenyl)-3-(4-acetoxy-phenyl)-2,3,4,5, 10,11- hexahydro-dibenzo[b,e] [ 1 ,4] diazepin- 1 -one
  • Example 8 preparation of l l-(4-diethylamino-phenyl)-3-(3,4-dimethoxy-phenyl)- 2,3,4,5, 10, 11 -hexahydro-dibenzo[b,e ⁇ j[ " 1 ,4 ⁇ jdiazepin- 1 -one
  • Example 9 preparation of 10-Acetyl-l l-(4-diethylamino-phenylV3-(3,4-dimethoxy- phenyl)-2,3,4,5,10j l-hexahvdro-dibenzorb 1 eiri,41diazepin-l-one
  • Example 10 preparation of 10-Acetyl-l l -(4-diethylamino-phenyl)-3-(3 1 4-dihvdroxy- phenvD-2,3 ,4,5, 10, 11 -hexahydro-dibenzo
  • Example 12 preparation of 10-Acetyl-l l -(4-diethylamino-phenyl)-3-(2,3-dimethoxy- phenyl)-2,3 ,4,5, 10, 11 -hexahvdro-dibenzo [b,e " [ [ ⁇ ,4] diazepin- 1 -one
  • Example 13 preparation of 11 -(4-diethylamino-phenyl ' )-3-(2,4-dimethoxy-phenyl)- 2,3,4,5,10,11 -hexahydro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
  • Compound 32 was obtained following protocols described for Example 3, step 1 with 500mg (2.01mmol) of 5-(2,4-dimethoxy-phenyl)-cyclohexane-l,3-dione, 218mg (2.02mmol) of phenylenediamine in 2 mL of ethanol yielding 500mg (73 %) of an orange foam.
  • Example 14 preparation of 10-Acetyl-l l -(4-diethylamino-phenyl)-3-(2,4-dimethoxy- phenyl)-2,3 ,4,5, 10, 1 1 -hexahydro-dibenzo
  • Example 15 preparation of l l-(4-diethylamino-phenyl)-3-(2-methoxy-phenyl)- 2,3 ,4,5, 10, 1 1 -hexahydro-dibenzo[b,e] [ 1 ,4 " [diazepin- 1 -one
  • Example 16 preparation of 10-Acetyl-l l-(4-diethylamino-phenyl -3-(2-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l -one
  • Example 17 preparation of l l-(4-diethylamino-phenyl)-3-(3-methoxy-phenyl)- 2.3,4,5,10,1 1 -hexahydro-dibenzo b,e] [1,4] diazepin- 1 -one
  • Example 18 preparation of 10- Acetyl- 1 l-(4-diethylamino-phenyl -3-(3-methoxy-phenyl)- 2,3 ,4,5,10,11 -hexahydro-dibenzo
  • Step 1 Compound 40 : 10-Acetyl-ll-(4-diethylamino-phenyl)-3-(3-methoxy-phenyl)- enzo [b,e] [ 1 ,4] diazepin- 1 -one
  • Example 20 preparation of 10- Acetyl- 11 -(4-diethylamino-phenyl)-3-(4-morpholino- phenyl)-2,3,4,5J0,l l-hexahydro-dibenzo b,e1[l,4]diazepin-l-one Step l
  • Compound 45 was obtained following protocols described for Example 3, step 3 with 40mg (0.08mmol) of Compound 44, ⁇ 9 ⁇ a ⁇ L (0.15mmol) of anhydride acetic, 25 iL (0.31mmol) of pyridine in 2mL of DCM yielding 38mg (87%) of a solid.
  • Example 21 preparation of 1 l-(4-Diethylamino-phenyl -3-(4-dimethylamino-phenyl)-
  • Example 22 preparation of 10- Acetyl- 11 -(4-di ethyl amino-phenyl)-3 -(4-dimethylamino- phenyl)-2,3 ,4,5, 10, 11 -hexahydro-dibenzo[ " b,e] [ 1 ,4 " ]diazepin- 1 -one
  • Example 24 preparation of l l-(4-Diethylamino-phenvD-3-(4-methoxy-phenyl)-10-(2- oxo-propyl)-2.3,
  • Example 26 preparation of 10- Acetyl- 1 l-(4-di ethylamino-2 -methyl -phenyl)-3 -(4- methoxy-phenyl)-2,3 ,4,5, 10,11 -hexahydro-dibenzof b,e " [ ⁇ 1 ,41diazepin- 1 -one
  • Example 27 preparation of 10- Acetyl- l l-(4-diethylamino-2-methyl-phenyl)-3 -(4- hydroxy-phenvD-2,3 ,4,5, 10, 11 -hexahydro-dibenzo
  • Compound 54 was obtained following protocols described for Example 10, step 1 with 50mg (O.lOmmol) of Compound 53, 286 ⁇ (0.29mmol) of boron tribromide 1M in ImL of DCM yielding 17mg (45%) of a brown powder.
  • Example 28 preparation of l l-(2-acetoxy-4-diethylamino-phenyl)-3-(4-methoxy-phenyl)- 2,3.4,5,10,11 -hexahydro-dibenzo [b,e] f 1 ,4] diazepin- 1 -one
  • Example 29 preparation of 10-Acetyl-l l-(2-acetoxy-4-diethylamino-phenyl -3-(4- methoxy-phenyl)-2,3 ,4,5, 10, 11 -hexahydro-dibenzo[b, e] 1 ,4] diazepin- 1 -one
  • Example 30 preparation of 10- Acetyl- 1 l-(4-di ethyl amino-2-hydroxy-phenyl)-3 -(4- methoxy-phenyl)-2,3,4,5, 10,11 -hexahydro-dibenzo b,e] ⁇ 1 ,4]diazepin- 1 -one
  • Step 1 Compound 58 : 10-Acetyl-ll-(4-diethylamino-2-hydroxy-phenyl)-3-(4-methoxy- phenyl)-2,3,4,5, 10,11 -hexahy dro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
  • Example 31 10- Acetyl- 1 l-(4-(ethyl-2-hvdroxy-ethyl-amino)-2-methyl-phenyl)-3-(4- methoxy-phenvD-2,3 ,4,5, 10, 1 1 -hexahydro-dibenzo[ " b,e] ⁇ 1 ,4]diazepin- 1 -one
  • Compound 60 was obtained following protocols described for Example 25, stepl with 85 ⁇ (0.91mmol) of POC13, ImL of DMF and 135mg (0.61mmol) of Compound 59 yielding 70mg (46%) as an orange oil.
  • Compound 65 was obtained following protocols described for Example 3, step 3 with 40mg (0.08mmol) of Compound 64, ⁇ ⁇ ⁇ . (0.08mmol) of anhydride acetic, 15 ⁇ . (0.18mmol) of pyridine in 2mL of DCM yielding 39mg (90%) of a beige solid.
  • Example 33 preparation of 1 l-(4-tert-butyl-phenyl)-3-(4-methoxy-phenyl -2,3,4,5,10,l 1- hexahydro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one Step 1
  • Example 34 preparation of 10- Acetyl- 1 l-(4-tert-butyl -phenyl)-3 -(4-methoxy-phen yl)- 2,3 ,4,5, 10,11 -hexahydro-dibenzo b,el 1 ,4 " jdiazepin- 1 -one
  • Example 35 preparation of 10- Acetyl- 11 -(4-tert-butyl-phenyl)-3 -(4-hydroxy-phenyl)-
  • Compound 68 was obtained following protocols described for Example 10, step 1 with 95mg (0.19mmol) of Compound 67, 576 ⁇ (0.58mmol) of boron tribromide 1M in ImL of DCM yielding 73mg (79%) of a light yellow crystals.
  • Example 36 preparation of 1 l-(4-isopropyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo[ " b,e][l ,4]diazepin-l -one
  • Example 37 preparation of 10-Acetyl-l l-(4-isopropyl-phenyl)-3-(4-methoxy-phenyl - 2,3,4,5, 10, 1 1 -hexahydro-dibenzo[ " b,e] [ 1 ,4]diazepin- 1 -one Step 1
  • Compound 70 was obtained following protocols described for Example 3, step 3 with 70mg (0.16mmol) of Compound 69, 41 i (0.26mmol) of anhydride acetic, 43 ⁇ (0.53mmol) of pyridine in lmL of DCM yielding 34mg (43%) of a solid.
  • Example 38 preparation of l l-(4-(ethyl-isopropyl-amino)-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,11 -hexahydro-dibenzo b,e][ " l,4]diazepin-l -one
  • Example 39 preparation of 10-Acetyl-l l -(4-(ethyl-isopropyl-amino ' )-phenyl -3-(4- methoxy-phenyl)-2,3 ,4,5, 10, 1 1 -hexahydro-dibenzo
  • Example 75 was obtained following protocols described for Example 1, step 3 with 25mg (0.08mmol) of Compound 2, 17mg (0.08mmol) of Compound 74 in ImL of EtOH yielding 30mg (73%) of a beige solid.
  • Example 41 preparation of 10- Acetyl- 11 -(4-Diisopropylamino-phenyl)-3-(4-methoxy- phenyl)-2, 3,4,5, 10, 1 1 -hexahydro-dibenzo[ " b,eir 1 ,4]diazepin- 1 -one
  • Compound 76 was obtained following protocols described for Example 3, step 3 with 28mg (0.06mmol) of Compound 75, 2 ⁇ ⁇ iL (0.17mmol) of anhydride acetic, 28 ⁇ . (0.97mmol) of pyridine in 2mL of DCM yielding 23mg (76%) of a beige solid.
  • Example 42 preparation of 10- Acetyl- 1 1 -(4-Diisopropylamino-phenyl)-3-(4-hydroxy- phenyl)-2,3 A5, 10, 1 1 -hexahydro-dibenzo [b,e] 1 ,4]diazepin- 1 -one
  • Example 43 preparation of l l -(4-Diisopropylamino-2-methyl-phenyl -3-( " 4-methoxy- phenyp-2,3,4,5, 10,1 1 -hexahydro-dibenzo [b,e] [ 1 ,4]diazepin- 1 -one
  • Step l ompound 78 2-methyl-4-diisopropylamino benzaldehyde
  • Example 44 preparation of 10- Acetyl- 1 l-(4-diisopropylamino-2-methyl -phenyl >3 -(4- methoxy-phenyl)-2,3,4,5, 10, 11 -hexahydro-dibenzo[ " b,e ⁇ j[ 1 ,4]diazepin-l -one
  • Example 45 preparation of 10-Acetyl-l l-(4-diisopropylamino-2-methyl-phenyl)-3-(4- hydroxy-phenyl)-2,3,4,5, 10, 11 -hexahydro-dibenzo b,e1 1 ,4]diazepin- 1 -one
  • Example 46 preparation of 1 l-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy- phenvD-2,3, 4,5,10, 1 1 -hexahydro-dibenzo
  • Example 47 preparation of 1 l-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-hydroxy- phenyD-2,3,4,5, 10, 11 -hexahydro-dibenzo b,e1 ⁇ 1 ,41 diazepin- 1 -one
  • Example 48 preparation of 10- Acetyl- 1 1 -(4-diisopropylamino-2-methoxy-phenyl)-3-(4- methoxy-phenvD-2,3,4,5, 10, 11 -hexahydro-dibenzo b,e] 1 ,4 "
  • Example 50 preparation of l l-(2-acetoxy-4-diisopropylamino-phenyl)-3-(4-methoxy- phenyl)-2,3 ,4,5, 10, 11 -hexahydro-dibenzo[ " b,e1 ⁇ 1 ,4]diazepin- 1 -one
  • Example 51 preparation of 1 l-(4-Diisopropylamino-2-hydroxy-phenyl)-3-(4-methoxy- phenyl)-2,3 A5, 10,11 -hexahydro-dibenzo
  • Step l Compound 92 : ll-(4-DiisopropyIamino-2-hydroxy-phenyI)-3-(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo [b,e] [1,4] diazepin-l-one
  • Example 52 preparation of 10-Acetyl-l l -(2-acetoxy-4-diisopropylamino-phenyl -3-(4- methoxy-phenyl)-2,3,4,5, 10, 1 1 -hexahydro-dibenzo[ " b,e " [[ 1 ,41diazepin-l -one
  • Example 53 preparation of 10-Acetyl-l l -(2-hydroxy-4-diisopropylamino-phenyl)-3-( ' 4- methoxy-phenyl)-2,3 ,4,5, 10, 1 1 -hexahydro-dibenzo [b-e] 1 ,4]diazepin-l -one
  • Compound 94 was obtained following protocols described for Example 31 , step 5 with 29mg (0.05mmol) of Compound 93, ⁇ ⁇ ⁇ of NaOH IN and ImL of dioxane yielding 19mg (71%) as a beige solid.
  • Example 54 preparation of 1 l-(4-diisopropylamino-2-isopropoxy-phenyl -3-(4-methoxy- phenyl)-2,3 ,4,5,10,1 1 -hexahvdro-dibenzo[ " b,e] 1 ,4]diazepin- 1 -one
  • Example 55 preparation of 10- Acetyl- 11 -(4-diisopropylamino-2-isopropoxy-phenyl)-3 -
  • Example 56 preparation of 1 l-(4-diisopropylamino-2-sec-butoxy-phenyl)-3-(4-methoxy- phenyD-2,,3 A5, 10, 11 -hexahydro-dibenzo[b,el [ 1 ,4]diazepin-l -one
  • Example 57 preparation of 10- Acetyl- 1 l-(4-diisopropylamino-2-sec-butoxy-phenyl)-3- (4-methoxy-phenyl)-2,3 A5, 10, 11 -hexahydro-dibenzof b,e] f 1 ,41diazepin- 1 -one

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention is directed to inhibitors of cystathionine beta synthase which, among other biochemical effects, allow reduction of the neurotoxic overproduction of endogenous hydrogen sulphide. These compounds and pharmaceutical compositions containing them are useful for the prevention and treatment of cognitive disorders such as cognitive disorders in Down syndrome. The invention also relates to methods for preventing or treating cognitive disorders including cognitive disorders in Down Syndrome.

Description

Inhibitors of cystathionine beta synthase to reduce the neurotoxic overproduction of endogenous hydrogen sulfide
Background
The invention relates to inhibitors of cystathionine beta synthase (CBS), in particular EC 4.2.1.22, for treatment of Down syndrome, in particular for treatment and/or prevention of cognitive disorders in Down syndrome.
Down syndrome or trisomy 21 is the most common genetic cause of mental retardation. It is a chromosomal condition characterized by the presence of an extra copy of genetic material on the 21st chromosome, either in whole (trisomy 21) or part (such as due to translocations). The gene encoding the cystathionine beta synthase enzyme is located on chromosome 21 and is overexpressed in children with Down syndrome, or trisomy 21. An enrichment in CBS in the brain, an excess of CBS activity and endogenous hydrogen sulfide (¾S) overproduction have all been found in Down Syndrome [LEJEUNE Jerome. Commentarii vol. III. n° 9, pages 1-12; ICHINOHE et al. Biochemical and Biophysical Research Communications 338 (2005) 1547-1550; CHADEFAUX et al. Biochemical and Biophysical Research Communications, vol. 128 n° 1, 1985, 40-44; POGRIBNA et al. Genet. 69:88-95, 2001 ; KAMOUN et al. American Journal of Medical Genetics 116A 310-31 1 (2003)] and are thought to be, at least partially, responsible of cognitive disorders. CBS catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine and is the only enzyme of the brain that produces H2S. It has been proposed that ¾S may function as a neuro-modulator or transmitter in the brain (KIMURA, Hideo. Molecular Neurobiology, vol. 6, 13-19 (2002); KAMOUN, Pierre. Medecine/Sciences. Juin-juillet 2004, vol. 20, n° 6-7, P. 697-700). Exposure to hydrogen sulfide can also result in neurobehavioral effects in humans and animals. Alterations in balance, reaction time, visual field, and verbal recall were observed in individuals exposed to high concentrations of hydrogen sulfide for an acute duration and in individuals exposed to lower levels of hydrogen sulfide for a chronic duration; no monitoring data were provided. The severity of effects appeared to be related to the duration of exposure as well as the exposure concentration. Several animal studies provide suggestive evidence that hydrogen sulfide exposure results in a decrease in motor activity and task response rate. Compounds or compositions for preventing and/or treating cognitive disorders in Down syndrome have been proposed in WO 2010/072807.
The object of the invention is to provide new methods and compounds that inhibit the activity of CBS and consequently regulate overproduction of hydrogen sulfide (H2S) in trisomic 21 patients due to an overexpression of CBS.
Benzodiazepines are known for their therapeutic activities, such as sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, muscle relaxant and amnesic action, and also for treating Hepatitis C Virus infection. However, the use of benzodiazepine derivatives for treating Down syndrome by inhibiting CBS activity, in particular for preventing or treating cognitive disorders in Down syndrome has neither been described nor suggested.
Summary of the invention
The present invention relates to a compound having the formula (I) :
Figure imgf000003_0001
Formula (I)
wherein
- Ri, R2 and R3 represent independently H, an halogen atom, -Ra, -ORa, -NHRa, or - NRaRb, with
o Ra and Rb representing independently H, (Ci-C6)alkyl, -CO(CrC6)alkyl, or o Ra and Rb represent together a 5- or 6-membered cycle, in particular comprising
4 or 5 carbon atoms in the ring and optionally an oxygen atom in the ring, i.e. a morpholin,
- R represents
o H,
o a (CrC3)alkyl, in particular -CH3, -C2H5, and -CH(CH3)2,
o -CORdi with Rdi representing a (Ci-C3)alkyl, in particular -CH3, -C2H5, and
-CH(CH3)2, a saturated heterocyclic group or -CX3 with X representing a halogen,
o -COORd2 with Rd2 representing a (Ci-C4)alkyl, in particular -CH3, -C2H5, - CH(CH3)2 and -C¾-CH(CH3)2, or an aryl, in particular a phenyl, a benzyl radical, a substituted benzyl radical,
o -CONHRd3, with Rd3 representing a (Ci-C3)alkyl, in particular -CH3, -C2H5 and -CH(CH3)2, or -CH2-CH2-0-CH3, or o -S02Rd4, with Rd4 representing a (Ci-C3)alkyl, in particular -CH3, -C2H5, and -CH(CH3)2,
- R5 represents (C,-C6)alkyl, -ORe, -NHRe, -N(Re)2 or -NReRf, with
o Re and Rf representing independently a (C2-C3)alkyl or -CO(CrC2)alkyl, or o Re and Rf representing together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, i.e. a pyrrolidine or a piperidine, said pyrrolidine and piperidine may be alpha (di-)substituted, in particular as alpha methylated or alpha dimethylated,
- R6 represents H, methyl, ethyl, -ORh, with Rh representing H, (Ci-C6)alkyl, or - CO(d-C6) alkyl,
- R7 represents H or a (C2-C6)alkyl, and
- Rg and R9 represent each H,
and its enantiomers, diastereoisomers and pharmaceutically acceptable salts, for its use in the treatment of Down syndrome.
The invention further relates to a pharmaceutical composition comprising a compound of formula (I) as disclosed herein.
Definitions
As used herein, the terms "compound(s) according to the invention" or "compound(s) of the invention" designate compounds of formula I as described herein below and their enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof.
As used herein, the terms "inhibitor of cystathionine beta synthase" refers to a compound that inhibits the enzymatic activity of cystathionine beta synthase (EC 4.2.1.22) or that inhibits condensation of serine with homocysteine to form cystathionine and hydrogen sulfide (H2S) or that inhibits condensation of cysteine with homocysteine to form cystathionine and water. Inhibition of the enzymatic activity may be assessed according to the method published by Chen (Chen et al., J. Biol. Chem, 2004, 279) and disclosed in WO 2010/072807.
As used herein, the term "halogen" refers to the elements fluorine, chlorine, bromine and iodine.
As used herein, a "saturated heterocyclic group" refers to a saturated cyclic alkyl radical in which one or more carbon atoms (and any associated hydrogen atoms) is replaced with the same or different heteroatom. Examples heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Examples of saturated heterocyclic groups include, but are not limited to, groups derived from epoxides, morpholine, piperazine, piperidine, pyrrolidine,pyranyl.
As used herein, the term "aryl" refers to a functional group derived from an aromatic ring. Examples of "aryl" include, but are not limited to, phenyl, benzyl, naphtyl, tolyl, thienyl, xylil. The aryl group may be substituted. Examples of substituents include C1-C6 alkyl, C1-C6 alkoxy (for instance, methoxy, ethoxy), halogens. Examples of substituted aryl group include substituted phenyl or substituted benzyl, such as p-methoxybenzyl. Detailed description of the invention
The present invention relates to inhibitors of cystathionine beta synthase (CBS). These compounds are useful in the treatment of Down syndrome, in particular in the treatment and/or prevention of cognitive disorders in Down syndrome. Cognitive disorders include but are not limited to memory troubles, learning troubles and social relationship troubles. A compound useful in the treatment of Down syndrome is of formula (I):
Figure imgf000005_0001
Formula (I)
or an enantiomer, diastereoisomer or pharmaceutically acceptable salt thereof
wherein
- Ri, R2 and R3 represent independently H, an halogen atom, -Ra, -ORa, -NHRa, or - NRaRb, with
o Ra and Rb representing independently H, (Ci-C6)alkyl, -CO(CrC6)alkyl, or o Ra and Rb represent together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring and optionally an oxygen atom in the ring, i.e. a morpholin,
- R^. represents
o H,
o a (CrC3)alkyl, in particular -CH3, -C2H5, and -CH(CH3)2,
o -CORdi with Rdi representing a (Ci-C3)alkyl, in particular -CH3, -C2H5, and -CH(CH3)2, a saturated heterocyclic group or -CX3 with X representing a halogen, o -COORd2 with Rd2 representing a (Ci-C4)alkyl, in particular -CH3, -C2H5, - CH(CH3)2 and -CH2-CH(CH3)2, an aryl, in particular a phenyl, a benzyl radical or a substituted benzyl radical,
o -CONHRd3, with Rd3 representing a (Ci-C3)alkyl, in particular -CH3, -C2H5 and -CH(CH3)2, or -C¾-CH2-0-CH3, or
o -S02Rd4, with Rd4 representing a (CrC3)alkyl, in particular -CH3, -C2H5, and -CH(CH3)2,
R5 represents (C C6)alkyl, -ORe, -NHRe, -N(Re)2 or -NReRf, with
o Re and Rf representing independently a (C2-C3)alkyl or -CO(Ci-C2)alkyl, or o Re and Rf representing together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, i.e. a pyrrolidine or a piperidine, said pyrrolidine and piperidine may be alpha (di-)substituted, in particular as alpha methylated or alpha dimethylated,
- R6 represents H, methyl, ethyl, -ORh, with Rh representing H, (Ci-C6)alkyl, or - CO(Ci-C6) alkyl,
- R7 represents H, (C -C6)alkyl, and
- R8 and R9 represent each H.
In one embodiment R2 and R3 represent H, while Rj represents H, an halogen atom, -Ra, - ORa, -NHRa, or -NRaRb, with Ra and Rb representing independently H, (CrC6)alkyl, - CO(Ci-C )alkyl, or Ra and Rb represent together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, and optionally an oxygen atom in the ring, i.e. a morpholin, in particular Ri represents H, CI, Me, Et, -OH, -OMe, -OAc, -NMe2 or morpholin, more particularly the morpholin is linked to the aromatic cycle through the nitrogen.
In another embodiment, R3 represents H, while Ri and R2 represent independently an halogen atom, -Ra, -ORa, -NHRa, or -NRaRb, with Ra and Rb representing independently H, (C C6)alkyl, -CO(Ci-C6)alkyl, or Ra and Rb represent together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, i.e. a pyrrolidine or a piperidine. In particular Ri and R2 represent respectively -OMe, -OMe ; and -OH, -OH.
In another embodiment, Ri and R2 represent H, while R3 represent an halogen atom, -Ra, - ORa, -NHRa, or -NRaRb, with Ra and Rb representing independently H, (Ci-C6)alkyl, - CO(Ci-C6)alkyl, or Ra and Rb represent together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, i.e. a pyrrolidine or a piperidine. In particular R3 represents -OH, -OMe or morpholine. In particular, R5 represents iPr, tBu, -OiPr, -NHCOMe, -NEt2, -NiPr2, -N(Et)iPr, - NEt(CH2CH2OH), -NEt(CH2CH2OAc), alpha-methylated pyrrolidine, piperidine, alpha- methylated piperidine, or alpha-dimethylated piperidine. In particular, R6 represents H, Me, -OH, -OMe, -OiPr, -OCH(Me)Et, or -OAc.
In particular, R7 represents H or iPr.
The compound may in particular present a 3S and/or a 11R configuration, in particular a 3S,1 1R configuration. The carbon number 3 corresponding to the carbon bearing - Ph(Ri)(R2)(R3) and the carbon number 1 1 to the carbon bearing -Ph(R5)(R6)(R7).
In one embodiment, the compound has the formula (I) with:
- R5 representing a branched (C3-C )alkyl, -ORe, -N(Re)2 or -NReRf, with
o Re and Rf representing independently a (C2-C3)alkyl or -CO(Ci-C2)alkyl, or o Re and Rf representing together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, i.e. a pyrrolidine or a piperidine, said pyrrolidine and piperidine may be alpha (di-)substituted, in particular as alpha methylated or alpha dimethylated, and
- at least one from Ri, R2 and R3 representing an halogen atom, -Ra, -ORa, -NHRa, or -NRaRb, with
o Ra and Rb representing independently (Ci-C6)alkyl, -CO(Ci-C6)alkyl, or o Ra and Rb represent together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, i.e. a pyrrolidine or a piperidine, said pyrrolidine and piperidine may be alpha (di-)substituted, in particular as alpha methylated or alpha dimethylated,
and in particular with * being a (Q-C^alkyl, in particular Me , -CORdi, - COORd2, -CONHRd3, -S02Rd4, with Rdb Rd2, Rd3 and Rd4 representing a (C C3)alkyl, in particular Me, and more particularly R4 is -COCH3.
In another embodiment the compound has the formula (I) wherein:
- at least one of Rls R2 and R3 represents an halogen atom, (Ci-C6)alkyl, -0(Cr C6)alkyl, -NH(Ci-C6)alkyl or -N((Ci-C6)alkyl)2, in particular the alkyl is a branched alkyl,
- P4 is H, -CO(C C3)alkyl, -COO(C C3)alkyl or -CONH(C C3)alkyl
- R5 represents a sterically hindered group such as -N(C2-C3)alkyl, in particular - N(Et)2 or N(iPr)2, or -N is part of a 5- or 6-membered cycle , in particular such as pyrrolidine or piperidine, and - R6 represents a methyl group, an ethyl group, -0(Ci-C6)alkyl, -OCO(Ci-C6) alkyl.
In another embodiment, the compound has the formula (I) wherein:
- at least one of Rh R2 and R3 represents a (Ci-C6)alkyl, -0(C1-C6)alkyl, -NH(Cr C6)alkyl or -N((C|-C6)alkyl)2, in particular the alkyl is a branched alkyl,
- R4 is H, -CO(Ci-C3)alkyl, -COO(C C3)alkyl or -CONH(CrC3)alkyl, in particular - CO(Ci-C3)alkyl, more particularly an acetyl group,
- R5 represents a sterically hindered group such as -N(C2-C3)alkyl, in particular - N(Et)2 or N(iPr)2, or -N is part of a 5- or 6-membered cycle , in particular such as pyrrolidine or piperidine, and
- R6 is representing -0(Ci-C6)alkyl, in particular a methoxy group.
According to a specific embodiment, a compound of the invention is of Formula (I) wherein Ri is -OH or -OMe, R2 and R3 each represent H, R4 is Ac, R5 is -N(iPr)2, R6 is - OMe and R7 is H.
According to a further specific embodiment, a compound of the invention is of formula (I) wherein:
- Ri is -OMe,
- R2 and R3 each represent H,
- R4 represents
o -CORd] with Rdi representing -CF3, a tetrahydropyranyl group, or o -COORd2 with Rd2 representing -CH3,-CH(CH3)2 and -CH2-CH(CH3)2, - phenyl, benzyl, p-methoxybenzyl , or
o -CONHRd3, with Rd3 representing a (C1-C3)alkyl, in particular -CH3, -C2H5 and ~CH(CH3)2, -CH2-CH2-0-CH3, or
o -S02Rd4, with Rd4 representing -CH3,
- R5 is -N(iPr)2,
- R6 is -OMe and
-R7 is H.
The compound of formula (I) may be chosen from the list consisting of:
Compound 3
1 1 -(4-Diethylamino-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5, 10, 1 1 -hexahydro- dibenzo[b,e][l,4]diazepin-l-one ;
Compound 4
10- Acetyl- 11 -(4-diethylamino-phenyl)-3 -(4-methoxy-phenyl)-2,3 ,4,5 , 10, 1
1 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 5 10- Acetyl- 11 -(R)-(4-diethylamino-phenyl)-3 -(S)-(4-methoxy-phenyl)-2,3 ,4,5 , 10,11- hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 8
10- Acetyl- 11 -(4-diethylamino-phenyl)-3-(4-chloro-phenyl)-2,3,4,5, 10, 11 -hexahydro- dibenzo[b,e][l,4]diazepin-l-one ;
Compound 11
10-Acetyl-l 1 -(4-diethylamino-phenyl)-3-phenyl-2,3,4,5, 10, 11 -hexahydro- dibenzo[b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 16
10-Acetyl-l l-(4-Diethylamino-phenyl)-3-(4-ethyl-phenyl)-2,3,4,5,10,l 1-hexahydro- dibenzo[b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 22
10- Acetyl-11 -(4-Diethylamino-phenyl)-3-(4-acetoxy-phenyl)-2, 3,4,5, 10,11 -hexahydro- dibenzo[b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 24
11 -(4-diethylamino-phenyl)-3-(3,4-dimethoxy-phenyl)-2, 3,4,5, 10, 11 -hexahydro- dibenzo[b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 25
10-Acetyl-l l-(4-diethylamino-phenyl)-3-(3,4-dimethoxy-phenyl)-2,3,4,5,
10, 11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 26
10- Acetyl- 11 -(4-diethylamino-phenyl)-3 -(3 ,4-dihydroxy-phenyl)-2,3 ,4,5 , 10, 11 -hexahydro- dibenzo [b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 30
1 l-(4-diethylamino-phenyl)-3-(2,3-dimethoxy-phenyl)-2,3,4,5,10,l 1-hexahydro- dibenzo [b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 31
10- Acetyl- 11 -(4-diethylamino-phenyl)-3-(2,3 -dimethoxy-phenyl)-2,3 ,4,5,10,11- hexahydro-dibenzo[b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 33
11 -(4-diethylamino-phenyl)-3-(2,4-dimethoxy-phenyl)-2,3, 4,5,10, 11-hexahydro- dibenzo [b, e] [ 1 ,4] diazepin- 1 -one ;
Compound 34
10- Acetyl- 11 -(4-diethylamino-phenyl)-3-(2,4-dimethoxy-phenyl)-2,3 ,4,5,10,11- hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 36
11 -(4-diethylamino-phenyl)-3 -(2-methoxy-phenyl)-2,3,4,5, 10,11 -hexahydro- dibenzo [b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 37
1 l-(4-diethylamino-phenyl)-3-(2-methoxy-phenyl)-2,3,4,5,10,l 1-hexahydro- dibenzo [b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 39
11 -(4-diethylamino-phenyl)-3 -(3 -methoxy-phenyl)-2,3 ,4,5, 10, 11 -hexahydro- dibenzo [b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 40
10-Acetyl-l 1 -(4-diethylamino-phenyl)-3-(3-methoxy-phenyl)-2,3,4,5, 10, 11 -hexahydro- dibenzo [b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 44
11 -(4-diethylamino-phenyl)-3 -(4-morpholino-phenyl)-2,3 ,4,5, 10, 11 -hexahydro- dibenzo[b,e] [1,4] diazepin- 1 -one ; Compound 45
10-Acetyl-l l-(4-diethylamino-phenyl)-3-(4-morpholino-phenyl)-2,3,4,5, 10,11 -hexahydro- dibenzo [b, e] [ 1 ,4] diazepin- 1 -one ;
Compound 47
1 l-(4-Diethylamino-phenyl)-3-(4-dimethylamino-phenyl)-2, 3,4,5, 10,11-hexahydro- dibenzo[b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 48
10- Acetyl- 11 -(4-diethylamino-phenyl)-3 -(4-dimethylamino-phenyl)-2,3 ,4,5, 10,11 - hexahydro-dibenzo[b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 49
10- Acetyl- 1 1 -(4-diethylamino-phenyl)-3-(4-hydroxy-phenyl)-2,3 ,4,5,10,1
I -hexahydro-dibenzo[b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 50
I I -(4-Diethylamino-phenyl)-3-(4-methoxy-phenyl)- 10-(2-oxo-propyl)-2,3 ,4,5, 10,1 1- hexahydro-dibenzo [b,e][ 1,4] diazepin- 1 -one ;
Compound 52
1 1 -(4-Diethylamino-2-methyl-phenyl)-3 -(4-methoxy-phenyl)-2,3 ,4,5 , 10, 11 -hexahydro- dibenzo [b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 53
10-Acetyl-l l-(4-diethylamino-2-methyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 54
10- Acetyl- 11 -(4-diethylamino-2-methyl-phenyl)-3 -(4-hydroxy-phenyl)-2,3 ,4,5,10,1 1- hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 56
11 -(2-acetoxy-4-diethylamino-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,l 0,11 -hexahydro- dibenzo[b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 57
10- Acetyl- 11 -(2-acetoxy-4-diethylamino-phenyl)-3 -(4-methoxy-phenyl)-2,3 ,4,5,10,11- hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 58
10- Acetyl- 1 1 -(4-diethylamino-2-hydroxy-phenyl)-3-(4-methoxy-phenyl)-2,3 ,4,5, 10,11- hexahydro-dibenzo[b,e][l ,4]diazepin-l-one ;
Compound 62
10-Acetyl-l 1 -(4-(ethyl-2-acetoxy-ethyl-amino)-2-methyl-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 63
10-Acetyl-l 1 -(4-(ethyl-2-hydroxy-ethyl-amino)-2-methyl-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e] [1,4] diazepin- 1 -one ;
Compound 65
10- Acetyl- 11 -(4-acetamido-phenyl)-3-(4-methoxy-phenyl)-2,3 ,4,5, 10, 11 -hexahydro- dibenzo[b,e][l ,4]diazepin-l-one ;
Compound 66
1 1 -(4-tert-butyl-phenyl)-3 -(4-methoxy-phenyl)-2,3,4,5, 10, 1 1 -hexahydro- dibenzo[b,e][l,4]diazepin-l-one ;
Compound 67
10- Acetyl- 11 -(4-tert-butyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5, 10, 11 -hexahydro- dibenzo[b,e][l ,4]diazepin-l-one ;
Compound 68 10- Acetyl- 11 -(4-tert-butyl-phenyl)-3-(4-hydroxy-phenyl)-2,3 ,4,5,10,11 -hexahydro- dibenzo [b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 69
11 -(4-isopropyl-phenyl)-3 -(4-methoxy-phenyl)-2,3 ,4,5 , 10,11 -hexahydro- dibenzo [b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 70
10-Acetyl-l l-(4-isopropyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l 1-hexahydro- dibenzo[b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 72
11 -(4-(ethyl-isopropyl-amino)-phenyl)-3 -(4-methoxy-phenyl)-2,3 ,4,5 , 10, 11 -hexahydro- dibenzo[b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 73
Acetyl- 11 -(4-(ethyl-isopropyl-amino)-phenyl)-3 -(4-methoxy-phenyl)-2,3 ,4,5,10,11- hexahydro-dibenzo [b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 75
11 -(4-Diisopropylamino-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5, 10, 11 -hexahydro- dibenzo[b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 76
10-Acetyl-l 1 -(4-Diisopropylamino-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5, 10,11- hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 77
10- Acetyl- 11 -(4-Diisopropylamino-phenyl)-3 -(4-hydroxy-phenyl)-2,3 ,4,5,10,11- hexahydro-dibenzo [b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 79
11 -(4-Diisopropylamino-2-methyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5, 10, 11 - hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 80
10- Acetyl- 11 -(4-diisopropylamino-2-methyl-phenyl)-3 -(4-methoxy-phenyl)-2,3 ,4,5, 10,11- hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 81
10- Acetyl- 11 -(4-diisopropylamino-2-methyl-phenyl)-3-(4-hydroxy-phenyl)
-2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 85
11- (4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5, 10,11 - hexahydro-dibenzo[b,e] [1,4] diazepin- 1 -one ;
Compound 86
11 -(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-hydroxy-phenyl)-2,3,4,5, 10,11 - hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 87
10-Acetyl-l l-(4-diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 88
10- Acetyl- 11 -(4-diisopropylamino-2-methoxy-phenyl)-3 -(4-hydroxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 91
11 -(2-acetoxy-4-diisopropylamino-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5, 10,11- hexahydro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 92
11 -(4-Diisopropylamino-2-hydroxy-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5, 10, 11 - hexahydro-dibenzo[b,e][l,4]diazepin-l-one ; Compound 93
10-Acetyl-l 1 -(2-acetoxy-4-diisopropylamino-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l ,4]diazepin-l-one ;
Compound 94
10- Acetyl- 1 l-(2-hydroxy-4-diisopropylamino-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,1 l -hexahydro-dibenzo[b,e][l,4]diazepin-l -one ;
Compound 95
1 1 -(4-diisopropylamino-2-isopropoxy-phenyl)-3 -(4-methoxy-phenyl)-2,3 ,4,5 , 10,11- hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 96
10-Acetyl-l l-(4-diisopropylamino-2-isopropoxy-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l ,4]diazepin-l-one ;
Compound 99
I l-(4-diisopropylamino-2-sec-butoxy-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l l- hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 100
10-Acetyl-l l-(4-diisopropylamino-2-sec-butoxy-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 104
11 -(4-diisopropylamino-2-methoxy-phenyl)-3 -(4-methyl-phenyl)-2,3 ,4,5, 10, 11 -hexahydro- dibenzo[b,e][l ,4]diazepin-l-one ;
Compound 105
I I -(4-Diisopropylamino-2-methoxy-phenyl)-3 -(4-methoxy-phenyl)- 1 -oxo- 1 ,2,3 ,4,5 , 11 - hexahydro-dibenzo[b,e][l,4]diazepine-10-carboxylic acid isopropyl ester ;
Compound 106
1 1 -(4-Diisopropylamino-2-methoxy-phenyl)-3 -(4-methoxy-phenyl)- 1 -oxo- 1 ,2,3,4,5, 1 1 - hexahydro-dibenzo[b,e][l,4]diazepine-10-carboxylic acid ethylamide ;
Compound 107
1 1 -(4-Diisopropylamino-2-methoxy-phenyl)-3 -(4-methoxy-phenyl)- 1 -oxo- 1 ,2,3 ,4,5, 11 - hexahydro-dibenzo [b,e] [ 1 ,4] diazepine- 10-carboxylic acid methyl ester ;
Compound 108
1 1 -(4-Diisopropylamino-2-methoxy-phenyl)-3 -(4-methoxy-phenyl)- 1 -oxo- 1 ,2,3,4,5, 11 - hexahydro-dibenzo[b,e][l,4]diazepine-10-carboxylic acid iso-butyl ester ;
Compound 109
1 l-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-phenyl)-l-oxo-l,2,3,4,5,l 1- hexahydro-dibenzo[b,e][l,4]diazepine-10-carboxylic acid benzyl ester ;
Compound 1 10
11 -(4-Diisopropylamino-2-methoxy-phenyl)-3 -(4-methoxy-phenyl)- 1 -oxo- 1 ,2,3 ,4,5, 11 - hexahydro-dibenzo [b,e][ 1,4] diazepine- 10-carboxylic acid 4-methoxy-benzylamide ;
Compound 11 1
1 1 -(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-phenyl)-l -oxo- 1 ,2,3,4,5,11 - hexahydro-dibenzo[b,e][l,4]diazepine-l 0-carboxylic acid (2-methoxy-ethyl)-amide ;
Compound 112
11 -(4-Diisopropylamino-2-methoxy-phenyl)-3 -(4-methoxy-phenyl)- 10-(tetrahydro-pyran- 4-carbonyl)-2,3,4,5,10,l l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 113
11 -(4-Diisopropylamino-2-methoxy-phenyl)- 1 O-methanesulfonyl-3 -(4-methoxy-phenyl)- 2,3,4,5,10,11 -hexahydro-dibenzo [b,e][l, 4] diazepin-1 -one ;
Compound 117 10-Acetyl-3-(4-methoxy-phenyl)- 11 -(4-(2-methyl-pyrrolidine)phenyl)-2,3,4,5, 10,11- hexahydro-dibenzo [b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 118
3 -(4-Methoxy-phenyl)- 1 1 -(4-piperidin- 1 -yl-phenyl)-2,3 ,4,5 , 10,1 1 -hexahydro- dibenzo[b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 119
10- Acetyl-3 -(4-methoxy-phenyl)- 1 1 -(4-piperidin- 1 -yl-phenyl)-2,3 ,4,5,10,11- hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 123
lO-Acetyl-3 -(4-methoxy-phenyl)- 1 l-(2-methyl-4-piperidin-l-yl-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 126
3 -(4-Methoxy-phenyl)- 11 -(2-methoxy-4-piperidin- 1 -yl-phenyl)-2,3 ,4,5,10,11 -hexahydro- dibenzo [b,e] [ 1 ,4] diazepin- 1 -one ;
Compound 127
10- Acetyl-3 -(4-methoxy-phenyl)- 11 -(2-methoxy-4-piperidin- 1 -yl-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 130
11 -[2-methoxy-4-(2 -methyl -piperidin- 1 -yl)-phenyl]-3 -(4-methoxy-phenyl)-2,3 ,4,5, 10, 1 1 - hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 131
10- Acetyl- 11 - [2-methoxy-4-(2-methyl-piperidin- 1 -yl)-phenyl] -3 -(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e] [1,4] diazepin- 1 -one ;
Compound 134
11 - [2-methoxy-4-(2,6-dimethyl-piperidin- 1 -yl)-phenyl] -3 -(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one ;
Compound 135
10- Acetyl-l l-[2-methoxy-4-(2,6-dimethyl-piperidin-l -yl)-phenyl]-3-(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e] [1,4] diazepin- 1 -one ;
Compound 139
11- [4-(2,5-Dimethyl-pyrrol-l-yl)-2-methoxy-phenyl]-3-(4-methoxy-phenyl)-2,3,4,5, 10,11- hexahydro-dibenzo[b,e][l,4]diazepin-l-one ; and
Compound 142
10-Acetyl-l 1 -(2-methoxy-4-isopropoxy-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5, 10,11- hexahydro-dibenzo [b,e] [ 1 ,4]diazepin- 1 -one.
In the above list, the compounds numbering refers to the Examples, and the names were generated with AutoNom 2000 Add-in for ISIS/Draw 2.5.
In some embodiments, the invention is related to a compound of formula (I) wherein R5 is H and Ri, R2, R3, R4, R6, R7, R8 and R9 are as disclosed above. In particular, R7 may be iPr or tBu. The compounds may be chosen from the list consisting of:
Compound 143
11 -(2-methoxy-5-isopropyl-phenyl)-3-(4-methoxy-phenyl)-2,3, 4,5,10, 11 -hexahydro- dibenzo [b,e] [ 1 ,4]diazepin- 1 -one ;
Compound 144
10- Acetyl- 1 1 -(2-methoxy-5-isopropyl-phenyl)-3-(4-methoxy-phenyl)-2,3 ,4,5, 10,11- hexahydro-dibenzo[b,e] [ 1 ,4] diazepin- 1 -one ;
and Compound 145
10-Acetyl-l 1 -(2-methoxy-5-isopropyl-phenyl)-3-(4-hydroxy-phenyl)-2,3,4,5, 10,11- hexahydro-dibenzo [b,e] [ 1 ,4]diazepin- 1 -one. The present invention further relates to pharmaceutical compositions comprising an effective amount of a compound according to the invention and a pharmaceutically acceptable carrier.
As used herein, "an effective amount" refers to the amount of a compound that, when administered to a subject for treating a disease or disorder, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment of the disease, disorder, or symptom. The "effective amount" may vary depending, for example, on the compound, its formulation, the age, weight, and/or health of the patient to be treated, and the judgment of the prescribing physician. An appropriate amount in any given instance may be readily ascertained by those skilled in the art or capable of determination by routine experimentation.
As used herein, "pharmaceutically acceptable carriers" includes any and all solvents, dispersion media, coatings, and the like that are physiologically compatible.
The pharmaceutical compositions of the invention may be in a variety of forms. These include for example liquid, semi-solid, and solid dosage forms, but the preferred form depends on the intended mode of administration and therapeutic application.
These pharmaceutical compositions are preferably for systemic administration such as oral, subcutaneous, percutaneous and parenteral administration. For example, in preparing the compositions for parenteral administration, the carrier will usually comprises sterile water, at least in large part, though other ingredients, for example, to aid solubility and/or to increase stability, may be included. Injectable solutions, for example, may be prepared in which the carrier comprise saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the composition suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin.
The compound of the present invention may be orally administered. As solid compositions for oral administration, tablets, pills, powders (gelatine capsules, sachets) or granules may be used. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon stream. These compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a coloring, a coating (sugar-coated tablet) or a glaze. As liquid compositions for oral administration, there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions may comprise substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
The doses depend on the desired effect, the duration of the treatment and the route of administration used.
The invention also relates to the use of a compound according to the invention for the manufacture of a medicament for the treatment of Down syndrome, in particular for the prevention and/or treatment of cognitive disorders in Down syndrome.
The compounds of formula I, including enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof, are inhibitors of the CBS and may be useful in the treatment of diseases associated with CBS activity, in particular Down syndrome.
Thus, the present invention also provides a method for inhibiting CBS in a patient, in particular a patient with Down syndrome, comprising administering to a patient in need thereof an amount of a compound of the present invention or of a pharmaceutical composition, effective to inhibit CBS.
More particularly, the invention is directed to methods for preventing or treating cognitive disorders, which include administering an effective amount of a compound or a pharmaceutical composition according to the invention to a human or a patient in need thereof.
Even more particularly, the invention is directed to methods for treating patients with Down syndrome, in particular for preventing or treating cognitive disorders in Down syndrome, which include administering an effective amount of a compound or a pharmaceutical composition according to the invention to a patient in need thereof.
The present invention further relates to compounds as described herein for use as a medicament.
Exemplary compounds of the present invention can be readily prepared according to the methods of scheme 1 using readily available starting materials, reagents and conventional synthetic procedures. It is also possible to make use of variants of these process steps, which in themselves are known to and well within the preparatory skill of the medicinal chemist.
Figure imgf000016_0001
(V) (IV)
Scheme 1
In the method of scheme 1 , the cyclohexenone (I) can be converted into its corresponding chloro derivative (II) by use of an appropriate chlorinating agent such as oxalyl chloride. This intermediate can be reacted with 1 ,2-phenylenediamine in ethanol to afford the diamine (III). A range of substituted aldehyde can then made to react with diamine (III) to give the benzodiazepine (IV). Finally, the benzodiazepine core (IV) can be converted into its acetyl derivative via use of anhydride acetic in pyridine and DCM.
Example 1 : Preparation of 10- Acetyl- 11 -(4-Diethylamino-phenyl)-3-(4-methoxy-phenyl)- 2,3 , 4,5 , 10,11 -hexahvdro-dibenzo [b,e] Γ 1 ,4"]diazepin- 1 -one 5-(4-methoxy-phenyl)-cyclohex-2-enone
Figure imgf000016_0002
MW : 236.70
Formula : C13H13C102
LCMS : 100% MH+=237
1H NMR (250 MHz, DMSO d6) ppm 7.27 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 6.30 (d, J = 1.92 Hz, 1H), 3.73 (s, 3H), 3.58-3.36 (m, 1H), 3.01 (m, 1H), 2.89-2.63 (m, 2H), 2.46-2.34 (m, 1H)
A suspension of 12. Og (55.0mmol) of 5-[4-(Methoxyphenyl)]-l,3-cyclohexanedione with 5.5mL of DMF in 300mL of DCM was cooled to 0°C.Then, 5.6 mL (64.2mmol) of oxalyl chloride were added dropwise and the resulting solution was stirred 2h at room temperature. Water was added, the mixture was extracted with AcOEt, the combined organic layers were washed with water, dried over MgS04 and then evaporated under vacuum. The residue was purified by silica gel flash chromatography (DCM/ ethyl acetate 9/1) to give 9.9g (76%) of Compound 1 as a yellow oil which crystallised. Step2
Compound 2 : 3-(2-Amino-phenylamino)-5-(4-methoxy-phenyl)-cyclohex-2-enone
Figure imgf000017_0001
MW : 308.38
Formula : CI 9H20N2O2
LCMS : 100% MH+=309
1H NMR (250 MHz, DMSO-d6) ppm 8.31 (s, 1H), 7.27 (d, J = 8.6 Hz, 2H), 7.09-6.85 (m, 5H), 6.75 (d, J = 7.2 Hz, 1H), 6.56 (t, J = 7.1 Hz, 1H), 4.97 (bs, 2H), 4.69 (bs, 1H), 3.74 (s, 3H), 3.31-3.16 (m, 1H), 2.90-2.54 (m, 2H), 2.46-2.13 (m, 2H) A mixture of Compound 1 (9.9g, 42.0mmol) and 4.5g (42.0mmol) of 1,2- phenylenediamine with 8.8 mL of DIPEA in 70 mL ethanol was refluxed for 48h. The reaction mixture was filtered off, washed with EtOH to afford 10.9g (84%) of Compound 2 as a beige powder. Step 3
Compound 3 : ll-(4-Diethylamino-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000017_0002
MW : 467.62
Formula : C30H33N3O2
LCMS : 100% MH+=468
1H NMR (250 MHz, DMSO-d6) ppm 8.71 (d, J = 10.1 Hz, 1H), 7.36-7.25 (m, 2H), 7.03- 6.73 (m, 5H), 6.69-6.49 (m, 3H), 6.45-6.30 (m, 2H), 6.18-6.03 (m, 1H), 5.68-5.50 (m, 1H), 3.75 (d, J = 1.0 Hz, 3H), 3.48-3.10 (m, 5H), 3.07-2.29 (m, 5H), 1.10-0.90 (m, 6H)
A mixture of 200mg (0.65mmol) of Compound 2, 76mg (0.43mmol) of 4- diethylaminobenzaldehyde, a few drops of glacial acetic acid and HCl in 8 mL of EtOH was stirred overnight at room temperature. The reaction mixture was evaporated and then water was added to the residue and basified with NaOH IN to pH=14. The suspension was filtered off to give the 240mg (46%) of Compound 3 as a crystalline yellow foam. Step 4
Compound 4 : 10-Acetyl-ll-(4-diethylamino-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,1
l-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000018_0001
MW : 509.65
Formula : C32H35N303
LCMS : 94.5% MH+= 510
1H NMR (250 MHz, MeOD) δ ppm 7.52-7.20 (m, 6H), 7.15-7.05 (m, 2H), 6.96-6.78 (m, 4H), 3.78 (s, 3H), 3.63-3.40 (m, 5H), 2.83-2.58 (m, 2H), 1.94-1.88 (m, 3H), 0.94 (t, J = 7.1 Hz, 6H).
A mixture of Compound 3 (50mg, O.l lmmol), 0.01 mL (O.l lmmol) of acetic anhydride, 0.02 mL of pyridine (0.22mmol) in 1 mL of DCM was stirred overnight at room temperature. The mixture was evaporated and purified by silica gel flash chromatography (DCM/ EtOH 99/1 to 8/2) to give 38mg (69%) of Compound 4 as a beige powder.
Example 2 : Preparation of 10- Acetyl- 1 l-(4-di ethyl amino-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5, 10, 11 -hexahvdro-dibenzo|"b,e] [" 1 ,4]diazepin- 1 -one
Step 1
Compound 5 : 10-Acetyl-ll-(R)-(4-diethylamino-phenyl)-3-(S)-(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000018_0002
MW : 509.65
Formula : C32H35N303
LCMS : 95% MH+= 510
1H NMR (250 MHz, DMSO-d6) 6 ppm 9.19-9.00 (m, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.20 (s, 1H), 7.18-6.70 (m, 8H), 6.38 (d, J = 8.4, 2H), 3.74 (s, 3H), 3.25-3.10 (m, 4H), 3.10- 2.60 (m, 5H), 1.95-1.7 (m, 3H), 1.35-0.70(m, 6H)
Compound 5 was obtained following protocols described for Example 1, step 3 with 3.0g (64.1mmol) of Compound 3, 0.61mL (64.1mmol) of acetic anhydride and 1.03mL (12.82mmol) pyridine in 30mL of DCM. The solid collected was then subjected to two consecutive enantiomeric separation using preparative LCMS. The first purification was carried out with a column CHIRALPAK® IC, (250 x 20) mm 5μ and EtOH:DCM:DEA 90/10/0.1 as a mobile phase. The second purification was performed with a column CHIRALPAK® IC, (250 x 20) mm 5μ and Hexanes:DCM:MeOH:DEA 50/10/40/0.1 as a mobile phase. Those purifications afforded 167mg of a beige solid showing an isomeric purity of 97.2% of the S,R enantiomer.
Crystals were collected from the compound purified and analysed by X-ray, with an Oxford-Diffraction Gemini diffractometer using a copper source. Data were collected and analysed with the software CrysalisPro, and the structure was resolved by direct methods with the software Sir97.
Example 3 : preparation of 10- Acetyl- 1 l-(4-di ethylamino-phenyl)-3 -(4-chloro-phenyl)- 2,3,4,5, 10, 11 -hexahydro-dibenzo b,e1 [ 1 ,4]diazepin- 1 -one
Step l
Compound 6 : 3-(2-Amino-phenylamino)-5-(4-chloro-phenyl)-cyclohex-2-enone
Figure imgf000019_0001
MW : 312.80
Formula : CI 8H17C1N20
LCMS : 87.9%, M%H+=313
A mixture of l .Og (4.49mmol) of 5-(4-chlorophenyl)-l ,3-cyclohexanedione, 485mg (4.49mmol) of 1 ,2-phenylenediamine in 2 mL of ethanol in a sealed reaction vessel was irradiated under microwave conditions for 3h at 1 10°C. After cooling a precipitate was formed and was filtered to give 720mg (51%) of Compound 6 as a pale yellow powder.
Step 2
Compound 7 : ll-(4-diethylamino-phenyI)-3-(4-chIoro-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000019_0002
MW : 472.03
Formula : C29H30C1N3O
LCMS : 96.4%, MH+=473 1H NMR (250 MHz, DMSO-d6) ppm 8.85-8.66 (m, 1H), 7.52-7.36 (m, 5H), 7.02-6.70 (m, 4H), 6.68-6.50 (m, 3H), 6.46-6.26 (m, 2H), 6.23-6.07 (m, 1H), 5.70-5.51 (m, 1H), 3.54- 3.41 (m, 1H), 3.27-2.21 (m, 6H), 0.99 (dt, J = 6.7, 2.0 Hz, 6H) Compound 7 was obtained following protocols described for Example 1, step 3 with 710mg (2.27mmol) of Compound 6, 402mg (2.27mmol) of 4-di ethyl aminobenzaldehyde in 30mL of EtOH yielding 898mg (84%) of a beige solid.
Step 3
Compound 8 : 10-Acetyl-ll-(4-diethylamino-phenyl)-3-(4-chIoro-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000020_0001
MW : 514.07
Formula : C31H32C1N302
LCMS : 100, MH+=515
1H NMR (250 MHz, DMSo-d6) δ ppm 9.07 (s, 1H), 7.57-7.18 (m, 5H), 7.17-6.55 (m, 7H), 6.43-6.22 (m, 2H), 3.58-3.38 (m, 1H), 3.29-3.14 (m, 3H), 3.11-2.24 (m, 4H), 1.79 (s, 3H), 0.97 (t, J = 6.4 Hz, 6H) A mixture of 600mg (1.27mmol) of Compound 7, 232μί (2.54mmol) of anhydride acetic, 415μί (5.08mmol) of pyridine in l OmL of DCM, in a sealed reaction vessel, was heated under microwave conditions for 15min at 100°C. After cooling a precipitate was formed upon addition of Et20, it was then filtered off and washed with Et20 to give 450mg (69%) of Compound 8 as beige powder.
Example 4 : preparation of 1 l-(4-diethylamino-phenyl)-3-phenyl-2,3,4,5,10,l 1 -hexahvdro- dibenzo[b,e] l ,4]diazepin-l -one
Step 1
ino-phenylamino)-5-(phenyl)-cycIohex-2-
Figure imgf000020_0002
MW : 278.36
Formula : CI 8H18N20
LCMS : 100%, MH+=279 1H NMR (250 MHz, DMSO-d6) ppm 8.29 (s, 1H), 7.45-7.17 (m, 5H), 7.07-6.85 (m, 2H), 6.75 (d, J = 8.0 Hz, 1H), 6.57 (t, J = 7.4 Hz, 1H), 4.96 (bs, 2H), 4.70 (bs, 1H), 2.95-2.75 (m, 1H), 2.72-2.35 (m, 2H), 2.34-2.18 (m, 1H). Compound 9 was obtained following protocols described for Example 3, step 1 with 190mg of 5-Phenyl-l,3-cyclohexanedione, lOOmg of phenylenediamine in 2 mL of ethanol yielding 88mg (34 %) of a beige solide.
Step 2
Compound 10 : ll-(4-diethylamino-phenyl)-3-phenyl-2,3,4,5,10,ll-hexahydro- dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000021_0001
MW : 437.59
Formula : C29H31N30
LCMS : 100%, MH+=438
1H NMR (250 MHz, DMSO-d6) δ ppm 8.85-8.67 (m, 1H), 7.46-7.18 (m, 5H), 7.02-6.74 (m, 3H), 6.57-6.48(m, 2H), 6.47-6.27 (m, 2H), 6.23-6.02 (m, 1H), 5.72-5.45 (m, 1H), 3.45- 3.10 (m, 5H), 3.09-2.35 (m, 5H), 1.12-0.85 (m, 6H) Compound 10 was obtained following protocols described for Example 1, step 3 with 80mg (0.29mmol) of Compound 9, 51mg (0.29mmol) of 4-diethylaminobenzaldehyde in lmL of EtOH yielding 58mg (46%) of a beige solid.
Example 5 : preparation of 10-Acetyl-l l-(4-diethylamino-phenyl)-3-phenyl-2,3,4,5, 10,11- hexahydro-dibenzo b,e] l ,4]diazepin-l -one
Step 1
Compound 11 : 10-AcetyI-ll-(4-diethylamino-phenyl)-3-phenyl-2,3,4,5,10,ll- hexahy dro-dibenzo [b,e] [ 1 ,4] diazepin- 1-one
Figure imgf000021_0002
MW :479.63 Formula :C31H33N302
LCMS 100% MH+=480
1H NMR (300 MHz, DMSO-d6) ppm 9.04 (s, 1H), 7.45-7.32 (m, 4H), 7.30-7.20 (m, 2H), 7.15-7.05 (m, 2H), 6.96-6.73 (m, 3H), 6.67 (d, J = 8.6 Hz, 1H), 6.42-6.30 (m, 2H), 3.51- 3.36 (m, 1H), 3.25 -3.11 (m, 4H), 3.10-2.35 (m, 4H), 1.80 (s, 3H), 1.1-0.90 (m, 6H) 44mg, 80%
Compound 11 was obtained following protocols described for Example 1, step 4 with 50mg (O.l lmmol) of Compound 10, Ι ΐ μί (O.l lmmol) of anhydride acetic, 19μΕ (0.23mmol) of pyridine in 2mL of DCM. The residue was purified by silica gel flash chromatography (DCM/EtOH 95/5), yielding 44mg (80%) of a beige solid.
Example 6 : preparation of 10- Acetyl- 11 -(4-Diethylamino-phenyl)-3 -(4-ethyl-phenyl)- 2,3 ,4,5 , 10, 11 -hexahydro-dibenzo[b,e1 1 ,4"]diazepin- 1 -one
Step 1
Compound 12 : (E)-4-(4-Ethyl-phenyl)-but-3-en-2-one
Figure imgf000022_0001
MW : 174.24
Formula : C12H140
LCMS : 93.8% MH+=175
A mixture of 2.0g (14.9mmol) of 4-Ethylbenzaldehyde, 12mL of acetone, 1.25mL of NaOH 50% aq in 60mL of water was stirred overnight at room temperature. The reaction mixture was then extracted with AcOEt, the combined organic layers were dried over MgS04 and concentrated. The residue was purified by silica gel flash chromatography (DCM/AcOEt 99/1) to afford 2.18g (78%) of Compound 12 as a yellow oil.
Step 2
Compound 13 : 5-(4-Ethyl-phenyl)-cyclohexane-l,3-dione
Figure imgf000022_0002
MW : 216.28
Formula : CI 4H1602
LCMS : 96.9% MH+=217 1.9mL (12.51mmol) of diethylmalonate and 2.18g (12.51mmol) of Compound 12 were added to a solution of 288mg (12.52mmol) of sodium in 40mL of EtOH. It was refluxed for 6h and then stirred 48h at room temperature. The reaction mixture was concentrated, 20mL of NaOH 2N were added and it was refluxed for 6 more hours. It was then acidified with H2S04 6N and then brought to reflux for 3h. The reaction mixture was extracted with AcOEt, the combined organic layers were dried over MgS04 and concentrated under vacuum. The residue was purified by silica gel flash chromatography (DCM/MeOH 99/1) to afford 173mg (6%) of Compound 13 as a white powder. henylamino)-5-(4-ethyl-phenyl)-cyclohex-2-enone
Figure imgf000023_0001
MW : 306.41
Formula : C20H22N2O
LCMS : 82% MH+=307
1H NMR (250 MHz, DMSO-d6) ppm 8.30 (s, 1H), 7.26 (d, J = 8.05 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.99 (t, J = 7.1 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.56 (t, J = 7.5 Hz, 1H), 4.96 (bs, 2H), 4.69 (s, 1H), 3.32-3.18 (m, 1H), 2.94-2.73 (m, 1H), 2.73-2.36 (m, 4H), 2.26 (d, J = 4.0 Hz, 1H), 1.17 (t, J = 7.6 Hz, 3H) Compound 14 was obtained following protocols described for Example 3, step 1 with 173mg (0.80 mmol) of 5-(4-Ethyl-phenyl)-cyclohexane-l,3-dione, 86mg (0.80mmol) of phenylenediamine in 2 mL of ethanol yielding 135mg (55 %) of a beige solid.
Step 4
Compound 15 : ll-(4-Diethylamino-phenyI)-3-(4-ethyl-phenyl)-2,3,4,5,10,ll- hexahy dro-dibenzo [b,e] [ 1 ,4] diazepin- 1-one
Figure imgf000023_0002
MW : 465.54
Formula : C31H35N30
LCMS : 100%, MH+=466
1H NMR (250 MHz, DMSO-d6) ppm 12.67-1 1.61 (m, 1H), 9.52-8.48 (m, 1H), 7.85-7.09 (m, 6H), 7.09-6.1 1 (m, 6H), 6.03-5.45 (m, 1H), 3.29-2.76 (m, 4H), 2.65-2.55 (m, 3H), 2.482.35 (m, 1H), 1.18 (t, J = 7.6 Hz, 3H), 1.10-0.60 (m, 6H)
Compound 15 was obtained following protocols described for Example 1, step 3 with 135mg (0.44mmol) of Compound 14, 80mg (0.45mmol) of 4-diethylaminobenzaldehyde in 5mL of EtOH yielding 130mg (63%) of a beige powder. Step 5 Compound 16 : 10-Acetyl-ll-(4-Diethylamino-phenyl)-3-(4-ethyl-phenyl)-2,3?4,5,10,ll- hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000024_0001
MW : 507.68
Formula : C33H37N302
LCMS : 100%, MH+=508
1H NMR (250 MHz, DMSO-d6) ppm 9.32 (bs, 1H), 7.75-6.59 (m, 12H), 3.71-3.55 (m, 6H), 3,42-2.25 (m, 6H), 1.83 (s, 3H), 1.18 (t, J = 7.6 Hz, 3H), 0.99-0.67 (m, 6H) Compound 16 was obtained following protocols described for Example 3, step 3 with 130mg (0.28mmol) of Compound 15, 53μΙ_, (0.56mmol) of anhydride acetic, 92μΙ. (1.12mmol) of pyridine in 2mL of DCM yielding 98mg (70%) of a pink solid.
Example 7 : 10-Acetyl-l l-(4-Diethylamino-phenyl)-3-(4-acetoxy-phenyl)-2,3,4,5, 10,11- hexahydro-dibenzo[b,e] [ 1 ,4] diazepin- 1 -one
Step l
Compound 17 : (E)-4-(4-tert-butoxy-phenyl)-but-3-en-2-one
Figure imgf000024_0002
MW : 218.30
Formula : CI 4H1802
LCMS : 94%, MH+=219
Compound 17 was obtained following protocols described for Example 6, step 1 with 730μί (4.81mmol) of diethylmalonate, 993mg (4.81mmol) of 4-tert-butoxy benzaldehyde, 11 lmg (4.81mmol) of sodium and 20mL of EtOH. The residue was purified by silica gel flash chromatography (DCM/MeOH 99/1) to afford 500mg (42%) as an orange oil. Step 2
Compound 18 : 5-(4-Hydroxy-phenyl)-cyclohexane-l,3-dione
Figure imgf000025_0001
MW : 204.23
Formula : C12H1203
LCMS : 96,0%, 2M+Na+=431
1H NMR (250 MHz, CDC13) 5 ppm 1 1.10 (bs, 1H), 9.25 (s, 1H), 7.11 (d, J = 8.5 Hz, 2H), 6.68 (d, J = 8.5 Hz, 2H), 5.25 (s, 1H), 3.26-3.10 (m, 2H), 2.46-2.1 1 (m, 1H)
Compound 18 was obtained following protocols described for Example 6, step 2 with 5.0g (28.1mmol) of Compound 17, 30mL of acetone, 2.32mL of NaOH 50% aq and 150mL of water. The residue was purified by silica gel flash chromatography (DCM/AcOEt 90/10) to afford 4.4 lg (72%) as a yellow oil. phenyl)-cyclohexane-l,3-dione
MW : 246.27
Formula : C14H1404
Compound 19 was obtained following protocols described for Example 3, step 3 with 540mg (2.65mmol) of Compound 18, 500μί (5.29mmol) of anhydride acetic, 865μΕ (10.6mmol) of pyridine in 2mL of DCM yielding 517mg of an orange oil. It was taken up without analysis in the next step.
Step 4
Compound 20 : 3-(2-Amino-phenylamino)-5-(4-acetoxy-phenyl)-cyclohex-2-enone
Figure imgf000025_0003
MW : 336.39
Formula : C20H20N2O3
LCMS : 81%, MH+=337
Compound 20 was obtained following protocols described for Example 3, step 1 with lOOmg (0.41 mmol) of Compound 19, 86mg (0.80mmol) of phenylenediamine in 2 mL of ethanol yielding 70mg (51%) of an orange oil. Step 5 Compound 21 : ll-(4-Diethylamino-phenyl)-3-(4-hydroxy-phenyl)-2,3,4,5,10,ll- hexahy dr o-dibenzo [b,e] [ 1 ,4] diazepin- 1-one
Figure imgf000026_0001
MW : 453.59
Formula : C29H31N302
LCMS : 74% MH+=454
Compound 21 was obtained following protocols described for Example 1, step 3 with 200mg (0.57mmol) of Compound 20, 106mg (0.59mmol) of 4-diethylaminobenzaldehyde in 1 mL of EtOH yielding 170mg (60%) of a black solid.
Step 6
Compound 22 : 10-Acetyl-ll-(4-Diethylamino-phenyl)-3-(4-acetoxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000026_0002
MW : 537.66
Formula : C33H35N304
LCMS : 100%, MH+=538
1H NMR (250 MHz, DMSO-d6) 5 ppm 9.13-8.99 (m, 1H), 7.50-7.44 (m, 2H), 7.16-7.05 (m, 4H), 6.98-6.59 (m, 4H), 6.49-6.26 (m, 2H), 3.27-3.11 (m, 4H), 3.09-2.30 (m, 4H), 2.27 (s, 3H), 2.22-2.03 (m, 1H), 1.79 (fd, J = 1.2 Hz, 3H), 1.12-0.80 (m, 6H)
Compound 22 was obtained following protocols described for Example 3, step 3 with 170mg (0.37mmol) of Compound 21, 141 μΙ. (0.74mmol) of anhydride acetic, 245μL· (1.48mmol) of pyridine in 2mL of DCM yielding 98mg (70%) of a pink solid.
Example 8 : preparation of l l-(4-diethylamino-phenyl)-3-(3,4-dimethoxy-phenyl)- 2,3,4,5, 10, 11 -hexahydro-dibenzo[b,e~j[" 1 ,4~jdiazepin- 1 -one
Step 1
Compound 23 : 3-(2-Amino-phenylamino)-5-(3,4-dimethoxy-phenyl)-cyclohex-2-enone
Figure imgf000027_0001
MW : 338.41
Formula : C20H22N2O3
LCMS : 96.8%, MH+=339
IH NMR (250 MHz, DMSO-d6) δ ppm 8.28 (s, IH), 7.04-6.82 (m, 5H), 6.75 (d, J = 7.8 Hz, IH), 6.56 (t, J = 7.5 Hz, IH), 4.96 (s, IH), 4.69 (s, IH), 3.75 (2s, 6H), 3.30-2.55 (m, 4H), 2.45-2.16 (m, 2H)
Compound 23 was obtained following protocols described for Example 3, step 1 with 203mg of 5-(3,4-dimethoxy-phenyl)-cyclohexane-l,3-dione, 83mg of phenylenediamine in 2 mL of ethanol yielding 141mg (55 %) of a beige solide.
Step 2
Compound 24 : ll-(4-diethylamino-phenyl)-3-(3,4-dimethoxy-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000027_0002
MW : 497.64
Formula : C31H35N303
LCMS 100%, MH+=498
IH NMR (250 MHz, DMSO-d6) ppm 12.60-12.38 (m, IH), 9.72-9.42 (m, IH), 7.76-7.21 (m, 4H), 7.20-6.60 (m, 7H), 6.21-5.97 (m, IH), 3.83-3.68 (m, 6H), 3.54-3.15 (m, 6H), 3.07-2.57 (m, 3H), 0.92-0.72 (m, 6H) Compound 24 was obtained following protocols described for Example 1, step 3 with 123mg (0.36mmol) of Compound 23, 65mg (0.37mmol) of 4-diethylaminobenzaldehyde in 2mL of EtOH yielding 143mg (79%) of a light yellow powder.
Example 9 : preparation of 10-Acetyl-l l-(4-diethylamino-phenylV3-(3,4-dimethoxy- phenyl)-2,3,4,5,10j l-hexahvdro-dibenzorb1eiri,41diazepin-l-one
Step l
Compound 25 : 10-Acetyl-ll-(4-diethylamino-phenyl)-3-(3,4-dimethoxy-phenyl)- 2,3,4,5,
10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000028_0001
MW :539.68
Formula :C33H37N304
LCMS 100% MH+=540
1H NMR (250 MHz, DMSO-d6) ppm 9.04 (s, 1H), 7.20 (s, 1H), 7.15-7.00 (m, 3H), 6.99- 6.7 (m, 5H), 6.71-6.50 (m, 1H), 6.46-6.28 (m, 2H), 3.89-3.61 (m, 6H), 3.26-3.09 (m, 4H), 3.11-2.31 (m, 5H), 1.79 (s, 3H), 1.04-0.92 (m, 6H)
Compound 25 was obtained following protocols described for Example 3, step 3 with 140mg (0.28mmol) of Compound 24, 53 (0.56mmol) of anhydride acetic, 92μί (1.12mmol) of pyridine in 3mL of DCM. The residue was purified by silica gel flash chromatography (DCM/MeOH 99.75/.025) yielding 94mg (61%) of a white powder.
Example 10 : preparation of 10-Acetyl-l l -(4-diethylamino-phenyl)-3-(314-dihvdroxy- phenvD-2,3 ,4,5, 10, 11 -hexahydro-dibenzo |"b,e] f 1 ,41 diazepin- 1 -one
Stepl
Compound 26 : 10-AcetyI-ll-(4-diethylamino-phenyI)-3-(3,4-dihydroxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000028_0002
MW : 51 1.63
Formula : C31H33N304
LCMS : 98.0%, MH+=512
A solution of 50mg (0.09mmol) of Compound 25 in ImL of DCM was cooled to 0°C, then 211 xL (0. 28mmol) of boron tribromide 1M were added. The resulting suspension was stirred at room temperature during 24h, then MeOH was added and the reaction mixture was refluxed for 30min. It was concentrated under vacuum and then extracted using water and AcOEt. The aqueous layer was basified and then extracted with AcOEt. The combined organic layers were dried over MgS04 and concentrated to afford 9mg (19%) of Compound 26 as a solid. Example 1 1 : preparation of l l-(4-diethylamino-phenyl)-3-(2,3-dimethoxy-phenyl)-
2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l ,41diazepin-l -one
Stepl
)-4-(2,3-dimethoxy-phenyl)-but-3-en-2-one
Figure imgf000029_0001
MW : 206.24
Formula ; CI 2H1403
LCMS : 95.0%, MH+=207
Compound 27 was obtained following protocols described for Example 6, step 1 with 1.0g (6.02mmol) of 2,3-dimethoxybenzaldehyde, 6mL of acetone, 0.25mL of NaOH 50% aq and 30mL of water. The residue was purified by silica gel flash chromatography (DCM/AcOEt 80/20) to afford 993mg (78%) as a colorless oil.
Step2
2,3-dimethoxy-phenyl)-cyclohexane-l,3-dione
Figure imgf000029_0002
MW : 248.28
Formula : C14H1604
LCMS : 87.5,%, MH+=249
1H NMR (250 MHz, CDC13) δ ppm 7.16-6.92 (m, 1 H), 6.95-6.64 (m, 2H), 3.96-3.77 (m, 6H), 3.55-3.40 (m, 3H), 3.08-2.44 (m, 4H)
Compound 28 was obtained following protocols described for Example 6, step 2 with 730μΙ. (4.81mmol) of diethylmalonate, 993mg (4.81mmol) of Compound 27, l l lmg (4.81mmol) of sodium and 20mL of EtOH. The residue was purified by silica gel flash chromatography (DCM/MeOH 99/1) to afford 500mg (42%) as an orange oil.
Step 3
mino-phenylamino)-5-(2,3-dimethoxy-phenyl)-cyclohex-2-enone
Figure imgf000029_0003
MW : 338.41 Formula : C20H22N2O3
LCMS : 96.9%, MH+=339
Compound 29 was obtained following protocols described for Example 3, step 1 with 500mg (2.01mmol) of Compound 28, 218mg (2.02mmol) of phenylenediamine in 2 mL of ethanol yielding 235mg (35 %) of an orange solid.
Step 4
Compound 30 : ll-(4-diethylamino-phenyl)-3-(2,3-dimethoxy-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000030_0001
MW : 497.64
Formula : C31H35N303
LCMS : 100%, MH+=498
1H NMR (250 MHz, DMSO-d6) δ ppm 8.86-8.64 (m, 1H), 7.20-6.77 (m, 6H), 6.70-6.02 (m, 6H), 5.73-5.47 (m, 1H), 3.80 (2s, 6H), 3.27-3.08 (m, 4H), 3.08-2.22 (m, 5H), 1.06-0.88 (m, 6H)
Compound 30 was obtained following protocols described for Example 1, step 3 with lOOmg (0.30mmol) of Compound 29, 53mg (0.30mmol) of 4-diethylaminobenzaldehyde in 2mL of EtOH. The residue was purified by silica gel flash chromatography (DCM/EtOH 98/2) to give 52mg (35%) of a beige solid.
Example 12 : preparation of 10-Acetyl-l l -(4-diethylamino-phenyl)-3-(2,3-dimethoxy- phenyl)-2,3 ,4,5, 10, 11 -hexahvdro-dibenzo [b,e"[ [Ί ,4] diazepin- 1 -one
Step 1
Compound 31 : 10-Acetyl-ll-(4-diethylamino-phenyl)-3-(2,3-dimethoxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000030_0002
MW : 539.68
Formula : C33H37N304
LCMS : 100%, MH+=540 1H NMR (250 MHz, DMSO-d6) δ ppm 9.10-8.92 (m, 1H), 7.22-6.66 (m, 10H), 6.46-6.27 (m, 2H), 3.78 (2s, 6H), 3.72-3.54 (m, 1H), 3.24-3.06 (m, 4H), 3.07-2.09 (m, 5H), 1.78 (2s, 3H), 0.96 (t, J = 6.4 Hz, 6H)
Compound 31 was obtained following protocols described for Example 3, step 3 with 25mg (0.05mmol) of Compound 30, 13μί (O.lOmmol) of anhydride acetic, 17μί (0.20mmol) of pyridine in lmL of DCM yielding 19mg (70%) of a beige solid.
Example 13 : preparation of 11 -(4-diethylamino-phenyl')-3-(2,4-dimethoxy-phenyl)- 2,3,4,5,10,11 -hexahydro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
Step 1
ino-phenylamino)-5-(2,4-dimethoxy-phenyl)-cyclohex-2-enone
Figure imgf000031_0001
MW : 338.41
Formula : C20H22N2O3
LCMS : 82.2%, MH+=339
Compound 32 was obtained following protocols described for Example 3, step 1 with 500mg (2.01mmol) of 5-(2,4-dimethoxy-phenyl)-cyclohexane-l,3-dione, 218mg (2.02mmol) of phenylenediamine in 2 mL of ethanol yielding 500mg (73 %) of an orange foam.
Step 2
Compound 33 : ll-(4-diethylamino-phenyl)-3-(2,4-dimethoxy-phenyl)-2,3?4,5,10,ll- hexahy dr o-dibenzo [b,e] [ 1 ,4] diazepin- 1-one
Figure imgf000031_0002
MW : 497.64
Formula : C31H35N303
LCMS : 91.6%, MH+=498
1H NMR (250 MHz, DMSO-d6) δ ppm 8.80-8.65 (m, 1H), 7.30-7.08 (m, 1H), 7.00-6.77 (m, 3H), 6.66-6.30 (m, 6H), 6.22-6.04 (m, 1H), 5.75-5.46 (m, 1H), 3.94-3.71 (2s, 6H), 3.65-3.38 (m, 2H), 3.28-3.10 (m, 4H), 3.02-2.24 (m, 5H), 1.19-0.90 (m, 6H), Compound 33 was obtained following protocols described for Example 1, step 3 with 150mg (0.44mmol) of Compound 23, 107mg (0.60mmol) of 4-diethylaminobenzaldehyde in 3mL of EtOH. The residue was purified by silica gel flash chromatography (DCM/EtOH 98/2) to give l Ol mg (34%) of a light orange powder.
Example 14 : preparation of 10-Acetyl-l l -(4-diethylamino-phenyl)-3-(2,4-dimethoxy- phenyl)-2,3 ,4,5, 10, 1 1 -hexahydro-dibenzo|"b,e] 1 ,4]diazepin- 1 -one
Step l
Compound 34 : 10-Acetyl-ll-(4-diethylamino-phenyl)-3-(2,4-dimethoxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000032_0001
MW : 539.68
Formula : C33H37N304
LCMS : 97.7%, MH+=540
1H NMR (250 MHz, DMSO-d6) δ ppm 9.09-8.97 (m, 1H), 7.27-6.98 (m, 4H), 6.95-6.24 (m, 7H), 3.78 (2s, 6H), 3.64-3.46 (m, 1H), 3.25-3.10 (m, 4H), 3.06-2.08 (m, 4H), 1.77 (d, J = 3.5 Hz, 3H), 0.96 (t, J = 6.2 Hz, 6H)
Compound 34 was obtained following protocols described for Example 3, step 3 with 30mg (0.06mmol) of Compound 33, \ 5 iL (0.12mmol) of anhydride acetic, 20μΕ (0.24mmol) of pyridine in 2mL of DCM yielding 23mg (70%) of a solid.
Example 15 : preparation of l l-(4-diethylamino-phenyl)-3-(2-methoxy-phenyl)- 2,3 ,4,5, 10, 1 1 -hexahydro-dibenzo[b,e] [ 1 ,4"[diazepin- 1 -one
Step 1
mino-phenylamino)-5-(2-methoxy-phenyl)-cyclohex-2-enone
Figure imgf000032_0002
MW : 308.38
Formula : CI 9H20N2O2
LCMS : 70%, MH+=309
Compound 35 was obtained following protocols described for Example 3, step 1 with 785mg (3.59mmol) of 5-(2-methoxy-phenyl)-cyclohexane-l ,3-dione, 390mg (3.59mmol) of phenyl enediamine in 15 mL of ethanol yielding 756mg (68 %) of a beige solid. Step 2
Compound 36 : ll-(4-diethyIamino-phenyl)-3-(2-methoxy-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000033_0001
MW : 467.62
Formula : C30H33N3O2
LCMS : 97.6%, MH+=468
1H NMR (250 MHz, DMSO-d6) 6 ppm 8.76 (s, 1H), 7.38-7.20 (m, 2H), 7 '.09-6.77 (m, 5H), 6.72-6.28 (m, 4H), 6.12 (t, J = 6.6 Hz, 1H), 5.70-5.52 (m, 1H), 3.83 (s, 3H), 3.78-3.51 (m, 1H), 3.50-3.35 (m, 1H), 3.28-3.10 (m, 4H), 3.05-2.31 (m, 4H), 1.13-0.83 (m, 6H),
Compound 36 was obtained following protocols described for Example 1, step 3 with 150mg (0.49mmol) of Compound 35, 88mg (0.49mmol) of 4-diethylaminobenzaldehyde in 3mL of EtOH. The residue was purified by silica gel chromatography (DCM/EtOH 95/5) to give 148mg (65%) of an orange oil.
Example 16 : preparation of 10-Acetyl-l l-(4-diethylamino-phenyl -3-(2-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l -one
Step 1
Compound 37 : ll-(4-diethylamino-phenyl)-3-(2-methoxy-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000033_0002
MW : 509.65
Formula : C32H35N303
LCMS : 95.8%, MH+=510, RT=5.56
1H NMR (400 MHz, DMSO-d6) ppm 9.03 (d, J = 4.8 Hz, 1H), 7.38-7.18 (m, 3H), 7.14- 6.64 (m, 8H), 6.37 (dd, J = 23.5, 8.7 Hz, 2H), 3.84 (s, 3H), 3.76-3.59 (m, 1H), 3.26-3.13 (m, 4H), 3.10-2.95 (m, 1H), 2.93-2.77 (m, 1H), 2.72-2.54 (m, 1H), 2.45-2.30 (m, 1H), 1.79 (2s, 3H), 1.02-0.94 (m, 6H) Compound 37 was obtained following protocols described for Example 3, step 3 with 40mg (0.09mmol) of Compound 36, 22μΙ, (0.17mmol) of anhydride acetic, 28μΙ. (0.34mmol) of pyridine in 2mL of DCM yielding 41mg (94%) of a solid. Example 17 : preparation of l l-(4-diethylamino-phenyl)-3-(3-methoxy-phenyl)- 2.3,4,5,10,1 1 -hexahydro-dibenzo b,e] [1,4] diazepin- 1 -one
Step 1
ino-phenylamino)-5-(3-methoxy-phenyl)-cyclohex-2-enone
Figure imgf000034_0001
MW : 308.38
Formula : CI 9H20N2O2
LCMS : 92.3%, MH+=309
Compound 38 was obtained following protocols described for Example 3, step 1 with 448mg (2.05mmol) of 5-(3-methoxy-phenyl)-cyclohexane-l,3-dione, 222mg (2.05mmol) of phenyl enediamine in 15 mL of ethanol yielding 54mg (9 %) of a beige solid.
Step 2
Compound 39 : ll-(4-diethylamino-phenyl)-3-(3-methoxy-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo [b,e] [l,4]diazepin-l-one
Figure imgf000034_0002
MW : 467.62
Formula : C30H33N3O2
LCMS : 100%, MH+=468
1H NMR (250 MHz, DMSO-d6) δ ppm 8.85-8.65 (m, 1H), 7.40-7.15 (m, 1H), 7.10-6.01 (m, 12H), 5.71-5.43 (m, 1H), 3.92-3.64 (m, 3H), 3.26-2.70 (m, 9H), 1.11-0.87 (m, 6H)
Compound 39 was obtained following protocols described for Example 1, step 3 with 54mg (0.18mmol) of Compound 38, 31mg (0.18mmol) of 4-diethylaminobenzaldehyde in 3mL of EtOH. yielding 30mg (36%) of a beige solid.
Example 18 : preparation of 10- Acetyl- 1 l-(4-diethylamino-phenyl -3-(3-methoxy-phenyl)- 2,3 ,4,5,10,11 -hexahydro-dibenzo|"b,e] 1 ,4]diazepin- 1 -one
Step 1 Compound 40 : 10-Acetyl-ll-(4-diethylamino-phenyl)-3-(3-methoxy-phenyl)- enzo [b,e] [ 1 ,4] diazepin- 1 -one
Figure imgf000035_0001
MW : 509.65
Formula : C32H35N303
LCMS : 95.4%, MH+=510
1H NMR (250 MHz, DMSO-d6) δ ppm 9.29-9.14 (m, 1H), 7.31-6.60 (m, 12H), 6.46-6.24 (m, 2H), 3.76 (s, 3H), 3.25-3.12 (m, 4H), 3.10-2.30 (m, 5H), 1.84-1.56 (m, 3H), 0.97 (t, J = 5.81 Hz, 6H)
Compound 40 was obtained following protocols described for Example 3, step 3 with 25mg (0.05mmol) of Compound 39, 14μί (O.l lmmol) of anhydride acetic, 18μΙ. (0.21mmol) of pyridine in lmL of DCM yielding 18mg (66%) of a solid. Example 19 : preparation of l l-(4-diethylamino-phenyl)-3-(4-morpholino-phenyl - 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,41diazepin-l-one
Step l
rpholmo-phenyl)-but-3-en-2-one
Figure imgf000035_0002
MW : 231.30
Formula : C14H17N02
LCMS : 100%, MH+=232
Compound 41 was obtained following protocols described for Example 6, step 1 with 530mg (2.77mmol) of 4-morpholinobenzaldehyde, 3.2mL of acetone, 0.12mL of NaOH 50% aq and 16mL of water. The residue was purified by silica gel flash chromatography (DCM/AcOEt 80/20) to afford 619mg (96%) as a light yellow solid.
Step 2
Compound 42 : 5-(4-morpholino-phenyl)-cyclohexane-l,3-dione
Figure imgf000035_0003
MW : 273.33
Formula : C16H19N03
LCMS : 100%, MH+=274 Compound 42 was obtained following protocols described for Example 6, step 2 with 404 L (2.66mmol) of diethylmalonate, 616mg (2.66mmol) of Compound 41, 61mg (4.81mmol) of sodium and 12mL of EtOH. The residue was triturated in DCM/heptane and the precipitate was filtered to afford 185mg (25%) as a white solid. amino)-5-(4-morpholino-phenyl)-cyclohex-2-enone
Figure imgf000036_0001
MW : 363.46
Formula : C22H25N302
LCMS : 91.1%, MH+=364
Compound 43 was obtained following protocols described for Example 3, step 1 with 185mg (0.68mmol) of Compound 42, 75mg (0.68mmol) of phenylenediamine in 10 mL of ethanol yielding 94mg (38 %) of a beige powder.
Step 4
Compound 44 : ll-(4-diethylamino-phenyl)-3-(4-morpholino-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
Figure imgf000036_0002
MW : 522.70
Formula : C33H38N402
LCMS : 97.8%, MH+=523
1H NMR (250 MHz, DMSO-d6) δ ppm 7.23-7.07 (m, 2H), 6.96-6.80 (m, 4H), 6.66-6.52 (m, 1H), 6.40-6.18 (m, 5H), 5.66-6.54 (m, 1H), 3.79-3.65 (m, 4H), 3.27-2.97 (m, 9H), 2.80-2.06 (m, 6H), 0.97 (dt, J = 6.8, 1.6 Hz, 6H) Compound 44 was obtained following protocols described for Example 1, step 3 with 94mg (0.26mmol) of Compound 43, 45mg (0.26mmol) of 4-diethylaminobenzaldehyde in 2mL of EtOH. yielding 1 lOmg (77%) of a beige solid.
Example 20 : preparation of 10- Acetyl- 11 -(4-diethylamino-phenyl)-3-(4-morpholino- phenyl)-2,3,4,5J0,l l-hexahydro-dibenzo b,e1[l,4]diazepin-l-one Step l
Compound 45 : 10-AcetyI-ll-(4-diethylamino-phenyl)-3-(4-morpholino-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000037_0001
MW : 564.73
Formula : C35H40N4O3
LCMS :100%, MH+=565
1H NMR (400 MHz, DMSO-d6) δ ppm 9.35-9.25 (m, 1H), 7.31-6.54 (m, 12H), 6.42-6.26 (m, 2H), 3.76-3.70 (m, 4H), 3.24-3.14 (m, 4H), 3.12-3.04 (m, 4H), 3.04-2.77 (m, 2H), 2.68-2.34 (m, 2H), 1.79 (s, 3H), 1.66-1.50 (m, 4H), 1.02-0.92 (m, 6H)
Compound 45 was obtained following protocols described for Example 3, step 3 with 40mg (0.08mmol) of Compound 44, \9\a~L (0.15mmol) of anhydride acetic, 25 iL (0.31mmol) of pyridine in 2mL of DCM yielding 38mg (87%) of a solid.
Example 21 : preparation of 1 l-(4-Diethylamino-phenyl -3-(4-dimethylamino-phenyl)-
2,3,4,5, 10, 11 -hexahydro-dibenzo b,e] [ 1 ,4~ldiazepin- 1 -one
Step l
Compound 46 : 3-(2-Amino-phenylamino)-5-(4-dimethyamino-phenyl)-cyclohex-2- enone
Figure imgf000037_0002
MW : 321.43
Formula : C20H23N3O
LCMS : 78.2%, MH+=322
1H NMR (250 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 7.16 (d, J = 8.5 Hz, 2H), 7.04-6.88 (m, 2H), 6.78-6.66 (m, 3H), 6.57 (t, J = 7.6 Hz, 1H), 4.96 (bs, 2H), 4.68 (bs, 1H), 3.25- 3.09 (m, 1H), 2.84 (s, 6H), 2.73-2.32 (m, 3H), 2.27-2.12 (m, 1H)
Compound 46 was obtained following protocols described for Example 3, step 1 with 300mg (1.29mmol) of 5-(4-dimethylamino-phenyl)-cyclohexane-l,3-dione, 140mg (1.29mmol) of phenylenediamine in 8mL of ethanol yielding 208mg (50 %) of a beige powder. Step 2
Compound 47 : ll-(4-Diethylamino-phenyl)-3-(4-dimethylamino-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000038_0001
MW :480.66
Formula : C31H36N40
LCMS : 100% MH+=481
1H NMR (250 MHz, DMSO-d6) 5 ppm 8.79-8.65 (m, 1H), 7.29-7.10 (m, 2H), 7.04-6.48 (m, 8H), 6.48-6.23 (m, 2H), 6.23-6.03 (m, 1H), 5.70-5.49 (m, 1H), 3.30-3.09 (m, 5H), 3.08-2.91 (m, 1H), 2.91-2.72 (m, 7H), 2.70-2.53 (m, 1H), 2.47-2.25 (m, 1H), 0.98 (d, J = 3.0 Hz, 6H)
Compound 47 was obtained following protocols described for Example 1, step 3 with 203mg (0.63mmol) of Compound 46, 112mg (0.63mmol) of 4-diethylaminobenzaldehyde in 4mL of EtOH. The residue was purified by silica gel chromatography (DCM/EtOH 98/2) yielding 206mg (68%) of a beige solid.
Example 22 : preparation of 10- Acetyl- 11 -(4-di ethyl amino-phenyl)-3 -(4-dimethylamino- phenyl)-2,3 ,4,5, 10, 11 -hexahydro-dibenzo["b,e] [ 1 ,4"]diazepin- 1 -one
Step 1
Compound 48 : 10-Acetyl-ll-(4-diethylamino-phenyl)-3-(4-dimethylamino-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000038_0002
MW : 522.70
Formula : C33H38N402
LCMS : 98.4% MH+=523
1H NMR (250 MHz, DMSO-d6) δ ppm 9.17-8.93 (m, 1H), 7.36-7.00 (m, 5H), 6.99-6.54 (m, 6H), 6.54-6.20 (m, 2H), 3.28-3.08 (m, 5H), 3.06-2.70 (m, 8H), 2.44-2.27 (m, 1H), 2.25-2.07 (m, 1H), 1.79 (s, 3H), 0.97 (s, 6H)
Compound 48 was obtained following protocols described for Example 3, step 3 with 200mg (0.42mmol) of Compound 47, 51 μί (0.42mmol) of anhydride acetic, 68 μΙ_, (0.83mmol) of pyridine in 7mL of DCM yielding 154mg (71%) of a solid. Example 23 : preparation of 10- Acetyl- 1 l-(4-di ethylamino-phenyl)-3-(4-hydroxy-phenyl)-
2,3 ,4,5, 10, 11 -hexahydro-dibenzo|"b,e] 1 ,4"]diazepin- 1 -one
Step l
Compound 49 : 10-Acetyl-ll-(4-diethylamino-phenyl)-3-(4-hydroxy-phenyl)- 2,3,4,5,10,1
1-hexahydro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
Figure imgf000039_0001
MW : 495.63
Formula : C31H33N303
LCMS : 96.5% MH+=496
1H NMR (250 MHz, DMSO-d6) δ ppm 9.36-9.16 (m, 1H), 9.12-8.95 (m, 1H),7.30- 7.15 (m, 2H), 7.15-7.00 (m, 2H), 6.95-6.60(m, 6H), 6.43-6.28 (m, 2H), 3.30-3.10 (m, 4H), 3.10- 2.30 (s, 5H), 1.79 (s, 3H), 1.10- 0.90 (m, 6H)
Compound 49 was obtained following protocols described for Example 10, step 1 with 50mg (O.lOmmol) of Compound 4, 450 xL (0.45mmol) of boron tribromide 1M in 2mL of DCM. After the work-up, the residue was purified by silica gel flash chromatography (DCM/EtOH 95/5) yielding 35mg (71%) of a brown powder.
Example 24 : preparation of l l-(4-Diethylamino-phenvD-3-(4-methoxy-phenyl)-10-(2- oxo-propyl)-2.3,
4,5, 10, 11 -hexahydro-dibenzo b,e] [ 1 ,4] diazepin- 1 -one
Step 1
Compound 50 : ll-(4-Diethylamino-phenyl)-3-(4-methoxy-phenyl)-10-(2-oxo-propyl)- 2,3,4,5, 10, 11-hexah dro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
Figure imgf000039_0002
MW : 523.68
Formula : C33H37N303
LCMS : 88% MH+=524
1H NMR (250 MHz, DMSO-d6) δ ppm 8.99-8.90 (m, 1H), 7.40-7.27 (m, 2H), 7.10-6.60 (m, 7H), 6.59-6.24 (m, 3H), 5.34 (d, J = 19.6Hz, 1H), 4.19-3.77 (m, 2H), 3.74 (s, 3H), 3.29-3.09 (m, 4H), 3.10-2.30 (m, 5H), 2.09 (d, J = 9.9 Hz, 3H), 1.08-0.88 (m, 6H) A mixture of 50mg (0.1 lmmol) of Compound 3, 13mg (0.16mmol) of chloroacetone with 29mg (0.21mmol) in ImL of acetonitrile in a sealed reaction vessel was irradiated under microwave conditions for 3h at 140°C. The reaction mixture was partitioned between water and DCM. The combined organic layers were dried over MgS04 and concentrated under vacuum. The residue was purified by silica gel flash chromatography (DCM/EtOH 98/2) to afford 20mg (36%) of Compound 50 as a beige solid.
2,3 ,4,5, 10 J 1 -hexahydro-dibenzo|"b,e] [ 1 ,4]diazepin- 1 -one
Step 1
Compound 51 : 4-Diethylamino-2-methyl-benzaldehyde
Figure imgf000040_0001
MW : 191.28
Formula : C12H17NO
LCMS : 96.3%, MH+=192
1H NMR (250 MHz, DMSO-άβ) δ ppm 9.82 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 6.59 (d, J = 8.9 Hz, 1H), 6.48 (s, 1H), 3.40 (q, J = 6.8 Hz, 1H), 3.31 (s, 3H), 1.10 (t, J = 6.8 Hz, 6H)
340μί (3.68mmol) of POC13 were added dropwise to 2mL of DMF cooled to 0°C. The solution was stirred 15 min at room temperature and 200mg (1.23mmol) of N,N-Diethyl- m-toluidine in ImL of DMF were then added. The reaction mixture was reflux ed for 2h and then quenched with water. It was basified and extracted with DCM. The combined organic layers were dried over MgS04 and concentrated under vacuum. The residue was purified by silica gel flash chromatography (cyclohexane/AcOEt) to afford 158mg (70%) of Compound 51 as an orange oil.
Step 2
Compound 52 : ll-(4-Diethylamino-2-methyl-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000040_0002
MW : 481.64
Formula : C3iH35N302
LCMS : 100% MH+=482 IH NMR (250 MHz, DMSO) δ ppm 8.84 (s, IH), 7.36-7.23 (m, 2H), 7.02-6.82 (m, 3H), 6.69-6.27 (m, 5H), 6.21-5.86 (m, IH), 5.72-5.50 (m, 2H), 3.74 (d, J = 2.6 Hz, 3H), 3.29- 2.75 (m, 7H), 2.48-2.21 (m, 5H), 1.11-0.86 (m, 6H) Compound 52 was obtained following protocols described for Example 1, step 3 with 134mg (0.44mmol) of Compound 2, 83mg (0.52mmol) of Compound 51 in 2mL of EtOH. The residue was purified by silica gel chromatography (DCM/EtOH 99/l).yielding 153mg (73%) of a beige solid. Example 26 : preparation of 10- Acetyl- 1 l-(4-di ethylamino-2 -methyl -phenyl)-3 -(4- methoxy-phenyl)-2,3 ,4,5, 10,11 -hexahydro-dibenzof b,e"[ \ 1 ,41diazepin- 1 -one
Step l
Compound 53 : 10-Acetyl-ll-(4-diethylamino-2-methyl-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000041_0001
MW : 523.68
Formula : C33H37N303
LCMS : 98.9% MH+=524
IH NMR (250 MHz, DMSO) δ ppm 9.11-8.99 (m, IH), 7.43-7.24 (m, 2H), 7.24-7.00 (m, 3H), 6.89 (d, J = 8.6 Hz, 2H), 6.84-6.68 (m, 2H), 6.56-6.17 (m, 2H), 6.16-5.87 (m, IH), 3.74 (s, 3H), 3.65-3.53 (m, IH), 3.24-3.09 (m, 4H), 3.08-2.58 (m, 2H), 2.45-2.31 (m, 2H), 2.25 (2s, 3H), 1.74 (2s, 3H), 1.05-0.87 (m, 6H)
Compound 53 was obtained following protocols described for Example 3, step 3 with 88mg (0.18mmol) of Compound 52, 18μί (0.18mmol) of anhydride acetic, 30μΙ. (0.36mmol) of pyridine in 3mL of DCM yielding 86mg (89%) of a beige solid.
Example 27 : preparation of 10- Acetyl- l l-(4-diethylamino-2-methyl-phenyl)-3 -(4- hydroxy-phenvD-2,3 ,4,5, 10, 11 -hexahydro-dibenzo|~b,e] 1 ,41diazepin- 1 -one
Step 1
Compound 54 : 10-Acetyl-ll-(4-diethylamino-2-methyl-phenyl)-3-(4-hydroxy-phenyl)- 2,3,4,5,10,H-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000042_0001
MW : 509.65
Formula : C32H35N303
LCMS : 100%, MH+=510
1H NMR (250 MHz, DMSO-d6 δ ppm 9.27 (s, 1H), 9.11-8.98 (m, 1H), 7.33-6.98 (m, 5H), 6.87-6.61 (m, 4H), 6.53-6.22 (m, 2H), 6.14-5.91 (m, 1H), 3.18 (q, J = 6.7Hz, 4H), 3.07- 2.53 (m, 4H), 2.43-2.30 (m, 1H), 2.26 (s, 3H), 1.74 (2s, 3H), 0.96 (t, J = 6.6 Hz, 6H)
Compound 54 was obtained following protocols described for Example 10, step 1 with 50mg (O.lOmmol) of Compound 53, 286μΕ (0.29mmol) of boron tribromide 1M in ImL of DCM yielding 17mg (45%) of a brown powder.
Example 28 : preparation of l l-(2-acetoxy-4-diethylamino-phenyl)-3-(4-methoxy-phenyl)- 2,3.4,5,10,11 -hexahydro-dibenzo [b,e] f 1 ,4] diazepin- 1 -one
Step 1
Compound 55 : 4-Diethylamino-2-acetoxy-benzaldehyde
Figure imgf000042_0002
MW : 235.29
Formula : C13H17NQ3
LCMS : 100%, MH+=236
1H NMR (250 MHz, DMSO-d6) ppm 9.64 (s, 1H), 7.62 (d, J = 8. 5 Hz, 1H), 6.66 (d, J = 9.0 Hz, 1H), 6.40 (s, 1H), 3.42 (dd, J = 13.7, 6.9 Hz, 4H), 2.29 (s, 3H), 1.11 (t, J = 6.5 Hz, 6H) Compound 55 was obtained following protocols described for Example 3, step 3 with lOOmg (0.52mmol) of 4-(Diethylamino)salicylaldehyde, 49μί (0.52mmol) of anhydride acetic, 2% xL (1.03mmol) of pyridine in 3mL of DCM. The residue was purified by silica gel flash chromatography (cyclohexane/AcOEt 80/20) yielding 50mg (68%) of a yellow oil.
Step 2
Compound 56 : ll-(2-acetoxy-4-diethylamino-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000043_0001
MW :525.65
Formula :C32H35N304
LCMS 96.0% MH+=526
1H NMR (250 MHz, MeOD) ppm 7.45-7.17 (m, 4H), 7.17-6.71 (m, 7H), 6.66-6.02 (m, 2H), 5.94-5.63 (m, 1H), 3.85-3.65 (m, 3H), 3.60-2.85 (s, 6H), 2.76-2.50 (m, 2H), 2.45-2.15 (m, 1H), 1.96-1.64 (m, 3H), 1.05-0.71 (m, 6H)
Compound 56 was obtained following protocols described for Example 1, step 3 with 62mg (0.20mmol) of Compound 2, 83mg (0.20mmol) of Compound 55 in 2mL of EtOH. The residue was purified by silica gel chromatography (DCM/EtOH 95/5).yielding 30mg (29%) of an orange solid.
Example 29 : preparation of 10-Acetyl-l l-(2-acetoxy-4-diethylamino-phenyl -3-(4- methoxy-phenyl)-2,3 ,4,5, 10, 11 -hexahydro-dibenzo[b, e] 1 ,4] diazepin- 1 -one
Step l
Compound 57 : 10-Acetyl-ll-(2-acetoxy-4-diethyIamino-phenyl)-3-(4-methoxy- phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000043_0002
MW :567.69
Formula : C34H37N305
LCMS : 100% MH+= 568
1H NMR (250 MHz, DMSO-d6) δ ppm 9.18-8.96 (m, 1H), 7.44-7.03 (m, 5H), 6.99-6.70 (m, 4H), 6.60-6.41 (m, 1H), 6.41-5.89 (m, 2H), 3.74 (s, 3H), 3.26-3.08 (m, 4H), 3.04-2.57 (m, 3H), 2.43-2.31 (m, 2H), 2.25 (s, 3H), 1.73 (s, 3H), 0.97 (t, J = 6.3 Hz, 6H)
Compound 57 was obtained following protocols described for Example 3, step 3 with 25mg (0.05mmol) of Compound 56, 9 i (O.lOmmol) of anhydride acetic, 15μΕ (0.20mmol) of pyridine in 3mL of DCM. The residue was purified by silica gel flash chromatography yielding 17mg (63%) of a pink solid.
Example 30 : preparation of 10- Acetyl- 1 l-(4-di ethyl amino-2-hydroxy-phenyl)-3 -(4- methoxy-phenyl)-2,3,4,5, 10,11 -hexahydro-dibenzo b,e] \ 1 ,4]diazepin- 1 -one
Step 1 Compound 58 : 10-Acetyl-ll-(4-diethylamino-2-hydroxy-phenyl)-3-(4-methoxy- phenyl)-2,3,4,5, 10,11 -hexahy dro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
Figure imgf000044_0001
MW : 525.65
Formula : C32H35N304
LCMS : 100% MH+=526
1H NMR (250 MHz, DMSO-d6) δ ppm 9.31-8.84 (m, 2H), 7.49-7.25 (m, 2H), 7.20-6.69 (m, 1H), 6.42-6.08 (m, 6H), 6.05-5.95 (m, 1H), 5.77-5.52 (m, 1H), 3.74 (s, 3H), 3.23-3.04 (m, 4H), 3.00-2.30 (m, 5H), 2.21-2.05 (m, 1H), 1.76-1.66 (m, 3H), 1.06-0.88 (m, 6H)
8mg (O.Olmmol) of Compound 57 was added to a solution of 2mg (0.09mmol) of sodium in lmL of EtOH. The reaction mixture was stirred at 50°C for 3h. It was concentrated and the residue was partitioned between water and DCM. The combined organic layers were dried over MgS04 and concentrated to afford 7mg (95%) of Compound 58 as a beige solid.
Example 31 : 10- Acetyl- 1 l-(4-(ethyl-2-hvdroxy-ethyl-amino)-2-methyl-phenyl)-3-(4- methoxy-phenvD-2,3 ,4,5, 10, 1 1 -hexahydro-dibenzo["b,e] \ 1 ,4]diazepin- 1 -one
Step 1
N-ethyI-acetoxy-ethyl-m-toluidine
Figure imgf000044_0002
MW : 221.30
Formula : CI 3H19N02
LCMS : 100%, MH+=222
Compound 59 was obtained following protocols described for Example 3, step 3 with 500μΕ (2.85mmol) of 2-(N-Ethyl-N-m-toluidino)ethanol, 634μΙ_, (5.09mmol) of anhydride acetic, 930μί (1 1.4mmol) of pyridine in 18mL of DCM) yielding 138mg (22%) of a yellow oil.
Step 2
Compound 60 : 4-(ethyl-(2-acetoxy-ethyl)-amino)-2-methyl-benzaldehyde
Figure imgf000045_0001
MW : 249.31
Formula : C14H19N03
LCMS : 91%, MH+=250
Compound 60 was obtained following protocols described for Example 25, stepl with 85μί (0.91mmol) of POC13, ImL of DMF and 135mg (0.61mmol) of Compound 59 yielding 70mg (46%) as an orange oil.
Step 3
Compound 61 : 1 l-(4-(ethyl-2-acetoxy-ethyl-amino)-2-methyl-phenyl)-3-(4-methoxy- phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000045_0002
MW : 539.68
Formula : C33H37N304
LCMS : 96.5%, MH+=540
1H NMR (250 MHz, DMSO-d6) ppm 8.85 (s, 1H), 7.41-7.21 (m, 2H), 7.06-6.80 (m, 3H), 6.65-6.30 (m, 5H), 6.21-5.96 (m, 1H), 5.86-5.52 (m, 2H), 4.07-3.95 (m, 2H), 3.73 (d, J = 2.5 Hz, 3H), 3.29-3.07 (m, 4H), 3.04-2.78 (m, 2H), 2.63-2.23 (m, 6H), 1.90 (s, 3H), 1.02- 0.93 (m, 3H)
Compound 61 was obtained following protocols described for Example 1 , step 3 with 87mg (0.28mmol) of Compound 2, 70mg (0.28mmol) of Compound 60 in 2mL of EtOH. The residue was purified by silica gel chromatography (DCM/EtOH 98/2).yielding 81mg (53%) of a beige solid.
Step 4
Compound 62 : 10-Acetyl-ll-(4-(ethyl-2-acetoxy-ethyl-amino)-2-methyl-phenyl)-3-(4- methoxy-pheny l)-2,3,4,5, 10,11-hexahy dro-dibenzo [b,e] [1 ,4] diazepin- 1 -one
Figure imgf000046_0001
MW : 581.72
Formula : C35H39N305
LCMS : 100%, MH+=582
1H NMR (250 MHz, DMSO-d6) δ ppm 9.14-8.98 (m, 1H), 7.40-7.26 (m, 2H), 7.22-7.00 (m, 3H), 6.96-6.68 (m, 4H), 6.54-5.96 (M, 3H), 4.07-3.95 (m, 2H), 3.73 (d, J = 2.5 Hz, 3H), 3.29-3.07 (m, 4H), 3.04-2.78 (m, 2H), 2.63-2.23 (m, 6H), 1.90 (s, 3H), 1.75 (s, 3H), 1.02-0.93 (m, 3H) Compound 62 was obtained following protocols described for Example 3, step 3 with 75mg (0.14mmol) of Compound 61, 35μΙ. (0.28mmol) of anhydride acetic, 45μΙν (0.55mmol) of pyridine in lmL of DCM yielding 46mg (57%) of a beige solid.
Step 5
Compound 63 : 10-Acetyl-ll-(4-(ethyl-2-hydroxy-ethyl-amino)-2-methyl-phenyI)-3-(4- methoxy-phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000046_0002
MW : 539.68
Formula : C33H37N304
LCMS : 100%, MH+=540
1H NMR (250 MHz, DMSO-d6) δ ppm 9.12-9.00 (m, 1H), 7.45-7.27 (m, 2H), 7.24-7.02 (m, 3H), 6.98-6.68 (m, 4H), 6.57-6.21 (m, 2H), 6.16-5.89 (m, 1H), 4.69-4.53 (m, 1H), 3.74 (s, 3H), 3.29-3.12 (m, 6H), 2.90-2.30 (m, 5H), 2.25 (d, J = 2.2 Hz, 3H), 1.75 (d, J = 2.3 Hz, 3H), 0.99-0.88 (m, 3H)
40mg (O.Olmmol) of Compound 62 were added to a solution of 140μί of NaOH IN in lmL of dioxane. The reaction mixture was reflu ed for lh. It was concentrated and the residue was partitioned between water and AcOEt. The combined organic layers were dried over MgS04 and concentrated to afford 16mg (43%) of Compound 63 as a beige solid. Example 32 : preparation of 10- Acetyl- 11 -(4-acetamido-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5, 10, 11 -hexahydro-dibenzo[b,e1 [1 ,4]diazepm-l -one
Step 1
Compound 64 : ll-(4-acetamido-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,ll- hexahy dro-dibenzo [b,e] [ 1 ,4] diazepin- 1-one
Figure imgf000047_0001
MW : 453.55
Formula : C28H27N303
LCMS : 100%, MH+=454
IH NMR (250 MHz, DMSO-d6) δ ppm 9.81-9.57 (m, IH), 8.96-8.50 (m, IH), 7.38-7.16 (m, 4H), 7.13-7.01 (m, IH), 7.00-6.76 (m, 3H), 6.65-6.46 (m, 4H), 6.33-6.08 (m, IH), 5.77-5.52 (m, IH), 3.74 (s, 3H), 3.13-2.19 (m, 5H), 1.94 (s, 3H) Compound 64 was obtained following protocols described for Example 1, step 3 with 150mg (0.49mmol) of Compound 2, 79mg (0.48mmol) of 4-Acetamidobenzaldehyde in 4mL of EtOH. The residue was purified by silica gel chromatography (DCM/EtOH 95/5) yielding 108mg (49%) of a beige solid. Step 2
Compound 65 : 10-AcetyI-ll-(4-acetamido-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000047_0002
MW : 495.58
Formula : C30H29N3O4
LCMS : 100%, MH+=496
IH NMR (250 MHz, DMSO-d6) δ ppm 9.84-9.68 (m, IH), 9.27-9.01 (m, IH), 7.46-6.70 (m, 13H), 3.75 (s, 3H), 3.34 (s, 6H), 3.17-2.30 (m, 5H)
Compound 65 was obtained following protocols described for Example 3, step 3 with 40mg (0.08mmol) of Compound 64, Ι Ι μΙ. (0.08mmol) of anhydride acetic, 15μΙ. (0.18mmol) of pyridine in 2mL of DCM yielding 39mg (90%) of a beige solid.
Example 33 : preparation of 1 l-(4-tert-butyl-phenyl)-3-(4-methoxy-phenyl -2,3,4,5,10,l 1- hexahydro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one Step 1
Compound 66 : ll-(4-tert-butyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000048_0001
MW : 452.60
Formula : C30H32N2O2
LCMS : 89.9%, MH+=453
1H NMR (250 MHz, DMSO-d6) ppm 8.81 (d, J = 12.9 Hz, 1H), 7.32 (dd, J = 10.6, 8.7 Hz, 2H), 7.24-7.03 (m, 3H), 7.01-6.81 (m, 4H), 6.71-6.47 (m, 3H), 6.28 (dd, J = 13.6, 6.0 Hz, 1H), 5.84-5.53 (m, 1H), 3.75 (s, 3H), 3.05-2.22 (m, 5H), 1.17 (2s,9H)
Compound 66 was obtained following protocols described Example 1 , step 3 with 1 OOmg (0.32mmol) of Compound 2, 79mg (0.33mmol) of 4-tert-butylbenzaldehyde in 2mL of EtOH yielding 139mg (94%) of a light yellow solid.
Example 34 : preparation of 10- Acetyl- 1 l-(4-tert-butyl -phenyl)-3 -(4-methoxy-phen yl)- 2,3 ,4,5, 10,11 -hexahydro-dibenzo b,el 1 ,4"jdiazepin- 1 -one
Step 1
Compound 67 : 10-Acetyl-ll-(4-tert-butyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000048_0002
MW : 494.64
Formula : C32H34N203
LCMS : 91.3%, MH+=495
1H NMR (250 MHz, DMSO-d6) δ ppm 9.10 (s, 1H), 7.42-7.25 (m, 3H), 7.22-6.95 (m, 5H), 6.99-6.69 (m, 6H), 3.73 (s, 3H), 3.13-2.28 (m, 4H), 1.80 (s, 3H), 1.14 (2s, 9H)
Compound 67 was obtained following protocols described for Example 3, step 3 with 139mg (0.31mmol) of Compound 66, 77μί (0.62mmol) of anhydride acetic, ΙΟΟμΙ, (1.24mmol) of pyridine in 6mL of DCM yielding 98mg (64%) of a solid.
Example 35 : preparation of 10- Acetyl- 11 -(4-tert-butyl-phenyl)-3 -(4-hydroxy-phenyl)-
2,3,4,5, 10,11 -hexahydro-dibenzo b,e1 1 ,4]diazepin- 1 -one Step l
Compound 68 : 10-AcetyI-ll-(4-tert-butyl-phenyl)-3-(4-hydroxy-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000049_0001
MW : 480.61
Formula : C31H32N203
LCMS : 100%, MH+=481
1H NMR (250 MHz, DMSO-d6) ppm 9.08 (s, 1H), 7.36-6.99 (m, 7H), 6.96-6.66 (m, 6H), 3.16-2.53 (m, 4H), 2.43-2.09 (m, 2H), 1.80 (s, 3H), 1.22-1.00 (m, 9H)
Compound 68 was obtained following protocols described for Example 10, step 1 with 95mg (0.19mmol) of Compound 67, 576μί (0.58mmol) of boron tribromide 1M in ImL of DCM yielding 73mg (79%) of a light yellow crystals.
Example 36 : preparation of 1 l-(4-isopropyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo["b,e][l ,4]diazepin-l -one
Step 1
Compound 69 : ll-(4-isopropyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
Figure imgf000049_0002
MW : 438.57
Formula : C29H30N2O2
LCMS : 95.5%, MH+=439
1H NMR (250 MHz, DMSO-d6) δ ppm 9.62-9.34 (m, 1H), 7.30 (t, J =9.0 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.06-6.83 (m, 7H), 6.83-6.68 (m, 1H), 6.13-5.91 (m, 1H), 3.74 (s,31H), 3.23-2.54 (m, 5H), 1.15-0.92 (m, 6H),
Compound 69 was obtained following protocols described for Example 1 , step 3 with 70mg (0.23mmol) of Compound 2, 34mg (0.23mmol) of 4-isopropylbenzaldehyde in 3mL of EtOH yielding 77mg (78%) of a beige solid.
Example 37 : preparation of 10-Acetyl-l l-(4-isopropyl-phenyl)-3-(4-methoxy-phenyl - 2,3,4,5, 10, 1 1 -hexahydro-dibenzo["b,e] [ 1 ,4]diazepin- 1 -one Step 1
Compound 70 : 10-Acetyl-ll-(4-isopropyl-phenyI)-3-(4-methoxy-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000050_0001
MW : 480.61
Formula : C31H32N203
LCMS : 99.0%, MH+=481
1H NMR (250 MHz, DMSO-d6) δ ppm 9.09 (s, 1H), 7.34 (dd, J = 8.7, 3.1 Hz, 3H), 7.21 (s, 1H), 7.14-6.70 (m, 9H), 3.75 (s, 3H), 3.14-2.92 (m, 1H), 2.91-2.56 (m, 3H), 2.47-2.12 (m, 2H), 1.81 (s, 3H), 1.13-0.97 (m, 6H)
Compound 70 was obtained following protocols described for Example 3, step 3 with 70mg (0.16mmol) of Compound 69, 41 i (0.26mmol) of anhydride acetic, 43μί (0.53mmol) of pyridine in lmL of DCM yielding 34mg (43%) of a solid.
Example 38 : preparation of l l-(4-(ethyl-isopropyl-amino)-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,11 -hexahydro-dibenzo b,e][" l,4]diazepin-l -one
Step 1
Compound 71 : 4-ethyl-isopropyl-amino-benzaldehyde
Figure imgf000050_0002
MW : 191.28
Formula : C12H17NO
LCMS : 95.9%, MH+=192
Compound 71 was obtained following protocols described for Example 25, stepl with 430μί (4.59mmol) of POC13, 4mL of DMF and 500mg (3.06mmol) of N-Ethyl-N- isopropylaniline yielding 370mg (63%) as a yellow oil.
Step 2
Compound 72 : ll-(4-(ethyl-isopropyl-amino)-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,1 ,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000051_0001
MW : 481.64
Formula : C31H35N302
LCMS : 91.8%, MH+=482
1H NMR (250 MHz, DMSO-d6) δ ppm 8.85-8.65 (m, 1H), 7.34 (t, J = 8.7 Hz, 2H), 7.08- 6.75 (m, 5H), 6.70-6.30 (m, 5H), 6.28-6.05 (m, 1H), 5.71-5.48 (m, 1H), 3.98-3.81 (m, 1H), 3.74 (d, J = 0.9 Hz, 3H), 3.26-2.17 (m, 7H), 1.13-0.86 (m, 9H)
Compound 72 was obtained following protocols described for Example 1, step 3 with lOOmg (0.32mmol) of Compound 2, 62mg (0.32mmol) of Compound 71 in 2mL of EtOH yielding 123mg (79%) of a beige powder.
Example 39 : preparation of 10-Acetyl-l l -(4-(ethyl-isopropyl-amino')-phenyl -3-(4- methoxy-phenyl)-2,3 ,4,5, 10, 1 1 -hexahydro-dibenzo|"b,e] 1 ,4"jdiazepin- 1 -one
Step 1
Compound 73 : 10-Acetyl-ll-(4-(ethyl-isopropyl-amino)-phenyl)-3-(4-methoxy- phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000051_0002
MW : 523.68
Formula : C33H37N303
LCMS : 92.5%, MH+=524
1H NMR (250 MHz, DMSO-d6) δ ppm 9.04 (s, 1H), 7.46-7.18 (m, 3H), 7.17-6.54 (m, 8H), 6.52-6.28 (m, 2H), 3.97-3.82 (m, 1H), 3.74 (s, 3H), 3.45-3.20 (m, 2H), 3.20-2.55 (m, 5H), 2.45-2.06 (m, 2H), 1.79 (s, 3H), 1.12-0.92 (m, 9H)
Compound 73 was obtained following protocols described for Example 3, step 3 with 120mg (0.25mmol) of Compound 72, 62μΙ. (0.50mmol) of anhydride acetic, 81 μΐ. (1.OOmmol) of pyridine in 6mL of DCM yielding 102mg (84%) of a beige solid. Example 40 : preparation of l l-(4-Diisopropylamino-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5, 10, 11 -hexahydro-dibenzo|"b,e] [ 1 ,4~]diazepin- 1 -one Step 1
diisopropyIamino benzaldehyde
Figure imgf000052_0001
MW : 205.30
Formula : CI 3H19NO
LCMS : 100%, MH+=206
Compound 74 was obtained following protocols described for Example 25, stepl with 458μί (4.91mmol) of POC13, 5mL of DMF and 579mg (3.27mmol) of N,N- diisopropylaniline. The residue was purified by silica gel flash chromatography (Petroleum ether/AcOEt 95/5) yielding 17mg (5%) as a yellow oil.
Step 2
Compound 75 : ll-(4-Diisopropylamino-phenyl)-3-(4-methoxy-phenyl)-2,3?4,5,10,ll- hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000052_0002
MW : 495.67
Formula : C32H37N302
LCMS : 90.2% MH+=496
Compound 75 was obtained following protocols described for Example 1, step 3 with 25mg (0.08mmol) of Compound 2, 17mg (0.08mmol) of Compound 74 in ImL of EtOH yielding 30mg (73%) of a beige solid. Example 41 : preparation of 10- Acetyl- 11 -(4-Diisopropylamino-phenyl)-3-(4-methoxy- phenyl)-2, 3,4,5, 10, 1 1 -hexahydro-dibenzo["b,eir 1 ,4]diazepin- 1 -one
Step 1
Compound 76 : 10-Acetyl-ll-(4-Diisopropylamino-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000053_0001
MW : 537.71
Formula : C34H39N303
LCMS : 97.1% MH+=538
1H NMR (250 MHz, DMSO-d6) δ ppm 9.20-9.01 (m, 1H), 7.42-7.01 (m, 5H), 7.00-6.71 (m, 5H), 6.71-6.45 (m, 3H), 3.74 (s, 3H), 3.67-3.45 (m, 2H), 3.16-2.56 (m, 3H), 2.46-2.07 (m, 2H), 1.80 (s, 3H), 1.15-0.90 (m, 12H)
Compound 76 was obtained following protocols described for Example 3, step 3 with 28mg (0.06mmol) of Compound 75, 2\ \iL (0.17mmol) of anhydride acetic, 28μΙ. (0.97mmol) of pyridine in 2mL of DCM yielding 23mg (76%) of a beige solid.
Example 42 : preparation of 10- Acetyl- 1 1 -(4-Diisopropylamino-phenyl)-3-(4-hydroxy- phenyl)-2,3 A5, 10, 1 1 -hexahydro-dibenzo [b,e] 1 ,4]diazepin- 1 -one
Step 1
Compound 77 : 10-Acetyl-ll-(4-Diisopropylamino-phenyl)-3-(4-hydroxy-phenyl)- 2,3,4,5, 10, 11-hexahy dro-dibenzo [b,e] [ 1 ,4] diazepin-1 -one
Figure imgf000053_0002
MW : 523.68
Formula : C33H37N303
LCMS : 94.1 % MH+=524
Compound 77 was obtained following protocols described for Example 10, step 1 with 1 lmg (0.02mmol) of Compound 76, βΐ μΐ, (0.06mmol) of boron tribromide 1M in ImL of DCM yielding 6mg (51%) of a brown powder.
Example 43 : preparation of l l -(4-Diisopropylamino-2-methyl-phenyl -3-("4-methoxy- phenyp-2,3,4,5, 10,1 1 -hexahydro-dibenzo [b,e] [ 1 ,4]diazepin- 1 -one
Step l ompound 78 : 2-methyl-4-diisopropylamino benzaldehyde
Figure imgf000054_0001
MW : 219.33
Formula : C14H21NO
LCMS : 94.6%, MH+=220
1H NMR (250 MHz, DMSO-d6) δ ppm 9.81 (s, 1H), 7.54 (d, J = 8.9 Hz, 1H), 6.74 (dd, J = 8.9, 2.7 Hz, 1H), 6.61 (dd, J = 6.3, 2.3 Hz, 1H), 4.02 (hep, J = 6.8 Hz, 2H), 2.51 (s, 3H), 1.26 (d, J = 6.8 Hz, 12H). Compound 78 was obtained following protocols described for Example 25, stepl with 295μΕ (3.16mmol) of POC13, 6mL of DMF and 403mg (2.1 1mmol) of the corresponding aniline. The residue was purified by silica gel flash chromatography (Petroleum ether/ AcOEt 95/5) yielding 220mg (47%) as a yellow oil.
Step 2
Compound 79 : ll-(4-Diisopropylamino-2-methyl-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000054_0002
MW : 509.70
Formula : C33H39N302
LCMS : 94.6% MH+=510
1H NMR (250 MHz, DMSO-d6) ppm 8.97-8.81 (m, 1H), 7.41-7.22 (m, 2H), 7.02-6.83 (m, 3H), 6.67-6.40 (m, 4H), 6.36-6.07 (m, 1H), 5.88-5.52 (m, 1H), 3.73 (s, 3H), 3.70-3.50 (m, 2H), 3.28-2.55 (m, 4H), 2.48 (s, 3H), 2.40-2.25 (m, 2H), 1.20-0.92 (m, 12H)
Compound 79 was obtained following protocols described for Example 1, step 3 with 309mg (l .OOmmol) of Compound 2, 220mg (l .OOmmol) of Compound 78 in lOmL of EtOH yielding 245mg (48%) of a beige solid. Example 44 : preparation of 10- Acetyl- 1 l-(4-diisopropylamino-2-methyl -phenyl >3 -(4- methoxy-phenyl)-2,3,4,5, 10, 11 -hexahydro-dibenzo["b,e~j[ 1 ,4]diazepin-l -one
Step l
Compound 80 : 10-Acetyl-ll-(4-diisopropylamino-2-methyl-phenyI)-3-(4-methoxy- dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000055_0001
MW : 551.74
Formula : C35H41N303
LCMS : 95.4% MH+=552
IH NMR (250 MHz, DMSO-d6) δ ppm 9.16 (s, IH), 7.46-7.27 (m, 2H), 7.25-6.99 (m, 3H), 6.89 (d, J = 8.6 Hz, 2H), 6.84-6.65 (m, 2H), 6.62-6.40 (m, 2H), 6.32-6.10 (m, IH), 3.74 (s, 3H), 3.65-3.47 (m, 2H), 3.46-3.20 (m, 2H), 3.14-2.74 (m, IH), 2.71-2.55 (m, IH), 2.43- 2.31 (m, IH), 2.30-2.19 (m, 3H), 1.80-1.65 (m, 3H), 1.04-0.88 (m, 12H)
Compound 80 was obtained following protocols described for Example 3, step 3 with 208mg (0.41mmol) of Compound 79, 101 μΐ. (0.82mmol) of anhydride acetic, 134μΙ, (1.63mmol) of pyridine in 3mL of DCM yielding 197mg (87%) of a beige solid.
Example 45 : preparation of 10-Acetyl-l l-(4-diisopropylamino-2-methyl-phenyl)-3-(4- hydroxy-phenyl)-2,3,4,5, 10, 11 -hexahydro-dibenzo b,e1 1 ,4]diazepin- 1 -one
Step l
Compound 81 : 10-Acetyl-ll-(4-diisopropylamino-2-methyl-phenyl)-3-(4-hydroxy- phenyl)
-2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000055_0002
MW : 537.71
Formula : C34H39N303
LCMS : 93.6% MH+=538
IH NMR (250 MHz, DMSO-d6) δ ppm 9.16 (s, IH), 7.28-6.99 (m, 5H), 6.82-6.65 (m, 4H), 6.55-6.40 (m, 2H), 6.32-6.10 (m, IH), 3.65-3.47 (m, 2H), 3.46-3.20 (m, 2H), 3.14-2.31 (m, 5H), 2.30-2.19 (m, 3H), 1.80-1.65 (m, 3H), 1.04-0.88 (m, 12H) Compound 81 was obtained following protocols described for Example 10, step 1 with 50mg (0.09mmol) of Compound 80, 272μί (0.27mmol) of boron tribromide 1M in ImL of DCM yielding 37mg (77%) of a beige powder. Example 46 : preparation of 1 l-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy- phenvD-2,3, 4,5,10, 1 1 -hexahydro-dibenzo|"b,el 1 ,4]diazepin-l -one
Step 1
Compound 82 : l-trifluoromethanesulfonate-2-methoxy phenyl
Figure imgf000056_0001
MW : 256.20
Formula : C8H7F304S
LCMS : 100%, MH+=257
1H NMR (250 MHz, DMSO-d6) δ ppm 7.52-7.38 (m, 2H), 7.33 (d, J
(td, J = 8.4, 1.1 Hz, 1H), 3.89 (s, 3H)
13.6g (48.4mmol) of trifluoromethanesulfonic anhydride were added to an inerted (Argon) solution of 3g (24.2mmol) of guaiacol and 10.6g (99.1mmol) of 2,6-lutidine in 120mL of anhydrous DCM. The reaction mixture was stirred overnight at room temperature and it was partitioned between water and Et20. The combined organic layers were washed with a saturated solution of CuS04, dried over MgS04 and concentrated under vacuum. The residue was purified by silica gel flash chromatography (petroleum ether/AcOEt 80/20) to afford 5.2 lg (84%) of Compound 82.
Step 2
Compound 83 : N,N-Diisopropyl-3-methoxyaniline
Figure imgf000056_0002
MW : 207.32
Formula : CI 3H21NO
LCMS : 77%, MH+=208
RMN : 1H NMR (250 MHz, DMSO-d6) 5 ppm 7.02 (t, J = 8.1 Hz, 1H), 6.41 (dd, J = 8.3, 2.2 Hz, 1H), 6.33-6.18 (m, 2H), 3.87-3.71 (m, 2H), 3.68 (s, 3H), 1.23-1.10 (m, 12H)
11. ImL of nBuLi 2M in hexane were added to an inerted (argon) solution of 20mL (14.8mmol) of freshly distilled diisopropylamine in 180mL of anhydrous THF cooled to - 78°C. 3.78g (14.8mmol) of Compound 82 were then added, the reaction mixture was stirred for lh30 at -78°C and then warmed up to room temperature. It was partitioned between water and AcOEt and the combined organic layers were dried over MgS04 and concentrated under vacuum to afford 2.88g (94%) of Compound 83 as an orange oil. Step 3
Compound 84 : 2-methoxy-4-diisopropyIamino benzaldehyde
Figure imgf000057_0001
MW : 235.33
Formula : CI 3H21NO
LCMS : 77%, MH+=208
Compound 84 was obtained following protocols described for Example 25, stepl with 1.6mL (17.4mmol) of POC13, 40mL of DMF and 2.40g (1 1.6mmol) of Compound 83. The residue was purified by silica gel flash chromatography (Petroleum ether/AcOEt 95/5) yielding 291mg (11%) as a yellow oil.
Step 4
Compound 85 : ll-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10, 11 -hexahydro-dibenzo [b,e] [1,4] diazepin- 1-one
Figure imgf000057_0002
MW :525.70
Formula : C33H39N303
LCMS : 94,5% MH+=526
1H NMR (250 MHz, DMSO-d6) 5 ppm 8.84 (s, 1H), 7.33 (t, J = 10.8, 2H), 6.96-6.84 (m, 4H), 6.67-6.39 (m, 4H), 6.33-6.16 (m, 1 H), 6.1 1-5.99 (m, 1H), 5.95-5.82 (m, 1H), 5.81- 5.71 (m, 1H), 5.36-5.21 (m, 1H), 3.85 (s, 3H), 3.78-3.66 (m, 5H), 3.19-2.30 (m, 4H), 1.09 (m, 12H)
Compound 85 was obtained following protocols described for Example 1, step 3 with 382mg (1.23mmol) of Compound 2, 291mg (1.23mmol) of Compound 84 in 16mL of EtOH yielding 329mg (51 %) of a beige solid.
Example 47 : preparation of 1 l-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-hydroxy- phenyD-2,3,4,5, 10, 11 -hexahydro-dibenzo b,e1 Γ 1 ,41 diazepin- 1 -one
Step 1
Compound 86 : ll-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-hydroxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000058_0001
MW : 51 1.67
Formula : C32H37N303
LCMS : 100%, MH+=512
IH NMR (250 MHz, DMSO-d6) ppm 8.87 (bs, IH), 7.17 (t, J = 8.5 Hz, 2Η), 6.97-6.82 (m, IH), 6.82-6.67 (m, 2H), 6.66-6.36 (m, 3H), 6.34-6.20 (m, IH), 6.11-5.63 (m, 2H), 5.15 (t, J = 6.2 Hz, IH), 3.85 (s, 3H), 3.75-3.54 (m, 2H), 3.07-2.35 (m, 5H), 1.60 (s, 2H), 1.12-1.04 (m, 12H) Compound 86 was obtained following protocols described for Example 10, step 1 with 80mg (0.15mmol) of Compound 85, 456μί (0.46mmol) of boron tribromide 1M in 4mL of DCM. After the work-up, the residue was triturated with Et20 and the resulting precipitate was filtered to afford 57mg (73%) of a beige solid. Example 48 : preparation of 10- Acetyl- 1 1 -(4-diisopropylamino-2-methoxy-phenyl)-3-(4- methoxy-phenvD-2,3,4,5, 10, 11 -hexahydro-dibenzo b,e] 1 ,4"|diazepin-l -one
Step 1
Compound 87 : 10-AcetyI-ll-(4-diisopropyIamino-2-methoxy-p enyl)-3-(4-methoxy- phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000058_0002
Formula : C35H41N304
LCMS : 100% MH+=568
IH NMR (250 MHz, DMSO-d6) δ ppm 9.21-8.97 (m, IH), 7.44-7.26 (m, 2H), 7.24-7.15 (m, IH), 7.10-6.87 (m, 4H), 6.82-6.58 (m, 2H), 6.50-6.34 (m, IH), 6.30-6.15 (m, IH), 6.09-5.86 (m, IH), 3.84 (1, I H), 3.79-3.68 (m, 4H), 3.68-3.50 (m, 2H), 3.20-2.54 (m, 4H), 2.23-2.05 (m, 2H), 1.73 (m, 2H), 1.18-0.89 (m, 12H)
Compound 87 was obtained following protocols described for Example 3, step 3 with 325mg (0.62mmol) of Compound 85, 154μΙ. (1.24mmol) of anhydride Βΰείϊϋ,202μΕ (2.47mmol) of pyridine in 5mL of DCM yielding 247mg (70%) of a beige solid. Example 49 : preparation of 10- Acetyl- 1 l-(4-diisopropylamino-2-methoxy-phenyl)-3-(4- hydroxy-phenyD-2,3,4,5 Λ 0, 1 1 -hexahydro-dibenzo[b,e] [" 1 ,4]diazepin-l -one
Step l
Compound 88 : 10-Acetyl-ll-(4-diisopropylamino-2-methoxy-phenyl)-3-(4-hydroxy- phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000059_0001
MW : 553.71
Formula : C34H39N304
LCMS : 98% MH+=554
1H NMR (250 MHz, DMSO-d6) δ ppm 9.28 (m, 1H), 9.24-8.91 (m, 1H), 7.35-7.14 (m, 2H), 7.10-6.85 (m, 2H), 6.78-6.60 (m, 4H), 6.58-6.31 (m, 1H), 6.27-6.18 (s, 1H), 6.11-5.82 (m, 1H), 3.80 (s, 3H), 3.70-3.51 (m, 2H), 3.50-3.35 (m, 1H), 3.13-2.55 (m, 3H), 2.12+1.72 (2d, 3H); 1.16-0.86 (m, 12H)
Compound 88 was obtained following protocols described for Example 10, step 1 with 50mg (0.09mmol) of Compound 87, 264μί (0.26mmol) of boron tribromide 1M in 2mL of DCM. After the work-up, the residue was purified by silica gel flash chromatography (DCM/EtOH 95/5) to afford 55mg (37%) of a solid.
Example 50 : preparation of l l-(2-acetoxy-4-diisopropylamino-phenyl)-3-(4-methoxy- phenyl)-2,3 ,4,5, 10, 11 -hexahydro-dibenzo["b,e1 \ 1 ,4]diazepin- 1 -one
Step l
Compound 89 : 2-hydroxy-4-diisopropylamino benzaldehyde
Figure imgf000059_0002
MW : 221.30
Formula : C13H19N02
LCMS : 95%, MH+=222
1H NMR (250 MHz, DMSO-d6) δ ppm 11.02 (s, 1H), 9.65 (bs, 1H), 7.38 (d, J = 9.0 Hz, 1H), 6.45 (dd, J = 9.1, 2.4 Hz, 1H), 6.18 (d, J - 2.4 Hz, 1H), 4.00 (hept, J = 6.9 Hz, 2H), 1.26 (d, 12H),
Compound 89 was obtained following protocols described for Example 25, stepl with 946μΕ (lO.lmmol) of POC13, 20mL of DMF and 1.4g (6.76mmol) of Compound 83 except that the reaction mixture was refluxed for 4h. The residue was purified by silica gel flash chromatography (Petroleum ether/ AcOEt 90/10) yielding 424mg (28%) as a yellow oil. Step 2
Compound 90 : 2-acetoxy-4-diisopropylamino benzaldehyde
Figure imgf000060_0001
MW : 263.34
Formula : CI 5H21N03
LCMS : 96%, MH+=264
1H NMR (250 MHz, DMSO-d6) δ ppm 9.65 (s, 1H), 7.58 (d, J = 9.0 Hz, 1H), 6.80 (dd, J = 9.0, 2.4 Hz, 1H), 6.49 (fd, J = 2.4 Hz, 1H), 4.03 (hept, J = 6.9 Hz, 2H), 2.28 (s, 3H), 1.26 (d, J = 6.9 Hz, 12H). Compound 90 was obtained following protocols described for Example 3, step 3 with 210mg (0.95mmol) of Compound 89, 237μί, (1.90mmol) of anhydride acetic, 310μΙ, (3.80mmol) of pyridine in 4mL of DCM). The residue was purified by silica gel flash chromatography (DCM/petroleum ether 90/10) yielding 121mg (48%) of an oil. Step 3
Compound 91 : ll-(2-acetoxy-4-diisopropylamino-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000060_0002
MW : 553.71
Formula : C34H39N304
LCMS : 100% MH+=554
Compound 91 was obtained following protocols described for Example 1 , step 3 with 63mg (0.21mmol) of Compound 2, 54mg (0.21mmol) of Compound 90 in 3mL of EtOH yielding 2mg (1%) of a red solid.
Example 51 : preparation of 1 l-(4-Diisopropylamino-2-hydroxy-phenyl)-3-(4-methoxy- phenyl)-2,3 A5, 10,11 -hexahydro-dibenzo|"b,e] \ 1 ,4]diazepin-l -one
Step l Compound 92 : ll-(4-DiisopropyIamino-2-hydroxy-phenyI)-3-(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo [b,e] [1,4] diazepin-l-one
Figure imgf000061_0001
MW :511.67
Formula : C32H37N303
LCMS : 86.2%, MH+=512
Compound 92 was obtained following protocols described for Example 1 , step 3 with 63mg (0.21mmol) of Compound 2, 54mg (0.21mmol) of Compound 90 in 3mL of EtOH yielding 5mg (4%) of a red solid.
Example 52 : preparation of 10-Acetyl-l l -(2-acetoxy-4-diisopropylamino-phenyl -3-(4- methoxy-phenyl)-2,3,4,5, 10, 1 1 -hexahydro-dibenzo["b,e"[[ 1 ,41diazepin-l -one
Step l
Compound 93 : 10-Acetyl-ll-(2-acetoxy-4-diisopropyIamino-phenyl)-3-(4-methoxy- phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000061_0002
MW : 595.75
Formula : C36H41N305
LCMS : 92.2%, MH+=596
Compound 93 was obtained following protocols described for Example 3, step 3 with 59mg (0.12mmol) of Compound 92, 29μΙ, (0.23mmol) of anhydride acetic, 38μΙ_, (0.46mmol) of pyridine in lmL of DCM. The residue was purified by silica gel chromatography (DCM/EtOH 95/5) yielding 12mg (17%) of a solid.
Example 53 : preparation of 10-Acetyl-l l -(2-hydroxy-4-diisopropylamino-phenyl)-3-('4- methoxy-phenyl)-2,3 ,4,5, 10, 1 1 -hexahydro-dibenzo [b-e] 1 ,4]diazepin-l -one
Step l
Compound 94 : 10-Acetyl-ll-(2-hydroxy-4-diisopropylamino-phenyl)-3-(4-methoxy- phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000062_0001
MW : 553.71
Formula : C34H39N304
LCMS : 100%, MH+= 554
1H NMR (250 MHz, DMSO-d6) δ ppm 9.29-8.83 (m, 2H), 7.47-6.54 (m, 8H), 6.44-6.06 (m, 2H), 5.98-5.74 (m, 1H), 3.75 (s, 3H), 3.66-3.44 (m, 2H), 3.15- 2.30 (m, 5H), 2.22-2.08 (d, J = 10.4 Hz, 1H), 1.71 (s, 2H), 1.01 (d, J = 5.6 Hz, 12H)
Compound 94 was obtained following protocols described for Example 31 , step 5 with 29mg (0.05mmol) of Compound 93, Ι ΟΟμΙ^ of NaOH IN and ImL of dioxane yielding 19mg (71%) as a beige solid.
Example 54 : preparation of 1 l-(4-diisopropylamino-2-isopropoxy-phenyl -3-(4-methoxy- phenyl)-2,3 ,4,5,10,1 1 -hexahvdro-dibenzo["b,e] 1 ,4]diazepin- 1 -one
Step 1
Compound 95 : 2-isopropoxy-4-diisopropylamino benzaldehyde
Figure imgf000062_0002
MW : 263.38
Formula : CI 6H25N02
LCMS : 95.5%, MH+=264
1H NMR (250 MHz, DMSO-d6) δ ppm 10.00 (s, 1H), 7.47 (d, J = 9.0 Hz, 1H), 6.47 (dd, J = 9.0, 2.1 Hz, 1H), 6.25 (fd, J = 6.0 Hz, 1H), 4.68 (hept, J = 2.2 Hz, 1H), 4.15-3.91 (m, 2H), 1.37-1.13 (m, 18H) A mixture of 213mg (0.96mmol) of Compound 89 with 106μΙ, (1.06mmol) of 2- iodopropane, 333mg (2.4mmol) of potassium carbonate in 3mL of DMF was stirred at room temperature for 3 days. The reaction mixture was partitioned between water and AcOEt, the combined organic layers were dried over MgS04 and concentrated under vacuum to afford 284mg (99%) of Compound 95 as an oil.
Step 2
Compound 96 : ll-(4-diisopropylamino-2-isopropoxy-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,11-hexahy dro-dibenzo [b,e] [1 ,4] diazepin-1 -one
Figure imgf000063_0001
MW : 553.75
Fomula : C35H43N303
LCMS : 82.6%, MH+=554
1H NMR (250 MHz, DMSO-d6) δ ppm 8.90-8.73 (m, 1H), 7.42-7.20 (m, 3H), 7.02-6.83 (m, 4H), 6.80-6.49 (m, 3H), 6.48-6.33 (m, 1H), 6.31-6.18 (m, 1H), 6.09-5.71 (m, 1H), 5.13-4.99 (m, 1H), 4.72-4.51 (m, 1H), 3.78-3.70 (m, 4H), 3.70-3.54 (m, 1H), 3.08-2.25 (m, 5H), 1.50-1.36 (m, 5H), 1.18-0.81 (m, 12H)
Compound 96 was obtained following protocols described for Example 1, step 3 with 292mg (0.95mmol) of Compound 2, 250mg (0.95mmol) of Compound 95 in 6mL of EtOH. The residue was purified by silica gel chromatography (DCM/AcOEt 98/2) yielding 67mg (14%) of a pink solid.
Example 55 : preparation of 10- Acetyl- 11 -(4-diisopropylamino-2-isopropoxy-phenyl)-3 -
(4-methoxy-phenyl)-2,3,4,5, 10,11 -hexahydro-dibenzo b.el Γ 1 ,4]diazepin- 1 -one
Step l
Compound 97 : 10-Acetyl-ll-(4-diisopropylamino-2-isopropoxy-phenyl)-3-(4- methoxy-phenyl)-2,3?4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000063_0002
MW : 595.79
Formula : C37H45N304
LCMS : 100% MH+=596
1H NMR (250 MHz, DMSO-d6) δ ppm 9.17-8.98 (m, 1H), 7.39-7.29 (m, 2H), 7.24-6.85 (m, 5H), 6.79-6.64 (m, 2H), 6.61-6.36 (m, 1H), 6.29-6.16 (m, 1H), 6.06-5.85 (m, 1H), 4.65-4.41 (m, 1H), 3.74 (s, 3H), 3.65-3.48 (m, 2H), 3.15-2.30 (m, 4H), 2.24-2.08 (d, J = 10.7 Hz, 1H), 1.74 (s, 2H), 1.36 (m, 6H), 1.01 (d, J = 6.1 Hz, 12H) Compound 97 was obtained following protocols described for Example 3, step 3 with 59mg (O.l lmmol) of Compound 96, 27μί (0.21mmol) of anhydride acetic, 35μί (0.42mmol) of pyridine in 1.5mL of DCM. The residue was purified by silica gel chromatography (DCM/EtOH 98/2) yielding 12mg (15%) of a solid. Example 56 : preparation of 1 l-(4-diisopropylamino-2-sec-butoxy-phenyl)-3-(4-methoxy- phenyD-2,,3 A5, 10, 11 -hexahydro-dibenzo[b,el [ 1 ,4]diazepin-l -one
Step l
Compound 98 : 2-sec-butoxy-4-diisopropylamino benzaldehyde
Figure imgf000064_0001
MW : 277.41
Formula : CI 7H27N02
LCMS : 94,1%, MH+=278
IH NMR (250 MHz, DMSO-d6) h ppm 10.02 (s, IH), 7.47 (d, J = 9.0 Hz, IH), 6.47 (dd, J = 8.9, 1.8 Hz, IH), 6.23 (fd, J = 2.0 Hz, IH), 4.47 (hex, J = 5.9 Hz, IH), 4.03 (hept, J = 6.8 Hz, 2H), 1.85-1.50 (m, 2H), 1.44-1.08 (m, 15H), 0.95 (t, J = 7.4 Hz, 3H)
Compound 98 was obtained following protocols described for Example 54, stepl with 88mg (0.40mmol) of Compound 89, 50μί (0.44mmol) of 2-iodobutane, 137mg (0.99mmol) of potassium carbonate in 2mL of DMF yielding 93mg (84%) as an oil.
Step 2
Compound 99 : ll-(4-diisopropylamino-2-sec-butoxy-phenyl)-3-(4-methoxy-phenyI)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000064_0002
MW : 567.78
Formula : C36H45N303
LCMS : 92.2%, MH+=568
IH NMR (250 MHz, DMSO-d6) ppm 8.82 (bs, IH), 7.33 (t, J = 8.9 Hz, 2H), 6.96-6.84 (m, 3H), 6.68-6.14 (m, 4H), 6.12-5.73 (m, 3H), 5.14-4.92 (m, IH), 4.49-4.29 (m, IH), 3.75 (d, J = 1.5 Hz, 3H), 3.71-3.53 (m, 2H), 2.99-2.25 (m, 7H), 1.97-1.65 (m, 2H), 1.42-1.32 (m, 3H), 1.24-0.93 (m, 13H) Compound 99 was obtained following protocols described for Example 1, step 3 with 103mg (0.33mmol) of Compound 2, 93mg (0.33mmol) of Compound 98 in 2mL of EtOH yielding 184mg (97%) of a beige foam. Example 57 : preparation of 10- Acetyl- 1 l-(4-diisopropylamino-2-sec-butoxy-phenyl)-3- (4-methoxy-phenyl)-2,3 A5, 10, 11 -hexahydro-dibenzof b,e] f 1 ,41diazepin- 1 -one
Step l
Compound 100 : 10-Acetyl-ll-(4-diisopropylamino-2-sec-butoxy-phenyl)-3-(4- methoxy-phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000065_0001
MW : 609.82
Formula : C38H47N304
LCMS : 96.3%, MH+=610
1H NMR (250 MHz, DMSO-d6) δ ppm 9.34-8.86 (m, 1H), 7.37-7.30 (m, 2H), 7.27-6.64 (m, 6H), 6.54-5.81 (m, 3H), 4.43-4.19 (m, 1H), 3.74 (s, 3H), 3.65-3.48 (m, 2H), 3.14-2.30 (m, 7H), 2.18-2.05 (m, 2H), 1.80-1.62 (m, 3H), 1.36-1.20 (m, 3H), 1.14-0.89 (m, 13H)
Compound 100 was obtained following protocols described for Example 3, step 3 with 184mg (0.32mmol) of Compound 99, 60μΙ. (0.65mmol) of anhydride αϋεΐϊο,105μΕ (1.30mmol) of pyridine in 2.5mL of DCM. The residue was purified by silica gel flash chromatography yielding 127mg (64%) of a beige solid.
Example 58 : preparation of l l-(4-diisopropylamino-2-methoxy-phenyl)-3-(4-methyl- phenyl -2,3 ,4,5, 10,11 -hexahydro-dibenzo b,e] 1 ,41diazepin-l -one
Step 1
-4-(4-methyI-phenyl)-but-3-en-2-one
Figure imgf000065_0002
MW : 160.22
Formula : CI 1H120
LCMS : 89%, MH+=161
Compound 101 was obtained following protocols described for Example 6, step 1 with 2.0g (16.65mmol) of 4-methylbenzaldehyde, 12mL of acetone, 1.40mL of NaOH 50% aq and 60mL of water. The residue was purified by silica gel flash chromatography (DCM/AcOEt 98/2) to afford 2.45g (91%) as a yellow oil.
Step 2 Compound 102 : 5-(4-methyl-phenyl)-cyclohexane-l,3-dione
Figure imgf000066_0001
MW : 202.26
Formula : C13H1402
LCMS : 91.5%, MH+=203
1H NMR (250 MHz, DMSO-d6) ppm 1 1.15 (bs, 1H), ou 7.15 (2d, 4H), 5.27 (s, 1H), 3.40- 3.21 (m, 1H), 2.75-2.50 (m, 4H), 2.26 (s, 3H).
Compound 102 was obtained following protocols described for Example 6, step 2 with 2.32mL (15.30mmol) of diethylmalonate, 2.45g (15.30mmol) of Compound 101, 366mg (15.91mmol) of sodium and 70mL of EtOH, yielding 2.80g (90%) as a beige solid. o-phenyIamino)-5-(4-methyl-phenyl)-cyclohex-2-enone
Figure imgf000066_0002
MW : 292.38
Formula : CI 9H20N2O
LCMS : 90%, MH+=293 Compound 103 was obtained following protocols described for Example 3, step 1 with 200mg (0.99mmol) of Compound 102, 107mg (0.99mmol) of phenylenediamine in 2 mL of ethanol yielding 192mg (66%) of an orange foam.
Step 4
Compound 104 : ll-(4-diisopropylamino-2-methoxy-phenyl)-3-(4-methyl-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000066_0003
MW : 509.70
Formula : C33H39N302
LCMS : 100%, MH+=510 Compound 104 was obtained following protocols described for Example 1 , step 3 with 50mg (0.17mmol) of Compound 103, 40mg (0.17mmol) of Compound 84 in ImL of EtOH yielding 30mg (35%) of a yellow oil. Example 59 : preparation of l l-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy- phenyl)- 1 -oxo- 1 ,2,3,4,5, 1 1 -hexahydro-dibenzo [b,e] [" 1 ,4]diazepine- 10-carboxylic acid isopropyl ester
Step 1
Compound 105 : ll-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-phenyI)-l- oxo-l,2,3,4,5,ll-hexahydro-dibenzo[b,e] [l,4]diazepine-10-carboxylic acid isopropyl
Figure imgf000067_0001
43μΙ, (0.31mmol) of isopropylchloroformate wad added to a solution of 150mg (0.29mmol) of Compound 85 with 72mg (0.86mmol) of sodium bicarbonate in ImL of water and ImL of THF. The reaction mixture was stirred at room temperature for 24h and it was then acidified with IN HC1. It was extracted with AcOEt, then the combined organic layers were dried over MgS04 and concentrated under vacuum. The residue was purified by silica gel flash chromatography (DCM/MeOH 95/5) to afford 23mg (13%) of Compound 105 as an orange solid. Example 60 : preparation of 1 l -(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy- phenvD-l-oxo-1 ,2, 3,4,5, l l -hexahvdro-dibenzo[b,e1[l ,4]diazepine-l 0-carboxylic acid ethylamide
Step l
Compound 106 . ll-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-phenyl)-l- oxo-l,2,3,4,5,ll-hexahydro-dibenzo[b,e] [l,4]diazepine-10-carboxylic acid ethylamide MW : 596.78
Formula : C36H44N404
LCMS : 96.1% MH+=597
1H NMR (250 MHz, DMSO-d6) δ ppm 8.93 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 8.5 Hz, 3H), 7.08-6.85 (m, 5H), 6.81-6.61 (m, 2H), 6.47-6.14 (m, 2H), 5.95 (m, 1H), 5.18 (m, 1H), 3.85-3.70 (m, 6H), 3.58 (m, 2H), 3.18-2.60 (m, 5H), 2.60-2.30 (m, 1H), 1.13-0.85 (m, 15H)
A mixture of 75μί (0.95mmol) of ethylisocyanate, lOOmg (0.19mmol) of Compound 85 and 0.25mL (1.78mmol) of triethylamine in lOmL of DCM was stirred at room temperature for 24h. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel flash chromatography (DCM/MeOH 95/5) to afford 29mg (26%) of Compound 106 as a brown solid. Example 61 : preparation of l l-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy- phenyl)- 1 -oxo- 1,2,3,4,5,11 -hexahydro-dibenzo[~b,el [ 1 ,4"]diazepine- 10-carboxylie acid methyl ester
Step 1
Compound 107 : ll-(4-Diisopropylamino-2-methoxy-phenyI)-3-(4-methoxy-phenyl)-l- oxo-l,2,3,4,5,ll-hexahydro-dibenzo[b,e] [l,4]diazepine-10-carboxylic acid methyl
Figure imgf000068_0001
MW : 583.73
Formula : C35H41N305
LCMS : 97.1% MH+=584
1H NMR (250 MHz, DMSO-d6) δ ppm 9.34-9.13 (m, 1H), 7.50-7.24 (m, 2H), 7.24-6.71 (m, 7H), 6.75-6.52 (m, 3H), 4.21-3.97 (m, 1H), 3.97-3.86 (m, 3H), 3.82-3.70 (m, 4H), 3.65-3.47 (m, 3H), 3.22-2.25 (m, 5H), 1.33-0.67 (m, 12H) Compound 107 was obtained following protocols described for Example 59, step 1 with 24μί (0.31mmol) of methyl chloroformate, 150mg (0.29mmol) of Compound 85, 72mg (0.86mmol) of sodium bicarbonate in lmL of water and lmL of THF. The residue was purified by silica gel flash chromatography (DCM/MeOH 95/5) to afford 35mg (21%) as an orange solid.
Example 62 : preparation of l l-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy- phenyl)-! -oxo- 1,2,3, 4,5,1 l-hexahvdro-dibenzoFb,ein ,4]diazepine-10-carboxylic acid iso- butyl ester
Step l Compound 108 : ll-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-phenyl)-l- oxo-l,2,3,4,5,ll-hexahydro-dibenzo[b,e] [l,4]diazepine-10-carboxylic acid iso-butyl
Figure imgf000069_0001
MW : 625.82
Formula : C38H47N305
LCMS : 100%, MH+=626
1H NMR (250 MHz, DMSO-d6) ppm 8.96 (m, 1H), 7.32 (t, 2H), 7.02-6.59 (m, 7H), 6.50- 6.15 (m, 2H), 5.99 (dd, 1H), 3.99-3.90 (m, 1H), 3.75 (2s, 6H), 3.65-3.49 (m, 3H), 3.10- 2.38 (m, 5H), 2.03-1.55 (m, 2H), 1.12-0,70 (m, 18H)
Compound 108 was obtained following protocols described for Example 59, step 1 with 55 iL (0.43mmol) of isobutyl chloroformate, 150mg (0.29mmol) of Compound 85, 72mg (0.86mmol) of sodium bicarbonate in ImL of water and ImL of THF. The residue was purified by silica gel flash chromatography (DCM/MeOH 98/2) to afford 72mg (40%) as a pink solid.
Example 63 : preparation of 11 -(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy- phenyl)- 1 -oxo- 1 ,2,3,4,5, 11 -hexahydro-dibenzo["b,e] 1 ,4]diazepine- 10-carboxylic acid benzyl ester
Step l
Compound 109 : ll-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-phenyI)-l- oxo-l,2,3,4,5,ll-hexahydro-dibenzo[b,e] [l,4]diazepine-10-carboxylic acid benzyl ester
Figure imgf000069_0002
MW : 659.83
Formula : C41H45N305
LCMS : 100%, MH+=660
1H NMR (250 MHz, DMSO-d6) ppm 9.05-8.55 (m, 1H), 7.50-7.21 (m, 7H), 7.08-6.58 (m, 7H), 6.46-6.20 (m, 2H), 5.93 (dd, 1H), 5.29-4.85 (m, 2H), 3.75-3.50 (m, 8H), 2.62-2.20 (m, 5H), 1.03 (2s, 12H) Compound 109 was obtained following protocols described for Example 59, step 1 with 55μL· (0.43mmol) of benzyl chloroformate, 150mg (0.29mmol) of Compound 85, 72mg (0.86mmol) of sodium bicarbonate in lmL of water and lmL of THF. The residue was purified by silica gel flash chromatography (DCM/MeOH 99/1) to afford 28mg (15%) as a yellow solid.
Example 64 : preparation of 1 l-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy- phenyl)-l-oxo-l ,2,3,4,5,l l-hexahydro-dibenzo b,eirL41diazepine-10-carboxylic acid 4- methoxy-benzylamide
Step 1
Compound 110 : ll-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-phenyl)-l- oxo-l,2,3,4,5,H-hexahydro-dibenzo[b,e][l,4]diazepine-10-carboxylic acid 4-methoxy- benzylamide
Figure imgf000070_0001
MW : 688.87
Formula : C42H48N405
LCMS : 92.2%, MH+=689
1H NMR (250 MHz, DMSO-d6) ppm 8.98 (bs, 1H), 7.36-7.32 (m, 2H), 7.14 (d, 2H), 7.10- 6.62 (m, 9H), 6.23-5.65 (m, 4H), 4.32-3.50 (m, 14H), 3.08-2.15 (m, 4H), 1.03 (2s, 12H)
Compound 110 was obtained following protocols described for Example 60, step 1 with 135μΙν (0.95mmol) of 4-Methoxybenzyl isocyanate, lOOmg (0.19mmol) of Compound 85, 0.25mL (1.78mmol) of triethylamine and lOmL of DCM. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel flash chromatography (DCM/MeOH 98/2) to afford 38mg (29%) as a brown solid.
Example 65 : preparation of l l-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-
Figure imgf000070_0002
methoxy-ethyl)-amide
Step 1
Compound 1 1 1 : ll-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-phenyl)-l- oxo-l,2,3,4,5,ll-hexahydro-dibenzo[b,e] [l,4]diazepine-10-carboxylic acid (2-methoxy- ethyl)-amide
Figure imgf000071_0001
MW : 626.80
Formula : C37H46N405
LCMS : 100%, MH+=627
1H NMR (250 MHz, DMSO-d6) ppm 8.96-8.93 (m, 1H), 7.33 (t, 2H), 7.10-6.55 (m, 7H), 6.42-5.80 (m, 6H), 5.20-5.15 (m, 1H), 3.74 (2s, 6H), 3.70-3.90 (m, 2H), 3.40-3.10 (m, 7H), 2.95-2.20 (m, 2H), 1.30-0.95 (m, 14H)
Compound 1 1 1 was obtained following protocols described for Example 60, step 1 with 96mg (0.95mmol) of 1 -Isocyanato-2-methoxyethane, 1 OOmg (0.1 mmol) of Compound 85, 0.25mL (1.78mmol) of triethylamine and lOmL of DCM. The reaction mixture was concentrated under vacuum and the residue was purified by silica gel flash chromatography (DCM/MeOH 99/1) to afford lOOmg (84%) as a solid. Example 66 : preparation of 1 l-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy- phenyiy 10-(tetrahydro-pyran-4-carbonyl)-2,3 ,4,5, 10 J 1 -hexahydro- dibenzo["b,e] 1 ,4]diazepin- 1 -one
Step 1
Compound 112 : ll-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-phenyl)- 10-(tetrahydro-pyran-4-carbonyl)-2,3,4,5,10,H-hexahydro-dibenzo[b,e][l,4]diazepin- 1-one
Figure imgf000071_0002
MW : 637.83
Formula : C39H47N305
LCMS : 100%; MH+=638
1H NMR (250 MHz, DMSO-d6) ppm 8.98 (s, 1H), 7.33 (d, 2H), 7 '.20-6.66 (m, 7H), 6.38 (d, 1H), 6.34-6.22 (m, 1H), 6.01 (dd, 1H), 3.86-3.50 (m, 10H), 3.25-2.30 (7H), 2.05-1.10 (m, 5H), 1.08-1.00 (m, 12H). ΙΟΟμΙ. (0.56mmol) of DIPEA and 50mg (0.34mmol) of Tetrahydro-2H-pyran-4-carbonyl chloride were added to an inerted solution of 150mg (0.28mmol) of Compound 85 in 2mL of anhydrous DCM. The reaction mixture was stirred at room temperature overnight and then partitioned between water and DCM. The combined organic layers were dried over MgS04 and concentrated under vacuum. The residue was purified by silica gel flash chromatography (DCM/MeOH 98/2) to afford 65mg (36%) of Compound 112 as a brown solid.
Example 67 : preparation of l l-(4-Diisopropylamino-2-methoxy-phenyl)-10- methanesulfonyl-3-(4-methoxy-phenyl)-2,3,4,5J0,l l-hexahydro- dibenzo b,e] [ 1 ,4] diazepin- 1 -one
Step 1
Compound 113 : ll-(4-Diisopropylamino-2-methoxy-phenyl)-10-methanesulfonyl-3-(4- methoxy-phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000072_0001
MW : 603.79
Formula : C34H41N305S
LCMS : 88.6%, MH+=604
17mg (0.43mmol) of sodium hydride was added to an inerted solution of 150mg (0.28mmol) of Compound 85 in 2mL of anhydrous DMF cooled to 0°C. The reaction mixture was stirred at 0°C for lh30 then 26μΙ, (0.34mmol) of methanesulfonyl chloride was added. It was stirred at room temperature overnight and then partitioned between water and AcOEt. The combined organic layers were dried over MgS04 and concentrated under vacuum. The residue was purified by silica gel flash chromatography (DCM/MeOH 95/5) to afford lOmg (6%) of Compound 113. Example 68 : preparation of 10-Acetyl-3-(4-methoxy-phenyl)-l 1 -(4-(2 -methyl - pyrrolidine)phenyl)-2,3,4,5,10,l l-hexahydro-dibenzo[b,el l,41diazepin-l-one
Step 1
Compound 114 : 2-methyl-pyrrolidine-phenyl
Figure imgf000072_0002
MW : 161.25
Formula : CI 1H15N
LCMS : 74%, MH+=162
RMN : 1H NMR (250 MHz, DMSO-d6) δ ppm 7.30-7.15 (m, 2H), 6.90-6.50 (m, 3H), 3.95-3.79 (m, 1H), 3.43 (q, J = 7.0 Hz, 2H), 2.18-1.81 (m, 3H), 1.78-1.55 (m, 1H), 1.15- 0.97 (m, 3H) A mixture of lmL (10.97mmol) of aniline with 1.5mL (10.97mmol) of 1,4- Dibromopentane and 1.5g (10.97mmol) of potassium carbonate in 5mL of DMF was stirred at room temperature overnight. It was partitioned between water and DCM, the combined organic layers were dried over MgS04 and concentrated under vacuum to afford 1.55g (85%) of Compound 1 14.
Step 2
Compound 115 : 4-(2-methyl-pyrroIidine)-benzaldehyde
Figure imgf000073_0001
MW : 189.26
Formula : CI 2H15NO
LCMS : 96.8% MH+=190
1H NMR (250 MHz, DMSO-d6) δ ppm 9.63 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H), 4.03 ( p, J = 6.1 Hz, 1H), 3.50-3.40 (m, 1H), 3.28-3.14 (m, 1H), 2.21-1.90 (m, 3H), 1.80-1.59 (m, 1H), 1.12 (d, J = 6.3 Hz, 3H)
Compound 115 was obtained following protocols described for Example 25, stepl with 1.3mL (H.Ommol) of POC13, 35mL of DMF and 1.50mg (9.30mmol) of Compound 1 14. The residue was purified by silica gel flash chromatography (Petroleum ether/AcOEt 90/10) yielding 592mg (33%) as an oil.
Step 3
Compound 1 16 : 3-(4-methoxy-phenyl)-ll-(4-(2-methyl-pyrrolidine)phi
2,3,4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000073_0002
MW : 479.63
Formula : C31H33N302
LCMS : 97.7%, MH+=480
1H NMR (250 MHz, DMSO-d6) δ ppm 8.79-8.62 (m, 1H), 7.43-7.22 (m, 2H), 7.00-6.75 (m, 5H), 6.70-6.45 (m, 3H), 6.37-6.00 (m, 3H), 5.74-5.47 (m, 1H), 3.75 (s, 3H), 3.48-3.10 (m, 4H), 3.07-2.74 (m, 3H), 2.70-2.25 (m, 1H), 2.07-1.77 (m, 3H), 1.66-1.46 (m, 1H), 1.15-0.96 (m, 3H) Compound 116 was obtained following protocols described for Example 1, step 3 with lOOmg (0.32mmol) of Compound 2, 62mg (0.32mmol) of Compound 1 15 in 2mL of EtOH. The residue was purified by silica gel chromatography (DCM/EtOH 98/2) yielding 61mg (39%) of a beige solid.
Step 4
Compound 117 : 10-Acetyl-3-(4-methoxy-phenyl)-ll-(4-(2-methyl- pyrrolidine)phenyl)-2,3,4,5, 10, 11-hexahydro-dibenzo [b,e] [1,4] diazepin-l-one
Figure imgf000074_0001
MW : 521.67
Formula : C33H35N303
LCMS : 98%, MH+=521
1H NMR (250 MHz, DMSO-d6) δ ppm 9.04 (bs, 1H), 7.44-7.28 (m, 2H), 7.26-7.18 (m, 1H), 7.12-7.04 (m, 2H), 7.02-6.60 (m, 6H), 6.34-6.13 (m, 1H), 3.74 (s, 3H), 3.42-3.15 (m, 4H), 3.11-2.56 (m, 4H), 2.47-2.12 (m, 2H), 2.02-1.55 (m, 6H), 1.12-0.95 (m, 3H)
Compound 117 was obtained following protocols described for Example 3, step 3 with 55mg (O.l lmmol) of Compound 116, 29μί (0.23mmol) of anhydride acetic, 38μΙ. (0.46mmol) of pyridine in lmL of DCM yielding 38mg (65%) of a beige solid.
Example 69 : preparation of 10-Acetyl-3-(4-methoxy-phenyl)-l l-(4-piperidin-l-yl- phenyl)-2,3 ,4,5, 10 J 1 -hexahydro-dibenzo|"b,el [ 1 ,41diazepin- 1 -one
Step 1
Compound 118 : 3-(4-Methoxy-phenyl)-ll-(4-piperidin-l-yl-phenyl)-2,3,4,5,10,ll- hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000074_0002
MW : 479.63
Formula : C31H33N302
LCMS : 98.1% MH+=480
1H NMR (250 MHz, DMSO-d6) δ ppm 9.56-9.35 (m, 1H), 7.75-7.45 (m, 2H), 7.45-7.19 (m, 5H), 7.17-7.04 (m, 1H), 7.01 -6.63 (m, 5H), 6.06-5.81 (m, 1H), 4.00-3.25 (m, 7H), 3.21-2.82 (m, 4H), 2.70-2.30 (m, 1H), 2.03-1.74 (m, 4H), 1.70-1.34 (m, 2H) Compound 1 18 was obtained following protocols described for Example 1, step 3 with 200mg (0.65mmol) of Compound 2, 122mg (0.65mmol) of 4-(l-Piperidinyl)benzaldehyde in 4mL of EtOH yielding 277mg (89%) of a beige solid.
Step 2
Compound 1 19 : 10-AcetyI-3-(4-methoxy-phenyl)-ll-(4-piperidin-l-yl-phenyl)- 2,3,4,5,10,11- hexahy dr o-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
Figure imgf000075_0001
MW : 521.67
Formula : C33H35N303
LCMS 100% MH+=522
1H NMR (250 MHz, DMSO-d6) ppm 9.38-9.18 (m, 1H), 7.50-7.30 (m, 4H), 7.28-6.75 (m, 9H), 3.75 (s, 3H), 3.30-2.75 (m, 4H), 2.70-2.00 (m, 5H), 1.83 (s, 3H), 1.80-1.40 (m, 6H)
Compound 119 was obtained following protocols described for Example 3, step 3 with 277mg (0.58mmol) of Compound 118, 71 μΕ (0.58mmol) of anhydride acetic, 94μΕ (1.15mmol) of pyridine in l OmL of DCM. The residue was purified by silica gel flash chromatography (DCM/EtOH 95/5) yielding 149mg (49%) of a beige solid.
Example 70 : preparation of 10-Acetyl-3-(4-methoxy-phenyl)-l l-(2-methyl-4-piperidin-l- yl-phenyl)-2,3,4,5,10,l l-hexahydro-dibenzo b,e1 l,4]diazepin-l-one
Step 1
Compound 120 : l-piperidine-3-methyl-phenyl
Figure imgf000075_0002
MW : 175.28
Formula : CI 2H17N
LCMS : 94.0%, MH+=1760
1H NMR (250 MHz, DMSO-d6) ppm 7.75-7.35 (m, 4H), 3.72-3.58 (m, 4H), 2.63 (s, 3H), 2.15-1.95 (m, 4H), 1.92-1.63 (m, 1H)
Compound 120 was obtained following protocols described for Example 68, step 1 with lmL (9.24mmol) of m-Toluidine, 1.3mL (9.24mmol) of 1,5-dibromopentane and 1.28g (9.24mmol) of potassium carbonate in 5mL of DMF. After the work-up, it was triturated with a mixture of EtOH and Et20 to afford 970mg (60%) as a solid. Step 2
Compound 121 : 2-methyI-4-piperidine-benzaldehyde
Figure imgf000076_0001
MW : 203.29
Formula : C13H17NO
LCMS : 100%, MH+=204
1H NMR (250 MHz, DMSO-d6) ppm 9.88 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 6.84 (dd, J = 8.8, 2.6 Hz, 1H), 6.76 (fd, J = 2.3 Hz, 1H), 3.44-3.37 (m, 4H), 2.52 (s, 3H), 1.65-1.50 (m, 6H)
Compound 121 was obtained following protocols described for Example 25, stepl with 766μί (8.22mmol) of POC13, 20mL of DMF and 960mg (5.48mmol) of Compound 120. The residue was purified by silica gel flash chromatography (Petroleum ether/AcOEt 95/5) yielding 137mg (12%) as an oil.
Step 3
Compound 122 : 3-(4-methoxy-phenyl)-ll-(2-methyl-4-piperidin-l-yl-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000076_0002
MW : 493.65
Formula : C32H35N302
LCMS : 95.4, MH+=494
1H NMR (250 MHz, DMSO-d6) δ ppm 9.48 (bs, 1H), 7.74-6.40 (m, 12H), 6.17-5.86 (m, 1H), 5.36-4.16 (m, 2H), 3.74 (s, 3H), 3.57-3.20 (m, 5H), 3.16-2.82 (m, 2H), 2.70-2.30 (m, 2H), 2.22-1.35 (m, 6H), 1.17-0.94 (m, 1H)
Compound 122 was obtained following protocols described Example 1, step 3 with lOOmg (0.32mmol) of Compound 2, 66mg (0.32mmol) of Compound 121 in 2mL of EtOH yielding 137mg (85%) of a beige solid.
Step 4
Compound 123 : 10-Acetyl-3-(4-methoxy-phenyI)-ll-(2-methyl-4-piperidin-l-yl- phenyl)-2,3,4,5, 10, 11-hexahydro-dibenzo [b,e] [1,4] diazepin-l-one
Figure imgf000077_0001
MW : 535.69
Formula : C34H37N303
LCMS : 100%, MH+=536
1H NMR (250 MHz, DMSO-d6) δ ppm 9.14-9.01 (m, 1H), 7.42-7.29 (m, 2H), 7.23-7.00 (m, 3H), 6.89 (d, J = 8.6 Hz, 2H), 6.84-6.68 (m, 2H), 6.67-6.55 (m, 1H), 6.55-6.16 (m, 2H), 3.74 (s, 3H), 3.15-2.73 (m, 6H), 2.66-2.33 (m, 3H), 2.26 (d, J = 2.0 Hz, 3H), 1.74 (d, J = 2.7 Hz, 3H), 1.57-1.40 (m, 6H) Compound 123 was obtained following protocols described for Example 3, step 3 with 65mg (0.13mmol) of Compound 122, 33μΙ. (0.26mmol) of anhydride acetic, 43 μL (0.52mmol) of pyridine in lmL of DCM yielding 40mg (57%) of a solid.
Example 71 : preparation of 3-(4-Methoxy-phenyl l l-(2-methoxy-4-piperidin-l-yl- phenvn-2,3A5,10
, 11 -hexahydro-dibenzo [~b,e] 1 ,4]diazepin- 1 -one
Step l
Compound 124 : l-piperidine-3-methoxy-phenyl
Figure imgf000077_0002
MW : 191.28
Formula : C12H17NO
LCMS : 100%, MH+=192
Compound 124 was obtained following protocols described for Example 68, step 1 with lmL (8.95mmol) of m-Anisidine, 1.2mL (8.95mmol) of 1,5-dibromopentane and 1.23g (8.95mmol) of potassium carbonate in 5mL of DMF. The residue was purified by silica gel flash chromatography (petroleum ether/AcOEt 98/2) to afford 970mg (57%) as a solid.
Step 2
Compound 125 : 2-methoxy-4-piperidine-benzaldehyde
Figure imgf000078_0001
MW : 219.29
Formula : C13H17N02
LCMS : 60%, MH+=220
Compound 125 was obtained following protocols described for Example 25, stepl with Ί Ι ΟμΙ, (7.60mmol) of POC13, 15mL of DMF and 970mg (5.07mmol) of Compound 124. The residue was purified by silica gel flash chromatography (Petroleum ether/ AcOEt 95/5) yielding 930mg (84%) as an oil.
Step 3
Compound 126 : 3-(4-Methoxy-phenyl)-ll-(2-methoxy-4-piperidin-l-yI-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000078_0002
MW : 509.65
Formula : C32H35N303
LCMS : 92%, MH+=510
Compound 126 was obtained following protocols described for Example 1 , step 3 with l OOmg (0.32mmol) of Compound 2, 71mg (0.32mmol) of Compound 125 in 4mL of EtOH yielding 51mg (31%) of a beige solid.
Example 72 : 10-Acetyl-3-(4-methoxy-phenyl)-l l -(2-methoxy-4-piperidin- l-yl-phenyl)- 2,3,4,5,10,1 1 -hexahydro-dibenzo["b,e~||T ,4]diazepin-l -one
Step 1
Compound 127 : 10-Acetyl-3-(4-methoxy-phenyl)-ll-(2-methoxy-4-piperidin-l-yl- phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000079_0001
MW : 551.69
Formula : C34H37N304
LCMS : 92.4%, MH+= 552
1H NMR (250 MHz, DMSO-d6) δ ppm 9.23-8.96 (m, 1H), 7.47-7.26 (m, 2H), 7.25-6.85 (m, 5H), 6.83-6.55 (m, 2H), 6.53-6.19 (m, 2H), 6.13-5.92 (m, 1H), 3.89-3.68 (m, 6H), 3.10-2.55 (m, 7H), 2.42-2.05 (m, 2H), 1.95 -1.72 (m, 3H), 1.6-1.3 (m, 6H) Compound 127 was obtained following protocols described for Example 3, step 3 with 43mg (0.08mmol) of Compound 126, 21 μΙ, (0.17mmol) of anhydride acetic, 28μΙ^ (0.34mmol) of pyridine in 2mL of DCM yielding 30mg (65%) of a beige solid.
Example 73 : preparation of l l- 2-methoxy-4-(2-methyl-piperidin-l -yl)-phenyl1-3-(4- methoxy-phenyl)-2,3 ,4,5, 10, 1 1 -hexahydro-dibenzo b,e1 [" 1 ,4]diazepin- 1 -one
Step 1
Compound 128 : l-(2-methyl-piperidine)-3-methoxy-phenyl
Figure imgf000079_0002
MW : 205.30
Formula : CI 3H19NO
LCMS : 96%, MH+=206
1H NMR (250 MHz, CDC13) δ ppm 7.15 (d, J = 8.0 Hz, 1H), 6.67-6.29 (m, 3H), 4.05-3.85 (m, 1H), 3.79 (s, 3H), 3.34-3.13 (m, 1H), 3.10-2.81 (m, 1H), 1.95-1.50 (m, 6H), 1.01 (d, J = 6.3 Hz, 3H)
Compound 128 was obtained following protocols described for Example 46, step 2 with 547mg (2.13mmol) of Compound 82, 1.60mL of nBuLi 2M in hexane, 2.51mL (21.35mmol) of 2-methylpiperidine and 30mL of anhydrous THF. The residue was purified by silica gel flash chromatography (petroleum ether/ AcOEt 95/5) yielding 199mg (45%) of an oil.
Step 2
Compound 129 : 2-methoxy-4-(2-methyl-piperidine) benzaldehyde
Figure imgf000080_0001
MW : 233.31
Formula : CI 4H19N02
LCMS : 93.2%, MH+=234
1H NMR (250 MHz, DMSO-d6) δ ppm 10.01 (s, 1H), 7.50 (d, J = 9.0 Hz, 1H), 6.55 (dd, J = 9.1, 1.8 Hz, 1H), 6.39 (fd, J = 2.2 Hz, 1H), 4.47-4.24 (m, 1H), 3.87 (s, 3H), 3.79-3.66 (m, 1H), 3.05-2.87 (m, 1H), 1.72-1.38 (m, 6H), 1.10 (d, J = 6.8 Hz, 3H)
Compound 129 was obtained following protocols described for Example 25, stepl with 130pL (1.45mmol) of POC13, 3mL of DMF and 198mg (0.97mmol) of Compound 128. The residue was purified by silica gel flash chromatography (Petroleum ether/AcOEt 95/5) yielding 220mg (98%) as an orange oil.
Step 3
Compound 130 : ll-[2-methoxy-4-(2-methyl-piperidin-l-yl)-phenyl]-3-(4-methoxy- phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000080_0002
MW : 523.68
Formula : C33H37N303
LCMS : 98%, MH+=524
1H NMR (250 MHz, DMSO-d6) δ ppm 8.82 (s, 1H), 7.31 (t, J = 8.5 Hz, 2H), 6.95-6.83 (m, 3H), 6.64-6.50 (m, 2H), 6.50-6.36 (m, 1H), 6.37-6.22 (m, 1H), 6.18-5.80 (m, 1H), 5.81-5.70 (m, 1H), 5.37-5.22 (m, 1H), 3.96-3.80 (m, 4H), 3.75 (s, 3H), 3.25-2.25 (m, 6H), 1.75-1.30 (m, 6H), 0.88-0.78 (m, 3H)
Compound 130 was obtained following protocols described for Example 1, step 3 with 236mg (0.76mmol) of Compound 2, 215mg (0.92mmol) of Compound 129 in 6mL of EtOH. The residue was purified by silica gel chromatography (DCM/MeOH 98/2) yielding 281mg (70%) of an orange foam. Example 74 : preparation of 10- Acetyl- 1 l-|"2-methoxy-4-(2 -methyl-piperidin- 1 -ylV phenyl]-3-(4-methoxy-phenyl)-2,3,4,5J 0, 11 -hexahydro-dibenzo b,e1 1 ,4]diazepin- 1 -one Step 1
hoxy-4-(2-methyl-piperidin-l-yl)-phenyl]-3-(4- methoxy-phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000081_0001
MW : 565.72
Formula : C35H39N304
LCMS : 94.4% MH+=566
1H NMR (250 MHz, DMSO-d6) δ ppm 9.23-8.94 (m, 1H), 7.45-7.26 (m, 2H), 7.24-6.84 (m, 5H), 6.84-6.56 (m, 2H), 6.56-6.17 (m, 2H), 6.16-5.85 (m, 1H), 3.98-3.67 (m, 8H), 3.21-2.59 (m, 5H), 2.44-2.26 (m, 1H), 2.23-2.06 (m, 1H), 1.82-1.50 (m, 4H), 1.50-1.32 (m, 4H), 0.78 (d, J = 6.2 Hz, 3H)
Compound 131 was obtained following protocols described for Example 3, step 3 with 262mg (0.50mmol) of Compound 130, 94μΙ. (l .OOmmol) of anhydride acetic, 160μΙν (2.00mmol) of pyridine in 4mL of DCM yielding 246mg (87%) of a yellow foam.
Example 75 : preparation of l l-[2-methoxy-4-(2,6-dimethyl-piperidin-l-yl)-phenyl1-3-(4- methoxy-phenyD-2,3,4,5 Λ 0,11 -hexahydro-dibenzorb,e] 1 ,4]diazepin- 1 -one
Step l
132 : l-(2,6-dimethyl-piperidine)-3-methoxy-phenyl
Figure imgf000081_0002
MW : 219.33
Formula : C14H21NO
LCMS : 76.1%, MH+=220
Compound 132 was obtained following protocols described for Example 46, step 2 with 500mg (1.95mmol) of Compound 82, 1.95mL of nBuLi 2M in hexane, 2.21g (19.5mmol) of cis-2,6-dimethylpiperidine and 30mL of anhydrous THF. The residue was purified by silica gel flash chromatography (petroleum ether/AcOEt 98/2) yielding 64mg (15%) as an oil. Step 2
Compound 133 : 2-methoxy-4-(2,6-dimethyI-piperidine) benzaldehyde
Figure imgf000082_0001
MW : 247.34
Formula : CI 5H21N02
LCMS : 62.7%, MH+=248
1H NMR (250 MHz, DMSO-d6) δ ppm 10.01 (s, 1H), 7.59-7.46 (m, 1H), 6.40-6.25 (m, 1H), 6.57-6.50 (m, 1H), 4.32-4.19 (m, 2H), 3.87 (s, 3H), 2.32-1.90 (m, 2H), 1.76-1.64 (m, 4H), 1.16 (d, J = 6.8 Hz, 6H),
Compound 133 was obtained following protocols described for Example 25, stepl with 41 (0.44mmol) of POC13, 2mL of DMF and 64mg (0.29mmol) of Compound 132 yielding 65mg (90%) as an oil.
Step 3
Compound 134 : ll-[2-methoxy-4-(2,6-dimethyl-piperidin-l-yl)-phenyl]-3-(4-methoxy- phenyl)-2,3,4,5,10,l 1-hexahydro-dibenzo [b,e] [1,4] diazepin-l-one
Figure imgf000082_0002
MW : 537.71
Formula : C34H39N303
LCMS : 86.8%, MH+=538 Compound 134 was obtained following protocols described for Example 1, step 3 with 62mg (0.20mmol) of Compound 2, 50mg (0.20mmol) of Compound 133 in 2mL of EtOH. The residue was purified by silica gel flash chromatography (DCM/EtOH 95/5) yielding 15mg (14%) of a beige solid. Example 76 : preparation of 10-Acetyl-l l- 2-methoxy-4-(2,6-dimethyl-piperidin-l-yl)- phenyl]-3-(4-methoxy-phenyl)-2,3A5J0,l l-hexahydro-dibenzol"b,e"[[T,4]diazepin-l-one Step l
Compound 135 : 10-Acetyl-ll-[2-methoxy-4-(2,6-dimethyl-piperidin-l-yl)-phenyl]-3- (4-methoxy-phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000083_0001
MW : 579.75
Formula : C34H39N303
LCMS : 88.0% MH+=580
Compound 135 was obtained following protocols described for Example 3, step 3 with 14mg (0.02mmol) of Compound 134, 7μΙ_ (0.05mmol) of anhydride acetic, 9μΙ. (O.lOmmol) of pyridine in 1.5mL of DCM yielding 7mg (50%) of a solid. Example 77 : preparation of l l- 4-(2,5-Dimethyl-pyrrol-l-yl)-2-methoxy-phenyl1-3-(4- methoxy-phenyl)-2, 3,4,5, 10, 1 1 -hexahvdro-dibenzorb,e"ir 1 ,41diazepin-l -one
Step l
Compound 136 : methyl 2-methoxy-4-(2,5-dimethyl-pyrrole)-benzoate
Figure imgf000083_0002
MW : 259.31
Formula : CI 5H17N03
LCMS : 96.7% MH+=260
1H NMR (250 MHz, CDC13) ppm 7.88 (d, J
2H), 3.93 (s, 3H); 3.89 (s, 3H), 2.06 (s, 6H)
A mixture of 1.25g (6.90mmol) of Methyl 4-amino-2-methoxybenzoate with 0.89mL (7.60mmol) of 2,5-hexanedione in 13mL of acetic acid was refluxed overnight. It was partitioned between water and DCM, and then the combined organic layers were dried over MgS04 and concentrated under vacuum. The residue was purified by silica gel flash chromatography (petroleum ether/ AcOEt 90/10) to afford 970mg (54%) of Compound 136 as a brown oil.
Step 2
Compound 137 : 2-methoxy-4-(2,5-dimethyl-pyrroIe)-benzylalcohol
Figure imgf000084_0001
MW : 231.30
Formula : CI 4H17N02
LCMS : 95.7%, MH+=232
1H NMR (250 MHz, CDC13) ppm 7.37 (d, J = 7.8 Hz, 1H), 6.82 (dd, J = 7.8, 1.9 Hz, 1H), 6.73 (fd, J = 1.8 Hz, 1H), 5.99-5.81 (m, 1H), 4.74 (s, 2H), 3.86 (s, 3H), 2.03 (s, 6H)
2.17ml (4.34mmol) of LiAlH4 2M in THF were added to an inerted solution of 450mg (1.73mmol) of Compound 136 in lOmL of anhydrous THF cooled to 0°C. It was then stirred at room temperature for 2h and the reaction mixture was quenched with water and ice. It was partitioned between a saturated solution of sodium sulfate and AcOEt and then the combined organic layers were dried over MgS04 and concentrated under vacuum. The residue was purified by silica gel flash chromatography (petroleum ether/ AcOEt 90/10) to afford 381mg (95%) of Compound 137 as a brown oil.
Step 2
Compound 138 : 2-methoxy-4-(2,5-dimethyl-pyrrole)-benzaIdehyde
Figure imgf000084_0002
MW : 229.28
Formula : CI 4H15N02
LCMS : 98.2%, MH+=230
A mixture of 63mg (0.27mmol) of Compound 137 with 251mg (2.89mmol) of Mn02 in 8mL of chloroform was refluxed for 2h. The reaction mixture was then filtrated and the filtrate was concentrated under vacuum. The residue was then purified by silica gel flash chromatography (petroleum ether/AcOEt 98/2) to afford 21mg (34%) of Compound 138 as a white solid.
Step 3
Compound 139 : ll-[4-(2,5-Dimethyl-pyrrol-l-yl)-2-methoxy-phenyI]-3-(4-methoxy- phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000085_0001
MW : 519.65
Formula : C33H33N303
LCMS : 94.9, MH+=520
1H NMR (250 MHz, DMSO-d6) ppm 8.95 (s,lH), 7.33 (t, 2H), 6.94-6.88 (m, 3H), 6.69- 6.30 (m, 7H), 5.93 (d, 1H), 5.69 (s, 2H), 5.50-5.40 (m, 1H), 3.92 (s, 3H), 3.74 (s, 3H), 3.37-3.28 (m, 2H), 3.25-2.40 (m, 4H), 1.79 (s, 6H).
Compound 139 was obtained following protocols described for Example 1, step 3 with 121mg (0.39mmol) of Compound 2, 90mg (0.39mmol) of Compound 138 in 2mL of EtOH. The residue was purified by silica gel chromatography (DCM/AcOEt 80/20) yielding 52mg (25%) of a beige solid.
Example 78 : preparation of 10- Acetyl- 1 l -(4-Isopropoxy-phenyl)-3-(4-methoxy-phenyl)- 2,3, 4,5, 10,11 -hexahydro-dibenzo["b,e1 |" 1 ,4] diazepin- 1 -one
Step 1
Compound 140 : 4-Isopropoxy-2-methoxy-benzaldehyde
Figure imgf000085_0002
MW : 194.23
Formula : CI 1H1403
LCMS : 100%, MH+=195
Compound 140 was obtained following protocols described for Example 54, stepl with 500mg (3.29mmol) of 4-Hydroxy-2-methoxybenzaldehyde, 360μΕ (3.61mmol) of 2- iodopropane, 1.13g (8.23mmol) of potassium carbonate in 6mL of DMF yielding 660mg (100%) as an orange oil.
Step 2
Compound 141 : ll-(2-methoxy-4-isopropoxy-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000086_0001
MW : 454.57
Formula : C29H30N2O3
LCMS : 44.7+55.3%, MH+=485, RT=4.19+4.33
RMN : 1H NMR (250 MHz, DMSO-d6) 5 ppm 7.34 (t, J = 9.2 Hz, 2H), 7.22-7.08 (m, 1H), 6.93 (dd, J = 8.7 Hz, 3H), 6.82-6.70 (m, 2H), 6.65-6.54 (m, 1H), 6.39-6.00 (m, 4H), 4.57- 4.37 (m, 1H), 3.92-3.87 (m, 3H), 3.75 (d, J = 1.32 Hz, 3H), 3.48-3.38 (m, 2H), 3.30-2.86 (m, 2H), 2.76-2.53 (m, 1H), 1.18-1.13 (m, 6H) Compound 141 was obtained following protocols described for Example 1, step 3 with lOOmg (0.32mmol) of Compound 2, 63mg (0.32mmol) of Compound 140 in lmL of EtOH yielding 277mg (89%) of a beige solid.
Step 3
Compound 142 : 10-Acetyl-ll-(2-methoxy-4-isopropoxy-phenyI)-3-(4-methoxy- phenyl)-2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000086_0002
MW : 526.64
Formula : C32H34N205
LCMS : 96%, MH+=527
RMN : 1H NMR (250 MHz, DMSO-d6) δ ppm 9.05 (bs, 1H), 7.40-7.30 (m, 2H), 7.20-5.95 (m, 9H), 4.57-4.37 (m, 1H), 3.86-3.70 (m, 6H), 3.34 (s, 3H), 3.15-2.55 (m, 3H), 2.25-2.10 (m, 2H), 1.75-1.68 (m, 1H), 1.18-1.13 (m, 6H) Compound 142 was obtained following protocols described for Example 3, step 3 with 120mg (0.25mmol) of Compound 141, 47μΙ. (0.50mmol) of anhydride acetic, 81 μΕ (l .OOmmol) of pyridine in 3mL of DCM. The residue was purified by silica gel flash chromatography yielding 113mg (87%) of a beige solid. Example 79 : l l-(2-methoxy-5-isopropyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l l- hexahvdro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
Step 1 Compound 143 : ll-(2-methoxy-5-isopropyl-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000087_0001
MW : 468.60
Formula : C30H32N2O3
LCMS : 100%, MH+=469
1H NMR (250 MHz, DMSO-d6) δ ppm 9.77-9.43 (m, 1H), 7.46-6.05 (m, 12H), 3.95-3.60 (m, 7H), 3.54-2.55 (m, 6H), 1.08-0.60 (m, 6H) Compound 143 was obtained following protocols described for Example 1, step 3 with 70mg (0.23mmol) of Compound 2, 41mg (0.23mmol) of 5-Isopropyl-2- methoxybenzaldehyde in 2mL of EtOH yielding 63mg (59%) of a beige solid.
Example 80 : preparation of 10- Acetyl- 1 l-(2-methoxy-5-isopropyl-phenyl)-3-(4-methoxy- phenvD-2,3,4,5, 10, 11 -hexahydro-dibenzo [~b,e] 1 ,4]diazepin- 1 -one
Step 1
Compound 144 : 10-Acetyl-ll-(2-methoxy-5-isopropyl-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
Figure imgf000087_0002
MW : 510.64
Formula : C32H34N204
LCMS : 100%, MH+=51 1
1H NMR (250 MHz, DMSO-d6) δ ppm 9.29-9.18 (m, 1H), 7.43-7.18 (m, 4H), 7.12-6.40 (m, 7H), 6.29-6.18 (m, 1H), 3.88-3.72 (m, 7H), 3.20-2.17 (m, 5H), 1.74 (s, 3H), 0.98-0.71 (m, 6H)
Compound 144 was obtained following protocols described for Example 3, step 3 with 260mg (0.56mmol) of Compound 143, 139μί (l .l lmmol) of anhydride acetic, 181 μΙ. (2.22mmol) of pyridine in 9mL of DCM. The residue was purified by silica gel flash chromatography yielding 178mg (63%) of a beige solid.
Example 81 : preparation of 10- Acetyl- 1 l-(2-methoxy-5 -isopropyl-phenyl -3 -(4-hydroxy- phenyD-2,3 ,4,5 , 10, 11 -hexahydro-dibenzo b,e] \ 1 ,41 diazepin- 1 -one
Step 1 Compound 145 : 10-Acetyl-ll-(2-methoxy-5-isopropyl-phenyl)-3-(4-hydroxy-phenyl)- 2,3,4,5,10,ll-hexahydro-dibenzo[b,e] [l,4]diazepin-l-one
Figure imgf000088_0001
MW : 496.61
Formula : C31H32N204
LCMS : 84.8%, MH+= 497;
1H NMR (250 MHz, DMSO-d6) δ ppm 9.35-9.04 (m, 2H), 7.76-7.65 (m, 1H), 7.35-6.35 (m, 12H), 3.87-3.75 (m, 3H), 3.30-2.06 (m, 5H), 1.74 (s, 3H), 1.00-0.60 (m, 6H) Compound 145 was obtained following protocols described for Example 10, step 1 with 30mg (0.06mmol) of Compound 144, 176μί (0.18mmol) of boron tribromide 1M in ImL of DCM. After the work-up, the residue was purified by silica gel flash chromatography (DCM/EtOH 98/2) to afford 8mg (27%) of a solid. Example 82 : In vitro activity of novel compounds
Inhibition of the enzymatic activity of EC 4.2.1.22 was assessed according to the method disclosed in WO 2010/072807.
Figure imgf000088_0002
Figure imgf000089_0001
Figure imgf000090_0001
63 61.4
65 18 29
66 48
67 50.4
68 42.8
69 22.5
70 25
72 50.3
73 64.6
75 57.5 80
76 70.6 85.9
77 67.5 85
79 79.9
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
94
Figure imgf000095_0001
REFERENCES
- CHADEFAUX et al. Cystathionine beta synthase: gene dosage effect in trisomy 21. Biochemical and Biophysical Research Communications, vol. 128 n° 1, 1985, 40-44
- CHEN et al, J. Biol. Chem, 2004, 279
- ICHINOHE et al. Cystathionine β-synthase is enriched in the brains of Down 's patients. Biochemical and Biophysical Research Communications 338 (2005) 1547- 1550
- KAMOUN, Pierre. H2S, un nouveau neuromodulateur. Medecine/Sciences. Juin-Juillet 2004, vol. 20, n° 6-7, P. 697-700
- KIMURA. Hydrogen Sulfide as a Neuromodulator. Molecular Neurobiology, vol. 6, 13- 19 (2002)
- LEJEUNE Jerome. Reflexion sur la debilite de V intelligence des enfants trisomiques 21. Commentarii vol. III. n° 9, pages 1-12
- POGRIBNA et al. Homocysteine Metabolism in Children with down Syndrome: In Vitro Modulation. Am. J. Hum. Genet. 69:88-95, 2001 ; Endogenous Hydrogen Sulfide Overproduction in Down Syndrome. American Journal of Medical Genetics 116A 310- 311 (2003)

Claims

Compound having the formula (I) :
Figure imgf000097_0001
Formula (I)
wherein
- Ri, R2 and R3 represent independently H, an halogen atom, -Ra, -ORa, -NHRa, or - NRaRb, with
o Ra and Rb representing independently H, (Ci-C6)alkyl, -CO(Ci-C6)alkyl, or o Ra and Rb represent together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring and optionally an oxygen atom in the ring, i.e. a morpholin,
- R4 represents
o H,
o a (Ci-C3)alkyl, in particular -CH3, -C2H5, and -CH(CH3)2,
o -CORdi with Rdi representing a (Ci-C3)alkyl, in particular -CH3, -C2H5, and
-CH(CH3)2, a saturated heterocyclic group or -CX3 with X representing a halogen,
o -COORd2 with Rd2 representing a (Ci-C4)alkyl, in particular -CH3, -C2H5, -
CH(CH3)2 and -CH2-CH(CH3)2, or an aryl, in particular a phenyl, a benzyl radical, a substituted benzyl radical,
o -CONHRd3, with Rd3 representing a (Ci-C3)alkyl, in particular -CH3, -C2H5 and -CH(CH3)2, or -CH2-CH2-0-CH3, or
o -S02Rd4, with Rd4 representing a (Ci-C3)alkyl, in particular -CH3, -C2H5, and -CH(CH3)2,
- R5 represents (C C6)alkyl, -ORe, -NHRe, -N(Re)2 or -NReRf, with
o Re and Rf representing independently a (C2-C3)alkyl or -CO(C!-C2)alkyl, or o Re and Rf representing together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, i.e. a pyrrolidine or a piperidine, said pyrrolidine and piperidine may be alpha (di-)substituted, in particular as alpha methylated or alpha dimethylated,
- R6 represents H, methyl, ethyl, -ORh, with Rh representing H, (Ci-C6)alkyl, or - CO(Ci-C6) alkyl,
- R7 represents H or a (C2-C6)alkyl, and
- R8 and R9 represent each H,
and its enantiomers, diastereoisomers and pharmaceutically acceptable salts, for its use in the treatment of Down syndrome.
2. Compound according to Claim 1 , characterized in that R2 and R3 represent H, while Ri represents H, an halogen atom, -Ra, -ORa, -NHRa or -NRaRb, with Ra and Rb representing independently H, (C1-C6)alkyl, -CO(Ci-C6)alkyl, or Ra and Rb represent together a 5- or 6-membered cycle.
3. Compound according to Claim 1, characterized in that R3 represents H, while Ri and R2 represent independently an halogen atom, -Ra, -ORa, -NHRa, or -NRaRb, with Ra and Rb representing independently H, (Ci-C6)alkyl, -CO(Ci-C6)alkyl, or Ra and Rb represent together a 5- or 6-membered cycle.
4. Compound according to Claim 1 , characterized in that Ri and R2 represent H, while R3 represent independently an halogen atom, -Ra, -ORa, -NHRa, or -NRaRb, with Ra and Rb representing independently H, (Ci-C )alkyl, -CO(Ci-C6)alkyl, or Ra and Rb represent together a 5- or 6-membered cycle, in particular comprising 4 or 5 carbon atoms in the ring, i.e. a pyrrolidine or a piperidine, in particular R3 represents respectively -OH, -OMe or morpholine.
5. Compound according to anyone of Claims 1 to 4, characterized in that R5 represents iPr, tBu, -OiPr, -NHCOMe, -NEt2, -NiPr2, -N(Et)iPr, -NEt(CH2CH2OH), -NEt(CH2CH2OAc), alpha-methylated pyrrolidine, piperidine, alpha-methylated piperidine, or alpha-dimethylated piperidine.
6. Compound according to anyone of Claims 1 to 5, characterized in that R6 represents H, Me, -OH, -OMe, -OiPr, -OCH(Me)Et, or -OAc.
7. Compound according to anyone of Claims 1 to 6, characterized in that R7 represents H or iPr. Compound according to claim 1 wherein:
- Ri is -OMe,
- R2 and R3 each represent H,
- R represents
■ -CORdj with Rdji representing -CF3, a tetrahydropyranyl group, or
■ -COORd2 with Rd2 representing -CH3,-CH(CH3)2 and -CH2 CH(CH3)2, phenyl, benzyl, p-methoxybenzyl , or
■ -CONHRd3, with Rd3 representing a (C C3)alkyl, -CH2-CH2-0 CH3, or
■ -S02Rd4, with Rd4 representing -CH3,
- R5 is -N(iPr)2,
- R6 is -OMe and
-R7 is H.
Compound according to claims 1 to 4 wherein:
a. R5 represents iPr, tBu, -OiPr, -NHCOMe, -NEt2, -NiPr2, -N(Et)iPr, - NEt(CH2CH2OH), -NEt(CH2CH2OAc), alpha-methylated pyrrolidine, piperidine, alpha-methylated piperidine, or alpha-dimethylated piperidine; b. R6 represents H, Me, -OH, -OMe, -OiPr, -OCH(Me)Et, or -OAc;
c. R7 represents H or iPr.
10. Compound according to claim 9 wherein:
a. R5 represents iPr, -NEt2, -N(Et)iPr, -NEt(CH2CH2OH), piperidine or alpha- methylated piperidine,
b. R6 represents H, Me, -OH, -OMe, -OiPr, -OCH(Me)Et, or -OAc;
c. R7 represents H or iPr.
11. Compound according to anyone of Claims 1 to 10, characterized in that it presents a 3S and/or a 11R configuration, in particular a 3S,11R configuration.
12. Compound according to Claim 1, characterized in that R5 represents a branched (C3-C6)alkyl, -ORe, -N(Re)2 or -NReRf, with o Re and Rf representing independently a (C2-C3)alkyl or -CO(Ci-C2)alkyl, or o Re and Rf representing together a 5- or 6-membered cycle, and
at least one from Ri, R2 and R3 representing an halogen atom, -Ra, -ORa, -NHRa, - NRaRb, with Ra and Rb representing independently (Ci-C6)alkyl, -CO(CrC6)alkyl, or Ra and Rb represent together a 5- or 6-membered cycle.
13. Compound according to Claim 1 , characterized in that
at least one of Rl5 R2 and R3 is representing an halogen atom, (Ci-C6)alkyl, - 0(Ci-C6)alkyl, -NH(C C6)alkyl or -N((CrC6)alkyl)2, in particular the alkyl is a branched alkyl,
- R4 is H, -CO(d-C3)alkyl, -COO(CrC3)alkyl or -CONH(Ci-C3)alkyl
- R5 is representing -N(C2-C3)alkyl, in particular -N(Et)2 or N(iPr)2, or -N is part of a 5- or 6-membered cycle , in particular such as pyrrolidine or piperidine, and
R6 is representing a methyl group, an ethyl group, -0(Ci-C6)alkyl, -OCO(Ci- C6) alkyl.
14. Compound according to Claim 1 , characterised in that
at least one of R] 5 R2 and R3 is representing an halogen atom, (Ci-C6)alkyl, - 0(C C6)alkyl, -NH(C C6)alkyl or -N((Ci-C6)alkyl)2, in particular the alkyl is a branched alkyl,
- R is H, -CO(Ci-C3)alkyl, -COO(Ci-C3)alkyl or -CONH(CrC3)alkyl, in particular -CO(C1-C3)alkyl, more particularly an acetyl group,
- R5 is representing -N(C2-C3)alkyl, in particular -N(Et)2 or -N(iPr)2, or -N is part of a 5- or 6-membered cycle, in particular such as pyrrolidine or piperidine, and
R6 is representing -0(Ci-C6)alkyl, in particular a methoxy group.
15. Compound according to Claim 1, characterised in that it is chosen from the list consisting of
- 1 l-(4-Diethylamino-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l 1-hexahydro- dibenzo[b,e] [ 1 ,4]diazepin-l -one
- 10- Acetyl- 11 -(4-diethylamino-phenyl)-3 -(4-methoxy-phenyl)-2,3 ,4,5, 10, 1
1 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin-l -one
- 10-Acetyl-l l-(R)-(4-diethylamino-phenyl)-3-(S)-(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
- 10-Acetyl-l l-(4-diethylamino-phenyl)-3-(4-chloro-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo[b,e][l ,4]diazepin-l -one
- 10-Acetyl-l l-(4-diethylamino-phenyl)-3-phenyl-2, 3,4,5, 10,11-hexahydro- dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
- 10-Acetyl-l l-(4-Diethylamino-phenyl)-3-(4-ethyl-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo [b,e] [ 1 ,4]diazepin- 1 -one
- 10-Acetyl-l l-(4-Diethylamino-phenyl)-3-(4-acetoxy-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 11 -(4-diethylamino-phenyl)-3 -(3 ,4-dimethoxy-phenyl)-2,3 ,4,5,10,11 -hexahydro- dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
- 10- Acetyl- 11 -(4-diethylamino-phenyl)-3-(3 ,4-dimethoxy-phenyl)-2,3 ,4,5,
10, 11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one - 10-Acetyl- 11 -(4-diethylamino-phenyl)-3-(3 ,4-dihydroxy-phenyl)-2,3 ,4,5,10,11- hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 1 l-(4-diethylamino-phenyl)-3-(2,3-dimethoxy-phenyl)-2,3,4,5,10,l 1-hexahydro- dibenzo [b,e] [ 1 ,4]diazepin- 1 -one
- 10-Acetyl-l l-(4-diethylamino-phenyl)-3-(2,3-dimethoxy-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo[b,e] [ 1 ,4] diazepin- 1 -one
- 1 l-(4-diethylamino-phenyl)-3-(2,4-dimethoxy-phenyl)-2,3,4,5,10,l 1-hexahydro- dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
- 10-Acetyl-l l-(4-diethylamino-phenyl)-3-(2,4-dimethoxy-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo[b,e] [1,4] diazepin- 1 -one
- 1 l-(4-diethylamino-phenyl)-3-(2-methoxy-phenyl)-2,3,4,5,10,l 1-hexahydro- dibenzo [b,e] [ 1 ,4]diazepin- 1 -one
- 1 l-(4-diethylamino-phenyl)-3-(2-methoxy-phenyl)-2,3,4,5,10,l 1-hexahydro- dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
- 1 l-(4-diethylamino-phenyl)-3-(3-methoxy-phenyl)-2,3,4,5,10,l 1-hexahydro- dibenzo [b,e] [ 1 ,4]diazepin- 1 -one
- 10-Acetyl-l l-(4-diethylamino-phenyl)-3-(3-methoxy-phenyl)-2,3,4,5, 10,11- hexahydro-dibenzo[b,e] [1 ,4]diazepin- 1 -one
- 1 l-(4-diethylamino-phenyl)-3-(4-mo holino-phenyl)-2,3,4,5,10,l 1-hexahydro- dibenzo[b,e][ 1 ,4] diazepin- 1 -one
- 10- Acetyl- 11 -(4-diethylamino-phenyl)-3-(4-morpholino-phenyl)-2,3 ,4,5, 10, 11 - hexahydro-dibenzo[b,e] [ 1 ,4]diazepin-l -one
- 11 -(4-Diethylamino-phenyl)-3 -(4-dimethylamino-phenyl)-2,3 ,4,5, 10,11- hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 10-Acetyl-l 1 -(4-di ethylamino-phenyl)-3 -(4-dimethylamino-phenyl)-
2,3,4,5, 10, 11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 10-Acetyl-l l-(4-diethylamino-phenyl)-3-(4-hydroxy-phenyl)-2,3,4,5, 10,1
1 -hexahydro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
- l l-(4-Diethylamino-phenyl)-3-(4-methoxy-phenyl)-10-(2-oxo-propyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
- 11 -(4-Diethylamino-2-methyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5, 10,11 - hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 10- Acetyl- 11 -(4-diethylamino-2-methyl-phenyl)-3 -(4-methoxy-phenyl)- 2,3,4,5,10, 11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 10-Acetyl- 11 -(4-diethylamino-2-methyl-phenyl)-3 -(4-hydroxy-phenyl)-
2,3 ,4,5 , 10, 11 -hexahydro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
11 -(2-acetoxy-4-diethylamino-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,l 0, 11 - hexahydro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
- 10-Acetyl- 11 -(2-acetoxy-4-diethylamino-phenyl)-3 -(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
- 10-Acetyl- 11 -(4-diethylamino-2-hydroxy-phenyl)-3 -(4-methoxy-phenyl)- 2,3,4,5, 10, 11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 10-Acetyl-l l-(4-(ethyl-2-acetoxy-ethyl-amino)-2-methyl-phenyl)-3-(4-methoxy- phenyl)-2,3,4,5, 10,11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 10-Acetyl-l l-(4-(ethyl-2-hydroxy-ethyl-amino)-2-methyl-phenyl)-3 -(4- methoxy-phenyl)-2,3,4,5, 10, 11 -hexahydro-dibenzo [b,e] [1 ,4] diazepin- 1 -one
- 10-Acetyl-l l-(4-acetamido-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 1 l-(4-tert-butyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l 1-hexahydro- dibenzo[b,e] [ 1 ,4]diazepin- 1 -one - 10-Acetyl-l l-(4-tert-butyl-phenyl)-3-(4-methoxy-p enyl)-2,3,4,5,10,l 1- hexahydro-dibenzo[b,e][l ,4]diazepin-l -one
- 10-Acetyl-l l-(4-tert-butyl-phenyl)-3-(4-hydroxy-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo[b,e][l,4]diazepin-l-one
- 1 l -(4-isopropyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l 1-hexahydro- dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
- 10-Acetyl-l l-(4-isopropyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l 1 - hexahydro-dibenzo [b,e] [ 1 ,4]diazepin- 1 -one
- 1 l-(4-(ethyl-isopropyl-amino)-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo [b,e] [ 1 ,4]diazepin- 1 -one
- Acetyl- 11 -(4-(ethyl-isopropyl-amino)-phenyl)-3 -(4-methoxy-phenyl)- 2,3,4,5, 10,11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 1 l-(4-Diisopropylamino-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l 1-hexahydro- dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
- 10-Acetyl-l l-(4-Diisopropylamino-phenyl)-3-(4-methoxy-phenyl)-
2,3 ,4,5, 10, 1 1 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 10-Acetyl-l l-(4-Diisopropylamino-phenyl)-3-(4-hydroxy-phenyl)-2,3,4,5, 10,1 1- hexahydro-dibenzo [b,e] [ 1 ,4]diazepin- 1 -one
- 1 l-(4-Diisopropylamino-2-methyl-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 10-Acetyl-l l-(4-diisopropylamino-2-methyl-phenyl)-3-(4-methoxy-phenyl)- 2,3, 4,5, 10,11 -hexahydro-dibenzo[b,e] [1,4] diazepin- 1 -one
- 10-Acetyl-l l-(4-diisopropylamino-2-methyl-phenyl)-3-(4-hydroxy-phenyl) -2,3 ,4,5, 10, 1 1 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 1 l-(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l l- hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 11 -(4-Diisopropylamino-2-methoxy-phenyl)-3-(4-hydroxy-phenyl)- 2,3 ,4,5, 10, 11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 10- Acetyl- 11 -(4-diisopropylamino-2-methoxy-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
- 10- Acetyl- 11 -(4-diisopropylamino-2-methoxy-phenyl)-3 -(4-hydroxy-phenyl)- 2,3 ,4,5 , 10, 1 1 -hexahydro-dibenzo [b,e] [ 1 ,4] diazepin- 1 -one
- 1 l-(2-acetoxy-4-diisopropylamino-phenyl)-3-(4-methoxy-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo[b,e][ 1 ,4]diazepin- 1 -one
- 1 l-(4-Diisopropylamino-2-hydroxy-phenyl)-3-(4-methoxy-phenyl)-
2,3 ,4,5, 10, 11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 10- Acetyl- 11 -(2-acetoxy-4-diisopropylamino-phenyl)-3 -(4-methoxy-phenyl)- 2,3 ,4,5, 10, 11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 10-Acetyl- 11 -(2-hydroxy-4-diisopropylamino-phenyl)-3 -(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
- 11 -(4-diisopropylamino-2-isopropoxy-phenyl)-3-(4-methoxy-phenyl)- 2,3,4,5, 10, 1 1 -hexahydro-dibenzo [b,e] [ 1 ,4]diazepin- 1 -one
- 10-Acetyl-l l-(4-diisopropylamino-2-isopropoxy-phenyl)-3-(4-methoxy- phenyl)-2,3 ,4,5, 10, 11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 1 l-(4-diisopropylamino-2-sec-butoxy-phenyl)-3-(4-methoxy-phenyl)-
2,3 ,4,5 , 10, 11 -hexahydro-dibenzo [b,e] [ 1 ,4]diazepin- 1 -one
- 10- Acetyl- 11 -(4-diisopropylamino-2-sec-butoxy-phenyl)-3 -(4-methoxy-phenyl)- 2,3 ,4,5, 10, 11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 1 l-(4-diisopropylamino-2-methoxy-phenyl)-3-(4-methyl-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one - 11 -(4-Diisopropylamino-2-methoxy-phenyl)-3 -(4-methoxy-phenyl)- 1 -oxo- 1,2,3,4,5,1 l-hexahydro-dibenzo[b,e][l,4]diazepine-10-carboxylic acid isopropyl ester
- 11 -(4-Diisopropylamino-2-methoxy-phenyl)-3 -(4-methoxy-phenyl)- 1 -oxo- 1,2,3,4,5,1 l-hexahydro-dibenzo[b,e][l,4]diazepine-10-carboxylic acid ethylamide
- 11 -(4-Diisopropylamino-2-methoxy-phenyl)-3 -(4-methoxy-phenyl)- 1 -oxo- 1,2,3,4,5,1 l-hexahydro-dibenzo[b,e][l,4]diazepine-10-carboxylic acid methyl ester
- 11 -(4-Diisopropylamino-2-methoxy-phenyl)-3 -(4-methoxy-phenyl)- 1-oxo-
1,2,3,4,5,1 l-hexahydro-dibenzo[b,e][l,4]diazepine-10-carboxylic acid iso-butyl ester
- 11 -(4-Diisopropylamino-2-methoxy-phenyl)-3 -(4-methoxy-phenyl)- 1 -oxo- 1,2,3,4,5,1 l-hexahydro-dibenzo[b,e][l,4]diazepine-10-carboxylic acid benzyl ester
- 11 -(4-Diisopropylamino-2-methoxy-phenyl)-3 -(4-methoxy-phenyl)- 1 -oxo- 1,2,3,4,5,1 l-hexahydro-dibenzo[b,e][l,4]diazepine-10-carboxylic acid 4- methoxy-benzylamide
- 11 -(4-Diisopropylamino-2-methoxy-phenyl)-3 -(4-methoxy-phenyl)- 1 -oxo- 1,2,3,4,5,1 l-hexahydro-dibenzo[b,e][l,4]diazepine-10-carboxylic acid (2- methoxy-ethyl)-amide
- 11 -(4-Diisopropylamino-2-methoxy-phenyl)-3 -(4-methoxy-phenyl)- 10- (tetrahydro-pyran-4-carbonyl)-2,3,4,5,l 0,11 -hexahydro- dibenzo[b,e] [ 1 ,4] diazepin- 1 -one
- 1 l-(4-Diisopropylamino-2-methoxy-phenyl)-10-methanesulfonyl-3-(4-methoxy- phenyl)-2,3 ,4,5 , 10, 11 -hexahydro-dibenzo[b,e] [1,4] diazepin- 1 -one
- 10- Acetyl-3 -(4-methoxy-phenyl)- 11 -(4-(2 -methyl -pyrrolidine)phenyl)- 2,3,4,5,10,11 -hexahydro-dibenzo[b,e][l ,4]diazepin-l -one
- 3-(4-Methoxy-phenyl)-l l-(4-piperidin-l-yl-phenyl)-2,3, 4,5, 10,11-hexahydro- dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 10- Acetyl-3 -(4-methoxy-phenyl)- 1 l-(4-piperidin-l-yl-phenyl)-2,3,4,5,10,l 1- hexahydro-dibenzo[b,e] [ 1 ,4] diazepin- 1 -one
10-Acetyl-3-(4-methoxy-phenyl)-l 1 -(2-methyl-4-piperidin- 1 -yl-phenyl)- 2,3 ,4,5,10,11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 3-(4-Methoxy-phenyl)-l l-(2-methoxy-4-piperidin-l-yl-phenyl)-2,3, 4,5, 10,11- hexahydro-dibenzo[b,e][l ,4]diazepin-l -one
- 10- Acetyl-3 -(4-methoxy-phenyl)- 11 -(2-methoxy-4-piperidin- 1 -yl-phenyl)- 2,3 ,4,5, 10, 11 -hexahydro-dibenzo[b,e] [ 1 ,4] diazepin- 1 -one
- l l-[2-methoxy-4-(2-methyl-piperidin-l-yl)-phenyl]-3-(4-methoxy-phenyl)- 2,3,4,5,10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
- 10- Acetyl- 11 - [2-methoxy-4-(2-methyl-piperidin- 1 -yl)-phenyl] -3 -(4-methoxy- phenyl)-2,3 ,4,5, 10,11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- l l-[2-methoxy-4-(2,6-dimethyl-piperidin-l-yl)-phenyl]-3-(4-methoxy-phenyl)- 2,3,4,5, 10, 11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one
- 10-Acetyl-l l-[2-methoxy-4-(2,6-dimethyl-piperidin-l-yl)-phenyl]-3-(4- methoxy-phenyl)-2,3,4,5,10,l l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one
- l l-[4-(2,5-Dimethyl-pyrrol-l-yl)-2-methoxy-phenyl]-3-(4-methoxy-phenyl)- 2,3 ,4,5 , 10, 11 -hexahydro-dibenzo [b,e] [ 1 ,4]diazepin- 1 -one
10- Acetyl- 11 -(2-methoxy-4-isopropoxy-phenyl)-3 -(4-methoxy-phenyl)- 2,3,4,5,10,11 -hexahydro-dibenzo [b,e][ 1,4] diazepin- 1 -one.
16. Pharmaceutical composition comprising an effective amount of a compound according to any of the preceding claims and a pharmaceutically acceptable carrier.
PCT/EP2012/072410 2011-11-10 2012-11-12 Inhibitors of cystathionine beta synthase to reduce the neurotoxic overproduction of endogenous hydrogen sulfide WO2013068592A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201161558111P 2011-11-10 2011-11-10
EP11306467 2011-11-10
US61/558,111 2011-11-10
EP11306467.9 2011-11-10

Publications (1)

Publication Number Publication Date
WO2013068592A1 true WO2013068592A1 (en) 2013-05-16

Family

ID=48288562

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/072410 WO2013068592A1 (en) 2011-11-10 2012-11-12 Inhibitors of cystathionine beta synthase to reduce the neurotoxic overproduction of endogenous hydrogen sulfide

Country Status (1)

Country Link
WO (1) WO2013068592A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103601690A (en) * 2013-10-23 2014-02-26 江苏科技大学 3-phenylbis(benzodiazepine)-1-one series derivatives, and preparation method and application thereof
WO2019191327A1 (en) * 2018-03-27 2019-10-03 Board Of Regents, The University Of Texas System Ox2r compounds
EP3594336A1 (en) * 2018-07-13 2020-01-15 Université de Strasbourg Treatment of down syndrome

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007026024A2 (en) * 2005-09-02 2007-03-08 Tibotec Pharmaceuticals Ltd. Benzodiazepines as hcv inhibitors
US20080293699A1 (en) * 2007-05-25 2008-11-27 Burnham Institute For Medical Research Inhibitors of thapsigargin-induced cell death
WO2009004038A2 (en) * 2007-07-02 2009-01-08 Ac Immune S.A. Therapeutic compound
WO2009055001A2 (en) * 2007-10-23 2009-04-30 Fred Hutchinson Cancer Research Center Methods of treating aging and methods of screening candidate agents therefor
WO2010072807A2 (en) 2008-12-23 2010-07-01 Fondation Jerome Lejeune Inhibitors of cystathionine beta synthase to reduce the neurotoxic overproduction of endogenous hydrogen sulfide
WO2011029054A1 (en) * 2009-09-04 2011-03-10 The Regents Of The University Of Michigan Compositions and methods for treatment of leukemia

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007026024A2 (en) * 2005-09-02 2007-03-08 Tibotec Pharmaceuticals Ltd. Benzodiazepines as hcv inhibitors
US20080293699A1 (en) * 2007-05-25 2008-11-27 Burnham Institute For Medical Research Inhibitors of thapsigargin-induced cell death
WO2009004038A2 (en) * 2007-07-02 2009-01-08 Ac Immune S.A. Therapeutic compound
WO2009055001A2 (en) * 2007-10-23 2009-04-30 Fred Hutchinson Cancer Research Center Methods of treating aging and methods of screening candidate agents therefor
WO2010072807A2 (en) 2008-12-23 2010-07-01 Fondation Jerome Lejeune Inhibitors of cystathionine beta synthase to reduce the neurotoxic overproduction of endogenous hydrogen sulfide
WO2011029054A1 (en) * 2009-09-04 2011-03-10 The Regents Of The University Of Michigan Compositions and methods for treatment of leukemia

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
"Endogenous Hydrogen Sulfide Overproduction in Down Syndrome", AMERICAN JOURNAL OF MEDICAL GENETICS, vol. 116A, 2003, pages 310 - 311
CHADEFAUX ET AL., BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 128, no. 1, 1985, pages 40 - 44
CHADEFAUX ET AL.: "Cystathionine beta synthase: gene dosage effect in trisomy 21", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 128, no. 1, 1985, pages 40 - 44
CHEN ET AL., J. BIOL. CHEM, 2004, pages 279
CHRISTINE BUTLER ET AL: "The Production of Transgenic Mice Expressing Human Cystathionine Beta-Synthase to Study Down Syndrome", BEHAVIOR GENETICS, KLUWER ACADEMIC PUBLISHERS-PLENUM PUBLISHERS, NE, vol. 36, no. 3, 16 March 2006 (2006-03-16), pages 429 - 438, XP019391324, ISSN: 1573-3297, DOI: 10.1007/S10519-006-9046-Y *
ICHINOHE ET AL.: "Cystathionine 8-synthase is enriched in the brains of Down's patients", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 338, 2005, pages 1547 - 1550
ICHINOHE ET AL: "Cystathionine beta-synthase is enriched in the brains of Down's patients", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ACADEMIC PRESS INC. ORLANDO, FL, US, vol. 338, no. 3, 23 December 2005 (2005-12-23), pages 1547 - 1550, XP005153717, ISSN: 0006-291X, DOI: 10.1016/J.BBRC.2005.10.118 *
ICHINOHE, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 338, 2005, pages 1547 - 1550
KAMOUN, AMERICAN JOURNAL OF MEDICAL GENETICS, vol. 116A, 2003, pages 310 - 311
KAMOUN, PIERRE, MEDECINE/SCIENCES, vol. 20, no. 6-7, June 2004 (2004-06-01), pages 697 - 700
KAMOUN, PIERRE: "H2S, un nouveau neuromodulateur", MÉDECINE/SCIENCES, vol. 20, no. 6-7, June 2004 (2004-06-01), pages 697 - 700
KIMURA, HIDEO, MOLECULAR NEUROBIOLOGY, vol. 6, 2002, pages 13 - 19
KIMURA: "Hydrogen Sulfide as a Neuromodulator", MOLECULAR NEUROBIOLOGY, vol. 6, 2002, pages 13 - 19
LEJEUNE JEROME, COMMENTARII, vol. III, no. 9, pages 1 - 12
LEJEUNE JÉRÔME: "Reflexion sur la débilité de l'intelligence des enfants trisomiques 21", COMMENTARII, vol. III, no. 9, pages 1 - 12
POGRIBNA ET AL., GENET, vol. 69, 2001, pages 88 - 95
POGRIBNA ET AL.: "Homocysteine Metabolism in Children with down Syndrome: In Vitro Modulation", AM. J. HUM. GENET., vol. 69, 2001, pages 88 - 95

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103601690A (en) * 2013-10-23 2014-02-26 江苏科技大学 3-phenylbis(benzodiazepine)-1-one series derivatives, and preparation method and application thereof
CN103601690B (en) * 2013-10-23 2015-09-02 江苏科技大学 3-phenyl dibenzodiazepine-1-ketone series derivates and its preparation method and application
WO2019191327A1 (en) * 2018-03-27 2019-10-03 Board Of Regents, The University Of Texas System Ox2r compounds
EP3594336A1 (en) * 2018-07-13 2020-01-15 Université de Strasbourg Treatment of down syndrome

Similar Documents

Publication Publication Date Title
CN111836798B (en) Prodrugs of ketamine, compositions and uses thereof
CN101151248B (en) 3-aryl-3-hydroxy-2-amino-propionic acid amides, 3-heteroayryl-3-hydroxy-2-amino-propionic acid amides and related compounds having analgesic and/or immunostimulant activity
EP0858996B1 (en) Nerve cell protective agents
WO2008023847A1 (en) P2x4 receptor antagonist
CN104592128A (en) Substituted cinnoline derivatives as gabaa-receptor modulators and method for their synthesis
EP3166613A1 (en) Compositions and methods for the repair of myelin
CN106008340A (en) Condensed ring derivative, preparation method, intermediate, pharmaceutical composition and application thereof
US20070161628A1 (en) Phosphodiesterase inhibitors
US20110207714A1 (en) Serotonin receptor modulators
CN101778849A (en) Fused quinoline derivatives useful as gaba modulators
JPH02290841A (en) Novel compound, its production, and pharmaceutical composition containing the same
WO2013068592A1 (en) Inhibitors of cystathionine beta synthase to reduce the neurotoxic overproduction of endogenous hydrogen sulfide
KR20240019063A (en) Phenalkylamine and methods of making and using the same
CN115667226A (en) Tricyclic compounds as EGFR inhibitors
CA2103561A1 (en) Antiserotonin heterocyclic derivatives, preparation thereof and medicaments containing them
TW202110831A (en) Pyridone derivatives, a preparation method thereof, and medical applications thereof
BR112016027096B1 (en) PHARMACEUTICAL COMPOSITIONS AND SEROTONIN TARGET RECEPTOR COMPOUNDS AND THEIR USES
US8957059B2 (en) Modulators of serotonin receptors
EP1828125A1 (en) Arylpiperazine derivatives and their use as ligangs selective of the dopamine d3 receptor
JP3856829B2 (en) Oxazolidinone derivatives, their production and therapeutic use
US20200239493A1 (en) Substituted dihydrothienopyrimidines and their use as phosphodiesterase inhibitors
CN109020887A (en) Amides compound as prevention and treatment mental disorder
EP2546255A1 (en) Benzazepine compound
RU2141482C1 (en) Derivatives of oxazoloquinolinone, their synthesis and drug and pharmaceutical composition containing thereof
FR2567886A1 (en) 1- (2-PYRIMIDINYL) -PIPERAZINYL DERIVATIVES OF 1-PYRROLIDINE-2-ONES AND THEIR PSYCHOGERIATRIC APPLICATION

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12783616

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12783616

Country of ref document: EP

Kind code of ref document: A1