WO2000056721A1 - Solid phase synthesis of benzodiazepine diones - Google Patents

Solid phase synthesis of benzodiazepine diones Download PDF

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Publication number
WO2000056721A1
WO2000056721A1 PCT/US2000/007117 US0007117W WO0056721A1 WO 2000056721 A1 WO2000056721 A1 WO 2000056721A1 US 0007117 W US0007117 W US 0007117W WO 0056721 A1 WO0056721 A1 WO 0056721A1
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alkyl
aryl
formula
compound
branched
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PCT/US2000/007117
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French (fr)
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Jeffrey Mark Dener
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Axys Pharmaceuticals, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the present invention provides a novel method for solid phase and combinatorial synthesis of substituted benzodiazepine diones.
  • Solid phase synthesis One such method that has attracted attention is solid phase synthesis.
  • Known solid phase synthetic techniques are not always easily transferred to all solid phase reactions.
  • solid phase synthesis may be advantageous over traditional liquid phase synthesis, finding the appropriate reaction conditions can be a difficult task. This may be due to a limited choice of solvents which may be used with solid phase synthesis and the limited use of the classical tools for the quality control of intermediates.
  • implementation of known reactions to a solid support often requires a major effort and time investment.
  • the present invention provides a method for the synthesis of the therapeutically important class of substituted benzodiazepine diones. These benzodiazepine diones are known to exhibit biological/pharmacological activity. More particularly these compounds are known to be receptor antagonists, anticonvulsant agents, endothelin antagonists and fibrinogen receptor antagonists.
  • the present invention provides a synthetic process for the synthesis of benzodiazepine diones of Formula I. Also provided are compounds of Formula 7 and Formula 8, which are novel intermediates useful in the synthesis of individual as well as a library of substituted benzodiazepine diones.
  • the present invention thus provides a process for synthesizing a compound or an array of compounds of Formula I:
  • R 1 , R 6 and R 7 independently at each occurrence represent H, 0-C, .4 alkyl, O-aryl, C n . 4 alkyl, halogen, aryl, N0 2 , C(0)-C,. 4 alkyl, CN, C(0)0-C, .4 - alkyl or N(C 1 . 4 alkyl)-; alternatively when R 1 and R 6 are on adjacent carbon atoms they can be taken together to represent
  • R 2 represents H, C(0)-C 1.4 -alkyl, C(0)-aryl, C,. 4 alkyl, C, .4 alkyl-aryl or aryl ;
  • R 4 represents a group selected from C, . , 4 straight chain alkyl, C 3.10 branched alkyl, C 5.14 saturated or partially unsaturated cyclo alkyl, C 2.20 branched or straight chain partially unsaturated alkyl, aryl, chromen-4-one, or heteroaryl, said groups substituted with R 8 , R 9 and R 10 ;
  • R 5 is selected from C 5 . 14 saturated or partially unsaturated cycloalkyl, C, . , 4 alkyl, (CH 2 ), .4 -aryl, (CH 2 ) 1.4 -COOC 1.4 alkyl, halo aryl, aryl-C, .4 alkyl, aryl, C, .4 alkyl morpholino, and C 4 alkyl-S(0) n -optionally substituted aryl;
  • R 8 , R 9 and R 10 independently at each occurance are selected from H, halogen, C, .6 alkyl, C, .4 thio alkyl, thio aryl, OC, . ,- alkyl, NH 2 , NHC, .6 alkyl, N(C,. 6 alkyl) 2 , C, .4 alkyl aryl, OCF 3 , OCOOC, .4 alkyl, C 5.6 cycloalkyl, C 5.6 cycloalkylene, C 3. , 0 branched alkyl, (CH 2 ) 0.3 aryl, and CH(Ph) 2 ; and n represents an integer from 0 to 2; the process comprising:
  • R 1 , R 2 , R 6 and R 7 are as defined earlier, and SS represents a solid support
  • R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and SS are as defined earlier;
  • a preferred embodiment of the present invention provides a process wherein step (a) is carried out in the presence of a catalyst.
  • a preferred catalyst is selected from HOBt, 1 -hydroxy-7-azabenzotriazole (HOAt), N- hydroxysuccinimide and 4-hydroxy azotriazole.
  • the appropriate base in step (a) is selected from tertiary amines, N- methylmorpholine (NMM), N-ethylmorpholine, N-methylpiperidine, N-ethyl- piperidine, lutidine, pyridine, triethylamine and N,N-diisopropylethylamine (DIPEA);
  • the suitable base in step(b) is selected from 4-methyl morpholine (NMM), N-ethylmorpholine, N-methylpiperidine, N-ethylpiperidine, triethylamine and N,N-diisopropylethylamine (DIPEA).
  • step(c) is selected from an alkali metal salt of trimethyl silanol and lithium hydroxide
  • the mild acid in step(c) is selected from acetic acid, propionic acid, citric acid, butyric acid and valeric acid.
  • a further preferred process of the present invention is one wherein the strong acid in step(d) is selected from trifluoro acetic acid (TFA), trifluoromethane sulfonic acid, perfluorobutyric acid, hydrochloric acid, hydrobromic acid and hydrofluoric acid.
  • TFA trifluoro acetic acid
  • trifluoromethane sulfonic acid trifluoromethane sulfonic acid
  • perfluorobutyric acid hydrochloric acid
  • hydrobromic acid hydrofluoric acid
  • a particularly preferred embodiment of the present invention provides a process wherein R 1 , R 6 and R 7 are independently selected from H, OCH 3 , CH 3 , CI and Br; R 2 is selected from H and methyl; R 3 represents H, (CH-), . 4 alkyl-NH-C0 2 -CH 2 -Ph, CH 3 , (CH 2 ), .4 -NH-C0 2 -C(CH 3 ) 3 , (CH 2 ),. 3 -NH-
  • R 4 represents C 2. , 0 partialiy unsaturated alkyl, naphthyl or phenyl substituted with at least one substituent selected from the list consisting of OC,. 6 alkyl, OCF 3 , halogen, O- COO-CH-, phenyl, C,.
  • R 5 represents cyclohexyl, ethyl morpholino, / ⁇ -butyl, benzyl, CH 2 -COOMe or 2,6-dimethylphenyl.
  • R 1 , R 6 and R 7 independently at each occurrence represent H, 0-C, .4 alkyl, O- aryl, C, .4 alkyl, halogen, aryl, N0 2 , C(0)-C, .4 alkyl, CN, C(0)0-C, .4 -alkyl or
  • R 2 represents H, C(0)-C, .4 -alkyl, C(0)-aryl, C, .4 alkyl, C, .4 alkyl-aryl or aryl ;
  • R 3 represents (CH 2 ), .6 -NH-C0 2 -(CH 2 ), .3 -aryl, H, (CH 2 ), .3 -aryl-C(O)-(CH 2 ) 0.3 - C(CH 3 ) 3 , (CH 2 ), .6 -NH-CO 2 -(CH 2 ) 0.2 -C 4.
  • R 4 represents a group selected from C, . , 4 straight chain alkyl, C 3. , 0 branched alkyl, C 5. , 4 saturated or partially unsaturated cyclo alkyl, C 2.20 branched or straight chain partially unsaturated alkyl, aryl, chromen-4-one, or heteroaryl, said groups substituted with R 8 , R 9 and R 10 ;
  • R 5 is selected from C 5. , 4 saturated or partially unsaturated cycloalkyl, C, . , 4 alkyl, (CH 2 ), .4 -aryl, (CH 2 ), .4 -COOC, .4 alkyl, halo aryl, aryl-C,. 4 alkyl, aryl, C, .4 alkyl morpholino, and C, .4 alkyl-S(0) n -optionally substituted aryl;
  • SS represents a solid support
  • R 8 , R 9 and R 10 independently at each occurance are selected from H, halogen, C, .6 alkyl, C, .4 thio alkyl, thio aryl, OC, . , 0 alkyl, NH 2 , NHC, .6 alkyl,
  • R 1 , R 6 and R 7 independently at each occurrence represent H, O-C, 4 alkyl, O- aryl, C, 4 alkyl, halogen, aryl, NO 2 , C(0)-C, 4 alkyl, CN, C(0)0-C. 4 -alkyl or N(C, 4 alkyi) 2 ; alternatively when R 1 and R 6 are on adjacent carbon atoms they can be taken together to represent
  • R 2 represents H, C(0)-C, 4 -alkyl, C(0)-aryl, C, 4 alkyl, C, 4 alkyl-aryl or aryl ;
  • R 4 represents a group selected from C, 14 straight chain alkyl, C 3 10 branched alkyl, C 5 14 saturated or partially unsaturated cyclo alkyl, C 220 branched or straight chain partially unsaturated alkyl, aryl, chromen-4-one, or heteroaryl, said groups substituted with R 8 , R 9 and R 10 ;
  • R 5 is selected from C 5 14 saturated or partially unsaturated cycloalkyl, C, , 4 alkyl, (CH 2 ), 4 -aryl, (CH 2 ) 1 4 -COOC, 4 alkyl, halo aryl, aryl-C, 4 alkyl, aryl, C, 4 alkyl morpholino, and C, 4 alkyl-S(0) n -optionally substituted aryl;
  • SS represents a solid support;
  • R 8 , R 9 and R 10 independently at each occurrence are selected from H, halogen, C, 6 alkyl, C 1 4 thio alkyl, thio aryl, OC, , 0 alkyl, NH 2 , NHC, 6 alkyl, N(C, 5 alkyl)-, C, 4 alkyl aryl, OCF 3 , OCOOC 1 4 alkyl, C 56 cycloalkyl, C 56 cycloalkylene, C 3 10 branched alkyl, (CH 2 ) 03 aryl, and CH(Ph) 2 ; and n represents an integer from 0 to 2.
  • Anthranillic acid of Formula 2 400-800 mmol
  • a catalyst preferably HOBt
  • HOBt 0.5 to 1.5 equivalents with respect to the anthranillic acid
  • DCM-DMF 4:1 to 1 :1
  • the resulting mixture was cooled to a temperature of about 10°C to about -10°C.
  • an appropriate base 1 to 1.5 equivalents with respect to the anthranillic acid.
  • the preferred appropriate base is N,N- diisopropyl ethyl amine. This mixture was briefly stirred followed by the addition of a compound of Formula 1 (0.1 to 0.3 equivalents with respect to the anthranillic acid).
  • This mixture was stirred at the low temperature, of from about -50°C to about 5°C, for up to 30 minutes. Stirring was then continued at ambient temperature for 10 to 24 hours resulting in the formation of a compound of Formula 3.
  • This compound of Formula 3 was isolated by filtration and washed in succession with DMF (x3), DCM (x1 ), a 20% (v:v) acetic acid solution in DCM (x4), DCM (x2), methanol (x1 ), DCM (x1 ) and diethyl ether (x2). Upon drying the compound of Formula 3 was obtained in the form of greenish-brown resin beads.
  • a compound of Formula 3 was washed with DCM, followed by sequential addition of DCM, a compound of Formula 4 (0.480 mmol, in the form of a 1.5 M methanol solution), compound of Formula 5 (0.480 mmol, in the form of a 1.5 M solution in methanol) and optionally a suitable base, 4- methylmorpholine (0.480 mmol, in its neat form) to form an essentially homogenous mixture.
  • This homogenous mixture was agitated for up to 4 hours followed by the addition of a compound of Formula 6 (0.480 mmol) in DCM or DCE or CHCI 3 , and this resulting mixture was further agitated at ambient temperature for 8 to 24 hours leading to the formation of a compound of Formula 7.
  • the compound of Formula 7 was isolated by filtration and washed in succession with DMF (x3), DCM (x3) and methanol (x2). This compound of Formula 7 was preferably dried before further use.
  • the compound of Formula 7 was washed with THF (x2) followed by dilution with a solution of an appropriate base (preferably potassium trimethylsilanoate) in an inert solvent (preferably THF). This diluted mixture was stirred for about 8 to about 24 hours leading to the formation of a compound of Formula 8.
  • an appropriate base preferably potassium trimethylsilanoate
  • an inert solvent preferably THF
  • a compound of Formula 7 or 8 was added a mixture of a strong acid and an inert solvent, preferably a 1 :1 mixture of trifluoro acetic acid and DCM, and this resulting mixture was stirred at ambient temperature from about 1 to about 4 hours. The reaction mixture was then maintained at a low temperature for about 30 minutes leading to the formation of a compound of Formula I.
  • Compound(s) of Formula 1 which are used in Step B of the presently claimed novel process, can be prepared by synthetic methods known to one skilled in the art. One such method is discussed below.
  • 4-Nitrophenylcarbonate-Wang resin (Compound of Formula 1 ): A 5000 mL 3-neck round-bottom flask fitted with a nitrogen inlet, a mechanical stirrer and a glass stir rod with a Teflon stir blade was placed in a rectangular bucket. The flask was charged with 250g (312 mmol; 1.25 mmol) of Wang resin (MidWest Biotech, Cat. #20800) followed by 2000 mL of dry DCM. The resulting resin slurry was cooled in an ice bath and 170 mL (156.4g; 1.55 mol) of N-methylmorpholine was added.
  • novel process of the present invention can also be used to prepare an array of compounds of Formula I. Following is the general procedure to accomplish the same.
  • a mixture of 4,5-Dimethoxyanthranilic acid (123g; 625 mmol) and a catalyst, HOBWH.O (51 .9g; 385 mmol), in 750 mL of a 2:1 DCM-DMF solvent system was cooled in an ice bath.
  • the cooled mixture was then treated with an appropriate base, preferably 140 mL (104g; 803 mmol) of N,N-diisopropylethylamine in one portion, followed by a compound of Formula 1 , preferably 100g (126 mmol) of the 4-nitrophenylcarbonate Wang resin.
  • the mixture was then stirred for about 20 hours at ambient temperature.
  • the resin was isolated and then washed in succession with DMF (3x500 mL), DCM (500 mL), 20% acetic acid in DCM (v:v; 4x500 mL), DCM (2x500 mL), methanol (500 mL), DCM (2x500 mL) and finally diethyl ether (2x500 mL).
  • the final DCM washes were monitored by TLC to ensure absence of UV active material.
  • the resin was dried to yield 103g of greenish-brown colored resin beads.
  • Other anthranillic acids can be attached to the resin using the above described general procedure.
  • the resin supported anthranillic acids, compounds of Formula 3 from STEP B, Scheme A, were partitioned into Polyfiltronics plates using one resin per plate.
  • the plates were washed with 500 ⁇ L of DCM per well and drained.
  • the plates were placed in metal plate clamps with a teflon sheet lining the bottom of the plates.
  • the plates were then carefully undamped to minimize premature drainage and transferred to a TomTec vacuum box (cat. # 196-501). The solvents were drained and the plates were washed with DMF (3x1.0 mL), DCM (3x1.0 mL) and methanol (2x1.0 mL).
  • the washed plates from STEP C Scheme A were washed with tetrahydrofuran (2x1.0 mL) as soon as possible, but before the addition of the appropriate base (potassium trimethylsilanoate). After the washing was complete, the plates were clamped with a lower teflon sheet and 1.0 mL (900 ⁇ mol) of a 0.9M tetrahydrofuran solution of the potassium trimethylsilanoate (Gelest Inc.; cat. #SIP6901.0) was added to each well. The top of the plate is covered with a teflon sheet and metal plate and shaken on a Lab Line reciprocal shaker (VWR Scientific cat.
  • VWR Scientific cat. # 57008-195 Lab Line reciprocal shaker
  • the plates were allowed to drain into the Beckman plates for about 30 minutes, then each well was washed with 300 ⁇ L of a 1 :1 mixture of trifluoroacetic acid and DCM, followed by 300 ⁇ L of dichloromethane. The plates were then evaporated on a Savant SpeedVac for 3 hours using the medium drying setting.
  • 4,5-dimethoxyanthranillic acid (a compound of Formula 2, 123 g, 625 mmol) and HOBt (a catalyst, 51.9 g, 385 mmol) were dissolved in 500 mL of a 2:1 mixture of DCM-DMF. The resulting mixture was cooled to a temperature of about 0°C. To this cold reaction mixture was then added N,N-diisopropylethylamine (appropriate base, 104 g, 803 mmol). This mixture was briefly stirred followed by the addition of 4-nitrophenylcarbonate Wang resin (a compound of Formula 1 , 100g, 120 mmol). This mixture was stirred at the low temperature for up to 30 minutes.
  • the compound of Formula 7 was washed with THF (2 x 1 mL) followed by dilution with a solution of potassium trimethylsilanoate (appropriate base, 900 ⁇ M, 1 mL of a 0.9 M THF solution). This diluted reaction mixture was stirred for about 16 to about 20 hours leading to the formation of a compound of Formula 8.
  • This compound of Formula 8 was isolated and then washed in succession with DMF (3 x 1 mL), 20% acetic acid in DMF (3 x 1 mL), DCM (3 x 1 mL), methanol (2 x 1 mL) and DCM (2 x 1 mL). This washed compound of Formula 8 was further used after drying.
  • alkyl as used herein represents a hydrocarbon radical comprising from one to six carbon atoms, unless indicated otherwise.
  • aryl as used herein represents an aromatic hydrocarbon comprising from six to ten carbon atoms.
  • optionally substituted aryl represents an aryl group, as defined above, that can be substituted with one or more substitutents selected from a group consisting of OCF 3 , halogen, S-haloalkyl, S-haloaryl, NHC, .4 -CN, N(C, .4 -CN) 2 , and O- C(0)-C, .4 alkyl.
  • aryl as used under R 5 is indented to represent an aryl group as defined above which can be substituted with one to three substitutents selected from a group consisting of alkyl, halo, nitro, thio-alkyl, cyano, C, .4 alkoxy and phenyl.
  • halo or “halogen” is intended to represent CI, Br, I and F.
  • strong acid represents a protic or lewis acid that can cleave a chemical entity from the solid support and subsequently generate a heterocydic product.
  • strong acid are trifluoroacetic acid (TFA), trifluoromethanesulofonic acid, perfluorobutyric acid, sulfuric acid, hydrochloric acid, hydrofluoric acid and hydrobromic acid.
  • appropriate base as used in step (a) herein represents a base which will assist in effecting the reaction in step (a). Desirable bases are tertiary amine or alkali metal salt that can convert a 2- aminobenzoic acid derivative to the corresponding carboxylate salt.
  • an appropriate base is N-methylmorpholine (NMM), N-ethylmorpholine, N-methylpiperidine, N-ethylpiperidine, triethyl amine, pyridine, lutidine and N,N-diisopropylethylamine (DIPEA).
  • suitable base represents an amino compound which can convert a primary amine salt to its free base.
  • a desirable class of the suitable base is tertiary amines.
  • suitable base examples include N-methylmorpholine (NMM), N-ethylmorpholine, N- methylpiperidine, N-ethylpiperidine, triethyl amine, pyridine, lutidine and N,N- diisopropylethylamine (DIPEA).
  • NMM N-methylmorpholine
  • N-ethylmorpholine N-methylpiperidine
  • N-ethylpiperidine triethyl amine
  • pyridine lutidine
  • DIPEA N,N- diisopropylethylamine
  • solid support signifies polymeric material for supported synthesis.
  • linker molecule and solid support can be found in The Combinatorial Index, B. A. Bunin, Academic Press (1998), which is incorporated herein by reference.
  • inert solvent is intended to represent solvents which do not react with the reagents dissolved therein.
  • inert solvents are tetrahydrofuran (THF), methyiene chloride, dichloro methane (DCM), ethyl acetate (EtOAc), dimethyl formamide (DMF), diaoxane, chloroform, and DMSO.
  • drying agent also some times referred to as “drying agent” represents an agent which facilitates removal of any water or moisture which may be present in a reaction mixture or formed during a reaction. Typical dehydrating/drying agents known to one skilled in the art are intended to be included herein.
  • dehydrating/drying agents are magnesium sulfate, sodium sulfate, methyl orthoformate, ethyl orthoformate, methyl ortho acetate and ethyl ortho acetate, or any moisture which may be present in
  • catalyst is intended to represent an additive that facilitates the course of a reaction but does not get incorporated in to the final product.
  • Illustrative examples of catalysts are N-hydroxybenzotriazole (HOBt), 1 -hydroxy-7-azabenzotriazole (HOAt) and N-hydroxysuccinimide.
  • solid support (SS) as used in the present invention, signifies polymeric material for supported synthesis. A detailed description of the terms linker molecule, and solid support can be found in The Combinatorial Index, B. A. Bunin, 1998, which is incorporated herein by reference.
  • HOAt 1 -hydroxy-7-azabenzotriazole
  • HOBt N-hydroxybenzotriazole
  • NMM N-methylmorpholine (4-methylmorpholine)
  • TLC Thin-layer chromatography
  • TFA trifluoroacetic acid
  • TMOF Trimethylorthoformate

Abstract

The present invention provides a process for the synthesis of a compound or an array of compounds of formula (I). Compounds of formula (I) generally represent the therapeutically important class of compounds namely diversely substituted benzodiazepine diones.

Description

SOLID PHASE SYNTHESIS OF BENZODIAZEPINE DIONES
FIELD OF INVENTION The present invention provides a novel method for solid phase and combinatorial synthesis of substituted benzodiazepine diones.
BACKGROUND OF THE INVENTION Obtaining a better understanding of the important factors in molecular recognition in conjunction with developing new therapeutic agents has been a major focus of research in the pharmaceutical industry. This process generally begins with screening a large number of compounds against a specific receptor or enzyme. Methods are being developed which permit the synthesis of a large array of compounds, or of mixtures of compounds, that can be screened for their biological activity.
There are however only a few methods that facilitate the quick synthesis of small organic molecules. For this reason, small organic molecules of potential therapeutic interest are today still synthesized and evaluated one at a time, thus reducing the number of potential therapeutic agents that could be evaluated for their biological activity.
One such method that has attracted attention is solid phase synthesis. Known solid phase synthetic techniques are not always easily transferred to all solid phase reactions. Although solid phase synthesis may be advantageous over traditional liquid phase synthesis, finding the appropriate reaction conditions can be a difficult task. This may be due to a limited choice of solvents which may be used with solid phase synthesis and the limited use of the classical tools for the quality control of intermediates. For the preceding reasons, implementation of known reactions to a solid support often requires a major effort and time investment. The present invention provides a method for the synthesis of the therapeutically important class of substituted benzodiazepine diones. These benzodiazepine diones are known to exhibit biological/pharmacological activity. More particularly these compounds are known to be receptor antagonists, anticonvulsant agents, endothelin antagonists and fibrinogen receptor antagonists.
There is thus a need for synthetic methodology which will facilitate synthesis of a single as well as a large array of benzodiazepine based organic compounds.
SUMMARY OF THE INVENTION
Keeping the above discussed needs in mind the present invention provides a synthetic process for the synthesis of benzodiazepine diones of Formula I. Also provided are compounds of Formula 7 and Formula 8, which are novel intermediates useful in the synthesis of individual as well as a library of substituted benzodiazepine diones.
DETAILED DESCRIPTION OF THE INVENTION
The present invention thus provides a process for synthesizing a compound or an array of compounds of Formula I:
Figure imgf000004_0001
.Formula I wherein R1, R6 and R7 independently at each occurrence represent H, 0-C,.4 alkyl, O-aryl, Cn.4 alkyl, halogen, aryl, N02, C(0)-C,.4 alkyl, CN, C(0)0-C,.4- alkyl or N(C1.4 alkyl)-; alternatively when R1 and R6 are on adjacent carbon atoms they can be taken together to represent
Figure imgf000005_0001
R2 represents H, C(0)-C1.4-alkyl, C(0)-aryl, C,.4 alkyl, C,.4 alkyl-aryl or aryl ;
R3 represents (CH2),.6-NH-C02-(CH2),.3-aryl, H, (CH2)1.3-aryl-C(O)-(CH2)0.3- C(CH3)3, (CH-)1.6-NH-CO--(CH2)0..-C4.14 branched alkyl, (CH2),.6-NH-C(=NH)- NH2, C..14 straight chain alkyl, C3.10 branched alkyl, (CH2),.3-S-(CH-),.3-aryl, (CH2),.3-S-(CH2)0.--CH3, (CH2),.3-aryl, or (CH2),.3-aryl substituted with at least one of OH, O-C,.,0-alkyl, halogen, C,.4-alkyl or C3.10 branched alkyl; R4 represents a group selected from C,.,4 straight chain alkyl, C3.10 branched alkyl, C5.14 saturated or partially unsaturated cyclo alkyl, C2.20 branched or straight chain partially unsaturated alkyl, aryl, chromen-4-one, or heteroaryl, said groups substituted with R8, R9 and R10;
R5 is selected from C5.14 saturated or partially unsaturated cycloalkyl, C,.,4 alkyl, (CH2),.4-aryl, (CH2)1.4-COOC1.4 alkyl, halo aryl, aryl-C,.4 alkyl, aryl, C,.4 alkyl morpholino, and C 4 alkyl-S(0)n-optionally substituted aryl;
R8, R9 and R10 independently at each occurance are selected from H, halogen, C,.6 alkyl, C,.4 thio alkyl, thio aryl, OC,.,- alkyl, NH2, NHC,.6 alkyl, N(C,.6 alkyl)2, C,.4 alkyl aryl, OCF3, OCOOC,.4 alkyl, C5.6 cycloalkyl, C5.6 cycloalkylene, C3.,0 branched alkyl, (CH2)0.3 aryl, and CH(Ph)2; and n represents an integer from 0 to 2; the process comprising:
(a) treating an inert solvent mixture of a compound of Formula 2:
Figure imgf000006_0001
Formula 2, an appropriate base and an optional catalyst, with a compound of Formula 1
Figure imgf000006_0002
.Formula 1.
to form a compound of Formula 3
Figure imgf000006_0003
CH, SS .Formula 3,
where R1, R2, R6 and R7 are as defined earlier, and SS represents a solid support;
(b) treating a compound of Formula 3 with a protic and inert solvent solution of a mixture of compounds of Formula 4, Formula 5, and Formula 6
Figure imgf000007_0001
.Formula 4,
R4-CHO .Formula 5, and
+
Rs -N≡ .Formula 6, in the presence of an optional dehydrating agent and an optional suitable base to form a compound of Formula 7:
Figure imgf000007_0002
.Formula
7,
where R\ R2, R3, R4, R5, R6, R7 and SS are as defined earlier; (c) optionally treating an inert solvent solution of a compound of Formula 7 with an appropriate base followed by treatment with a mild acid to yield a compound of Formula 8:
Figure imgf000008_0001
.Formula
8,
where R\ R2, R3, R4, R5, R6, R7 and SS are as defined earlier; and
(d) treating an inert solvent solution of a compound of Formula 7 or Formula 8 with a strong acid to yield a compound of Formula I.
A preferred embodiment of the present invention provides a process wherein step (a) is carried out in the presence of a catalyst. A preferred catalyst is selected from HOBt, 1 -hydroxy-7-azabenzotriazole (HOAt), N- hydroxysuccinimide and 4-hydroxy azotriazole.
In another preferred embodiment is provided a process wherein: the appropriate base in step (a) is selected from tertiary amines, N- methylmorpholine (NMM), N-ethylmorpholine, N-methylpiperidine, N-ethyl- piperidine, lutidine, pyridine, triethylamine and N,N-diisopropylethylamine (DIPEA); the suitable base in step(b) is selected from 4-methyl morpholine (NMM), N-ethylmorpholine, N-methylpiperidine, N-ethylpiperidine, triethylamine and N,N-diisopropylethylamine (DIPEA). Yet another preferred embodiment provides a process wherein the appropriate base in step(c) is selected from an alkali metal salt of trimethyl silanol and lithium hydroxide, and the mild acid in step(c) is selected from acetic acid, propionic acid, citric acid, butyric acid and valeric acid.
A further preferred process of the present invention is one wherein the strong acid in step(d) is selected from trifluoro acetic acid (TFA), trifluoromethane sulfonic acid, perfluorobutyric acid, hydrochloric acid, hydrobromic acid and hydrofluoric acid.
A particularly preferred embodiment of the present invention provides a process wherein R1, R6 and R7 are independently selected from H, OCH3, CH3, CI and Br; R2 is selected from H and methyl; R3 represents H, (CH-),. 4alkyl-NH-C02-CH2-Ph, CH3, (CH2),.4-NH-C02-C(CH3)3, (CH2),.3-NH-
C(=NH)NH2, CH2-S-CH2-Ph, (CH2)2-S-CH3, CH(CH3)-ethyl, benzyl, CH2- CH(CH3)2, CH(CH3)2 or 4-(2,2-dimethyl-propionyl)-benzyl; R4 represents C2.,0 partialiy unsaturated alkyl, naphthyl or phenyl substituted with at least one substituent selected from the list consisting of OC,.6 alkyl, OCF3, halogen, O- COO-CH-, phenyl, C,.2 alkyl, pyridyl, cyclohexyl, cyclohexylene, C3.7 branched alkyl, CH(Ph)2, 2-phenyl-propane-1 -yl, CH2-CH2-Ph; and R5 represents cyclohexyl, ethyl morpholino, /■-butyl, benzyl, CH2-COOMe or 2,6-dimethylphenyl. Provided in another aspect of the present invention is a compound of
Formula 7:
Figure imgf000010_0001
.Formula
7,
wherein:
R1, R6 and R7 independently at each occurrence represent H, 0-C,.4 alkyl, O- aryl, C,.4 alkyl, halogen, aryl, N02, C(0)-C,.4 alkyl, CN, C(0)0-C,.4-alkyl or
N(C,.4alkyl)2; alternatively when R1 and R6 are on adjacent carbon atoms they can be taken together to represent
Figure imgf000010_0002
R2 represents H, C(0)-C,.4-alkyl, C(0)-aryl, C,.4 alkyl, C,.4 alkyl-aryl or aryl ; R3 represents (CH2),.6-NH-C02-(CH2),.3-aryl, H, (CH2),.3-aryl-C(O)-(CH2)0.3- C(CH3)3, (CH2),.6-NH-CO2-(CH2)0.2-C4.,4 branched alkyl, (CH2),.6-NH-C(=NH)- NH2, C,.14 straight chain alkyl, C3.,0 branched alkyl, (CH2),.3-S-(CH2)1 3-aryl, (CH2),.3-S-(CH2)0.2-CH3, (CH2),.3-aryl, or (CH2),.3-aryl substituted with at least one of OH, O-C,.,0-alkyl, halogen, C,.4-alkyl or C3.,0 branched alkyl;
R4 represents a group selected from C,.,4 straight chain alkyl, C3.,0 branched alkyl, C5.,4 saturated or partially unsaturated cyclo alkyl, C2.20 branched or straight chain partially unsaturated alkyl, aryl, chromen-4-one, or heteroaryl, said groups substituted with R8, R9 and R10;
R5 is selected from C5.,4 saturated or partially unsaturated cycloalkyl, C,.,4 alkyl, (CH2),.4-aryl, (CH2),.4-COOC,.4 alkyl, halo aryl, aryl-C,.4 alkyl, aryl, C,.4 alkyl morpholino, and C,.4 alkyl-S(0)n-optionally substituted aryl;
SS represents a solid support;
R8, R9 and R10 independently at each occurance are selected from H, halogen, C,.6 alkyl, C,.4 thio alkyl, thio aryl, OC,.,0 alkyl, NH2, NHC,.6 alkyl,
N(C,.6 alkyl)2, C,,4 alkyl aryl, OCF3, OCOOC,.4 alkyl, C5.6 cycloalkyl, C5.6 cycloalkylene, C3.,0 branched alkyl, (CH2)0.3 aryl, and CH(Ph)2; and n represents an integer from 0 to 2.
Yet another aspect of the present invention provides a compound of Formula 8:
Figure imgf000011_0001
.Formula 8
wherein: R1, R6 and R7 independently at each occurrence represent H, O-C, 4 alkyl, O- aryl, C, 4 alkyl, halogen, aryl, NO2, C(0)-C, 4 alkyl, CN, C(0)0-C.4-alkyl or N(C, 4alkyi)2; alternatively when R1 and R6 are on adjacent carbon atoms they can be taken together to represent
Figure imgf000012_0001
R2 represents H, C(0)-C, 4-alkyl, C(0)-aryl, C, 4 alkyl, C, 4 alkyl-aryl or aryl ;
R3 represents (CH2), 6-NH-C02-(CH2), 3-aryl, H, (CH2), 3-aryl-C(O)-(CH2)03- C(CH3)3, (CH2 , 6-NH-CO2-(CH2)02-C4 14 branched alkyl, (CH2), 6-NH-C(=NH)- NH2, C, ,4 straight chain alkyl, C3 10 branched alkyl, (CH2), 3-S-(CH2), 3-aryl, (CH2)1 3-S-(CH2)02-CH3, (CH2), 3-aryl, or (CH2), 3-aryl substituted with at least one of OH, O-C,.,0-alkyl, halogen, C, 4-alkyl or C3 10 branched alkyl; R4 represents a group selected from C, 14 straight chain alkyl, C3 10 branched alkyl, C5 14 saturated or partially unsaturated cyclo alkyl, C220 branched or straight chain partially unsaturated alkyl, aryl, chromen-4-one, or heteroaryl, said groups substituted with R8, R9 and R10;
R5 is selected from C5 14 saturated or partially unsaturated cycloalkyl, C, ,4 alkyl, (CH2), 4-aryl, (CH2)1 4-COOC, 4 alkyl, halo aryl, aryl-C, 4 alkyl, aryl, C, 4 alkyl morpholino, and C, 4 alkyl-S(0)n-optionally substituted aryl; SS represents a solid support;
R8, R9 and R10 independently at each occurrence are selected from H, halogen, C, 6 alkyl, C1 4 thio alkyl, thio aryl, OC, ,0 alkyl, NH2, NHC, 6 alkyl, N(C, 5 alkyl)-, C, 4 alkyl aryl, OCF3, OCOOC1 4 alkyl, C56 cycloalkyl, C56 cycloalkylene, C3 10 branched alkyl, (CH2)03 aryl, and CH(Ph)2; and n represents an integer from 0 to 2. Experimental Details
Compounds of Formula I can be synthesized by the novel process of the present invention. This novel process is described in Scheme A below:
Scheme A
Figure imgf000013_0001
Compound 4 Compound 5 Compound 6 optional suitable base, optional dehydrating agent
Figure imgf000013_0002
mert protic solvent
STEP C
base
Figure imgf000013_0003
Figure imgf000013_0004
Figure imgf000014_0001
Formula I
General Synthetic Procedure
Compounds of the present invention can be synthesized by the novel process outlined in Scheme A above. The general description of each step of this novel process is discussed below.
Synthesis of Compounds of Formula 3 (Step B)
Anthranillic acid of Formula 2 (400-800 mmol) and a catalyst, preferably HOBt, (0.5 to 1.5 equivalents with respect to the anthranillic acid), were dissolved in a DCM-DMF (4:1 to 1 :1 ) mixture. The resulting mixture was cooled to a temperature of about 10°C to about -10°C. To this cold reaction mixture was then added an appropriate base (1 to 1.5 equivalents with respect to the anthranillic acid). The preferred appropriate base is N,N- diisopropyl ethyl amine. This mixture was briefly stirred followed by the addition of a compound of Formula 1 (0.1 to 0.3 equivalents with respect to the anthranillic acid). This mixture was stirred at the low temperature, of from about -50°C to about 5°C, for up to 30 minutes. Stirring was then continued at ambient temperature for 10 to 24 hours resulting in the formation of a compound of Formula 3. This compound of Formula 3 was isolated by filtration and washed in succession with DMF (x3), DCM (x1 ), a 20% (v:v) acetic acid solution in DCM (x4), DCM (x2), methanol (x1 ), DCM (x1 ) and diethyl ether (x2). Upon drying the compound of Formula 3 was obtained in the form of greenish-brown resin beads.
Synthesis of Compounds of Formula 7 (Step C)
A compound of Formula 3 was washed with DCM, followed by sequential addition of DCM, a compound of Formula 4 (0.480 mmol, in the form of a 1.5 M methanol solution), compound of Formula 5 (0.480 mmol, in the form of a 1.5 M solution in methanol) and optionally a suitable base, 4- methylmorpholine (0.480 mmol, in its neat form) to form an essentially homogenous mixture. This homogenous mixture was agitated for up to 4 hours followed by the addition of a compound of Formula 6 (0.480 mmol) in DCM or DCE or CHCI3, and this resulting mixture was further agitated at ambient temperature for 8 to 24 hours leading to the formation of a compound of Formula 7.
The compound of Formula 7 was isolated by filtration and washed in succession with DMF (x3), DCM (x3) and methanol (x2). This compound of Formula 7 was preferably dried before further use.
Synthesis of Compounds of Formula 8
The compound of Formula 7 was washed with THF (x2) followed by dilution with a solution of an appropriate base (preferably potassium trimethylsilanoate) in an inert solvent (preferably THF). This diluted mixture was stirred for about 8 to about 24 hours leading to the formation of a compound of Formula 8.
This compound of Formula 8 was isolated and then washed in succession with DMF (x3), 20% acetic acid in DMF (x3), DCM (x3), methanol (x2) and DCM (x2). This washed compound of Formula 8 was further used after drying. Synthesis of a Compound of Formula I
To a compound of Formula 7 or 8 was added a mixture of a strong acid and an inert solvent, preferably a 1 :1 mixture of trifluoro acetic acid and DCM, and this resulting mixture was stirred at ambient temperature from about 1 to about 4 hours. The reaction mixture was then maintained at a low temperature for about 30 minutes leading to the formation of a compound of Formula I. Compound(s) of Formula 1 , which are used in Step B of the presently claimed novel process, can be prepared by synthetic methods known to one skilled in the art. One such method is discussed below.
4-Nitrophenylcarbonate-Wang resin (Compound of Formula 1 ): A 5000 mL 3-neck round-bottom flask fitted with a nitrogen inlet, a mechanical stirrer and a glass stir rod with a Teflon stir blade was placed in a rectangular bucket. The flask was charged with 250g (312 mmol; 1.25 mmol) of Wang resin (MidWest Biotech, Cat. #20800) followed by 2000 mL of dry DCM. The resulting resin slurry was cooled in an ice bath and 170 mL (156.4g; 1.55 mol) of N-methylmorpholine was added. After stirring the resulting resin slurry for about 30 minutes in the ice bath, 190g (942 mmol) of solid 4-nitrophenylchloroformate was added in one portion, followed by 100 mL of DCM. The resin slurry was further stirred for 18 hours at ambient temperature. The resin slurry was filtered isolating the resin which was then washed by diluting with 800-mL portions of dry DCM, stirring the resin with a stirrer for a few minutes before applying suction. The washes were continued until thin-layer chromatographic analysis of the filtrate showed no Ultra Violet (UV) active material in the washes. The resin was finally washed with two 700 mL portions of dry diethyl ether. The resin was dried to yield 301 g of a compound of Formula 1 in the form of yellow-colored resin beads. Synthesis of an Array of Compounds of Formula I
The novel process of the present invention can also be used to prepare an array of compounds of Formula I. Following is the general procedure to accomplish the same.
Attachment of the anthranillic acids to Wang resin (preparation of a compound of Formula 3)
A mixture of 4,5-Dimethoxyanthranilic acid (123g; 625 mmol) and a catalyst, HOBWH.O (51 .9g; 385 mmol), in 750 mL of a 2:1 DCM-DMF solvent system was cooled in an ice bath. The cooled mixture was then treated with an appropriate base, preferably 140 mL (104g; 803 mmol) of N,N-diisopropylethylamine in one portion, followed by a compound of Formula 1 , preferably 100g (126 mmol) of the 4-nitrophenylcarbonate Wang resin. The mixture was then stirred for about 20 hours at ambient temperature. The resin was isolated and then washed in succession with DMF (3x500 mL), DCM (500 mL), 20% acetic acid in DCM (v:v; 4x500 mL), DCM (2x500 mL), methanol (500 mL), DCM (2x500 mL) and finally diethyl ether (2x500 mL). The final DCM washes were monitored by TLC to ensure absence of UV active material. The resin was dried to yield 103g of greenish-brown colored resin beads. Other anthranillic acids can be attached to the resin using the above described general procedure.
Preparation of an Array of Compounds of Formula 7
The resin supported anthranillic acids, compounds of Formula 3 from STEP B, Scheme A, were partitioned into Polyfiltronics plates using one resin per plate. The plates were washed with 500 μL of DCM per well and drained. The plates were placed in metal plate clamps with a teflon sheet lining the bottom of the plates. To each well was sequentially added (i) 500 μL of DCM, (ii) 370 μL (0.480 mmol) of 1.5M methanol solution of the amino ester hydrochloride (compound of Formula 4), (iii) 370 μL (0.480 mmol) of a 1.5M methanol solution of the aldehyde (compound of Formula 5), (iv) 49 μL of neat 4-methylmorpholine (optional suitable base), and finally (v) 53 μL of trimethyl orthoformate (optional dehydrating agent). The resin and reagent mixtures were agitated with a pipettor and then the tops of the plates were covered with a teflon sheet and clamped. The plates were then shaken on a Lab Line reciprocal shaker (VWR Scientific, cat. # 57008-195; speed setting = 7) for 1-2 hours. The top plate and teflon sheet were removed and each well was treated with 46.6 μL (40.9 mg; 0.375 mmol) of a compound of Formula 6. The plates were again covered with teflon sheets and clamped. The covered plates were then shaken on a Lab Line reciprocal shaker (VWR Scientific, cat. # 57008-195; speed setting = 7) for 16-20 hours to yield an array of compounds of Formula 7.
The plates were then carefully undamped to minimize premature drainage and transferred to a TomTec vacuum box (cat. # 196-501). The solvents were drained and the plates were washed with DMF (3x1.0 mL), DCM (3x1.0 mL) and methanol (2x1.0 mL).
Ester Hydrolysis (Preparation of an Array of Compounds of Formula 8)
The washed plates from STEP C Scheme A were washed with tetrahydrofuran (2x1.0 mL) as soon as possible, but before the addition of the appropriate base (potassium trimethylsilanoate). After the washing was complete, the plates were clamped with a lower teflon sheet and 1.0 mL (900 μmol) of a 0.9M tetrahydrofuran solution of the potassium trimethylsilanoate (Gelest Inc.; cat. #SIP6901.0) was added to each well. The top of the plate is covered with a teflon sheet and metal plate and shaken on a Lab Line reciprocal shaker (VWR Scientific cat. # 57008-195; speed setting = 7) for 16-20 hours overnight. The plates were carefully undamped to minimize premature drainage and transferred to a TomTec vacuum box (cat. # 196-501 ). The solvents were drained and the plates were washed with DMF (3x1 .0 mL), 20% acetic acid in DMF (3x1 .0 mL), DCM (3x1 .0 mL), methanol (2x1 .0 mL), and DCM (2x1 .0 mL).
Cleavage and Cvclization - Preparation of an Array of Compounds of Formula I
The plates from STEP D Scheme A were clamped with a lower teflon sheet. Each well was then treated with 750 μL of a 1 :1 mixture of a strong acid, i.e., trifluoroacetic acid and DCM and the plates were covered with a teflon sheet and metal cover plate. The plate was shaken on a Lab Line reciprocal shaker (VWR Scientific cat. # 57008-195; speed setting = 7) for 2 hours, then the plates were placed in a container and covered with dry ice. The plates were kept in the ice for 30 minutes and then quickly undamped and transferred on top of a tared, 2-mL Beckman square well plate. The plates were allowed to drain into the Beckman plates for about 30 minutes, then each well was washed with 300 μL of a 1 :1 mixture of trifluoroacetic acid and DCM, followed by 300 μL of dichloromethane. The plates were then evaporated on a Savant SpeedVac for 3 hours using the medium drying setting.
Synthesis of Specific Compounds (Standards)
The following Standards were prepared using the novel process of the present invention.
Figure imgf000020_0001
Std. 1 Std. 2
Figure imgf000020_0002
Figure imgf000020_0003
Std. 5 Std. 6 Characterization data for the above standards is as follows:
Std-i: 'H-NMR (DMSO-d6, 270 MHz) δ : 10.25 (s), 8.26 (br d), 7.82 (br d), 7.75-7.66 (m), 7.54-7.27 (m), 7.21 (br t), 7.06 (br d), 6.30 (s), 3.80 (br s), 3.62 (br s), 1.85-1.48 (m), 1.34-1.00 (m).
MS: m/z = 468.2 [M+H], 100%
Std. 2: Η-NMR (CD3OD, 300 MHz; mixture of diastereomers) δ: 7.37 (d), 6.64 (d), 5.62 (t), 4.68 (t), 4.45 (dd), 3.88 (s), 3.86 (s), 2.81 (t), 2.70 (t), 1.95- 1.15 (m), 0.94 (f), 0.80 (f).
MS: m/z = 489.3 [(M+H)+, 100%]
Std. 3: Η-NMR (CD3OD, 300 MHz; mixture of diastereomers) δ : 8.18 (br d), 7.94 (br d), 7.89 (dd), 7.73 (d), 7.64 (dt), 7.53 (d), 7.50-7.20 (m), 6.98 (dt), 6.83 (dd), 6.71 (s), 5.57 (q), 5.61 (s), 4.27 (q), 3.72 (br s), 1.98-1.12 (m, with d at 1.53), 0.75 (d).
MS: m/z = 482.2 [(M+H)+, 100%]
Std. 4: Η-NMR (CD3OD, 300 MHz) δ: 8.29 (d), 7.70-7.64 (m), 7.51-7.31 (m), 7.12 (br s), 6.64 (s), 6.46 (br s), 6.39 (s), 3.88 (s), 3.87 (s), 3.73 (d), 1.19-1.12 (m).
MS: m/z = 528.2 [(M+H)+, 100%]
Std. 5: Η-NMR (CD3OD, 300 MHz) δ :7.90 (dd), 7.53 (dt), 7.38 (d), 7.32- 7.25 (m), 7.09 (dd), 7.99 (d), 6.32 (s), 3.73 (d), 3.15 (s), 2.99 (s), 1.92-1.72 (m), 1.66-1.15 (m).
MS: m/z = 435.1 [(M+H)+, 100%]
Std. 6 : Η-NMR (CD.OD, 300 MHz) δ 7.36 (s), 7.32 (s), 6.66 (s), 5.15 (dd), 3.88 (s), 3.87 (s), 1.90-1.62 (m), 1.40-1.19 (m), 0.96 (t).
MS: m/z = 418.1 [(M+H)+, 100%]
Synthesis of Standard 1( compound of Formula 1): 2-Biphenyl-4-yl-N- cyclohexyl-2-(2,5-dioxo-1 ,2,3,5-tetrahydro-benzo[e][1 ,4] diazepin-4-yl)- acetamide Synthesis of a Compound of Formula 3
Figure imgf000022_0001
4,5-dimethoxyanthranillic acid (a compound of Formula 2, 123 g, 625 mmol) and HOBt (a catalyst, 51.9 g, 385 mmol) were dissolved in 500 mL of a 2:1 mixture of DCM-DMF. The resulting mixture was cooled to a temperature of about 0°C. To this cold reaction mixture was then added N,N-diisopropylethylamine (appropriate base, 104 g, 803 mmol). This mixture was briefly stirred followed by the addition of 4-nitrophenylcarbonate Wang resin (a compound of Formula 1 , 100g, 120 mmol). This mixture was stirred at the low temperature for up to 30 minutes. Stirring was then continued at ambient temperature for 10 to 24 hours resulting in the formation of a compound of Formula 3. This compound of Formula 3 was isolated by filtration and washed in succession with DMF (3 x 500 mL), DCM (1 x 500 mL), a 20% (v:v) acetic acid solution in DCM (4 x 500 mL), DCM (2 x 500 mL), methanol (1 x 500 mL), DCM (1 x 500 mL) and diethyl ether (2 x 500 mL). The latter DCM washes were checked to ensure absence of UV active material. Upon drying the compound of Formula 3 was obtained as greenish-brown resin beads. Synthesis of Compounds of Formula 7 (Step C)
Compound of Formula 3, from Step B above, was washed with DCM, followed by sequential addition of DCM, amino-acetic acid methyl ester (a compound of Formula 4, 0.480 mmol, 370 μL of a 1.5 M methanol solution), biphenyl-4-carbaldehyde (a compound of Formula 5, 0.480 mmol, 370 μL of a 1.5 M solution in methanol) and NMM (suitable base, 0.480 mmol) to form an essentially homogenous mixture. This homogenous mixture was agitated for up to 4 hours followed by the addition of cyclohexylisocyanide (a compound of Formula 6, 550 μL of a 0.87 molar solution in DCM) and this resulting mixture was further agitated at ambient temperature for 8 to 24 hours leading to the formation of a compound of Formula 7.
The compound of Formula 7 was isolated by filtration and washed in succession with DMF (3 x 1 mL), DCM (3 x 1 mL) and methanol (2 x 1 mL). This compound of Formula 7 was preferably dried before further use. Synthesis of Compounds of Formula 8
Figure imgf000024_0001
....Formula 8
The compound of Formula 7 was washed with THF (2 x 1 mL) followed by dilution with a solution of potassium trimethylsilanoate (appropriate base, 900 μM, 1 mL of a 0.9 M THF solution). This diluted reaction mixture was stirred for about 16 to about 20 hours leading to the formation of a compound of Formula 8.
This compound of Formula 8 was isolated and then washed in succession with DMF (3 x 1 mL), 20% acetic acid in DMF (3 x 1 mL), DCM (3 x 1 mL), methanol (2 x 1 mL) and DCM (2 x 1 mL). This washed compound of Formula 8 was further used after drying.
Synthesis of Standard 1 ( compound of Formula 1): 2-Biphenyl-4-yl-N- cyclohexyl-2-(2,5-dioxo-1 ,2,3,5-tetrahydro-benzo[e][1 ,4] diazepin-4-yl)- acetamide
To a compound of Formula 8 above, was added 750 μl of a 1 :1 mixture of trifluoro acetic acid (a strong acid) and DCM, and this resulting mixture was stirred at ambient temperature from about 2 hours. The reaction mixture was then maintained at a low temperature of about -40°C for about 30 minutes leading to the formation of a compound of Formula I. Analysis Procedure
A. Chromatography: All validation samples were analyzed on a Hewlett Packard HP1100 HPLC employing a Zorbax 4.6 mm x 7.5 cm SP-C18 column with a guard column. Samples were monitored at UV settings of 214 and 254 nm. The column was heated at 40°C and the flow rate was 0.800 mL per minute for all runs. Gradient elution was performed using water with 0.05% TFA (solvent A) and acetonitrile containing 0.05% TFA (solvent B) as mobile phases. Most samples were prepared as dilute solutions in acetonitrile, methanol or mixtures thereof.
HPLC Gradient: Time (minutes) % Solvent B
0.00 0.00
5.00 100
8.00 100.0
9.50 0.00
B. Mass Spectrometrv: Identity of peaks observed by HPLC were determined by electrospray (ESI) LC/MS analysis on a Finnigan TSQ 7000 mass spectrometer with a Hewlett Packard HP1050 HPLC. Alternatively, purified compounds or relatively pure mixtures were analyzed with a Hewlett Packard 5989 particle beam mass spectrometer and Hewlett Packard 59980 LC/MS interface in either CI or El mode, with a Hewlett Packard HP1050 HPLC using methanol as mobile phase for direct injection of samples. Most samples were prepared as dilute solutions in acetonitrile or methanol. For analysis of both the test library and production library, direct injection MS analysis was performed on the Sciex 150 MCA, Shimadzu LC-10 HPLC, according to the following conditions:
LC/MS Assay:
Mobile A: Water (containing 0.05% AcOH and 1.0% MeOH) Mobile B: Methanol (containing 0.05% AcOH and 1.0% water) Flow Rate: 0.3 mlJmin Sample volume: 10.0 μL Column: Zorbax 3.0 x 50.0 mm column with inline filter Temp.: 40 °C Gradient: 0 to 100% B in 6.0 min, 100% B for 1.0 min, 0% B for
2.0 min.
Detection: UV monitoring at 214, 254, 280, and 320 nm
MS Assay:
Mode: Positive ion ESI injection volume 5 μL flow rate 0.3 mL/min, 50% solvent B.
C. Solid-Phase FT-IR: FT-IR spectra were obtained on a Nicolet Impact 420 FT-IR equipped with a Spectra Tech Inspect IR optical bench and Omnic V.3.1 software, using a single resin bead.
DEFINITIONS:
The term "alkyl" as used herein represents a hydrocarbon radical comprising from one to six carbon atoms, unless indicated otherwise. The term "aryl" as used herein represents an aromatic hydrocarbon comprising from six to ten carbon atoms. The term "optionally substituted aryl", unless indicated otherwise, represents an aryl group, as defined above, that can be substituted with one or more substitutents selected from a group consisting of OCF3, halogen, S-haloalkyl, S-haloaryl, NHC,.4-CN, N(C,.4-CN)2, and O- C(0)-C,.4 alkyl.
The term "optionally substituted aryl" as used under R5 is indented to represent an aryl group as defined above which can be substituted with one to three substitutents selected from a group consisting of alkyl, halo, nitro, thio-alkyl, cyano, C,.4 alkoxy and phenyl. The term "halo" or "halogen" is intended to represent CI, Br, I and F.
The term "strong acid" as used herein represents a protic or lewis acid that can cleave a chemical entity from the solid support and subsequently generate a heterocydic product. Illustrative examples of strong acid are trifluoroacetic acid (TFA), trifluoromethanesulofonic acid, perfluorobutyric acid, sulfuric acid, hydrochloric acid, hydrofluoric acid and hydrobromic acid. The term "appropriate base" as used in step (a) herein represents a base which will assist in effecting the reaction in step (a). Desirable bases are tertiary amine or alkali metal salt that can convert a 2- aminobenzoic acid derivative to the corresponding carboxylate salt. Illustrative examples of an appropriate base are N-methylmorpholine (NMM), N-ethylmorpholine, N-methylpiperidine, N-ethylpiperidine, triethyl amine, pyridine, lutidine and N,N-diisopropylethylamine (DIPEA). The term "suitable base" as used in step (b) herein represents an amino compound which can convert a primary amine salt to its free base. A desirable class of the suitable base is tertiary amines. Illustrative examples of the suitable base are N-methylmorpholine (NMM), N-ethylmorpholine, N- methylpiperidine, N-ethylpiperidine, triethyl amine, pyridine, lutidine and N,N- diisopropylethylamine (DIPEA). The term "appropriate base" as used in step (c) herein represents a compound that can convert a support-bound ester to the corresponding carboxylate salt. Illustrative examples of the appropriate base are alkali metal salts of trimethyl silanol, potassium trimethylsilanoate, tetrabutylammonium hydroxide, tetramethylammonium hydroxide and lithium hydroxide.
As used in the present invention, the illustration:
generally indicates a point of attachment of the group, comprising the illustration, to another group or atom. The term "solid support" (SS), as used in the present invention, signifies polymeric material for supported synthesis. A detailed description of the terms linker molecule and solid support can be found in The Combinatorial Index, B. A. Bunin, Academic Press (1998), which is incorporated herein by reference. The term "inert solvent" is intended to represent solvents which do not react with the reagents dissolved therein. Illustrative examples of inert solvents are tetrahydrofuran (THF), methyiene chloride, dichloro methane (DCM), ethyl acetate (EtOAc), dimethyl formamide (DMF), diaoxane, chloroform, and DMSO. As used herein the term "dehydrating agent" (also some times referred to as "drying agent") represents an agent which facilitates removal of any water or moisture which may be present in a reaction mixture or formed during a reaction. Typical dehydrating/drying agents known to one skilled in the art are intended to be included herein. Representative examples of dehydrating/drying agents are magnesium sulfate, sodium sulfate, methyl orthoformate, ethyl orthoformate, methyl ortho acetate and ethyl ortho acetate, or any moisture which may be present in
The term "catalyst " is intended to represent an additive that facilitates the course of a reaction but does not get incorporated in to the final product. Illustrative examples of catalysts are N-hydroxybenzotriazole (HOBt), 1 -hydroxy-7-azabenzotriazole (HOAt) and N-hydroxysuccinimide. The term solid support (SS), as used in the present invention, signifies polymeric material for supported synthesis. A detailed description of the terms linker molecule, and solid support can be found in The Combinatorial Index, B. A. Bunin, 1998, which is incorporated herein by reference.
The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase "optionally is substituted with one to three substituents" means that the group referred to may or may not be substituted in order to fall within the scope of the invention. Thus the term "optionally substituted" is intended to mean that any one or more hydrogens on a designated atom can be replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound. When the substituent is keto (=0) then 2 hydrogens on the atom are replaced. Abbreviations:
ACD = Available Chemicals Directory
ACN = acetonitrile
AcOH = acetic acid
AE = amino ester
AL = aldehyde BOO = t-butyloxycarbonyl tBu = tert-butyl
CBZ = benzyloxycarbonyl
CI = chemical ionization
1 ,2-DCE = 1 ,2-dichloroethane DCM = dichloromethane
DCE = dichloroethane
DMF = N,N-dimethylformamide
DMSO = dimethylsulfoxide
El = electron impact ESI = electrospray ionization
HOAt = 1 -hydroxy-7-azabenzotriazole
HOBt = N-hydroxybenzotriazole
IC = isocyanide
LC/MS = liquid chromatography/mass spectroscopy MS = mass spectroscopy
NMM = N-methylmorpholine (4-methylmorpholine)
RT = room temperature
THF = tetrahydrofuran
TLC = Thin-layer chromatography TFA = trifluoroacetic acid
TMOF = Trimethylorthoformate

Claims

1. A process for the synthesis of a compound of Formula I:
Figure imgf000030_0001
.Formula I
wherein
R\ R6 and R7 independently at each occurance represent H, 0-C,.4 alkyl, O- aryl, C,.4 alkyl, halogen, aryl, N02, C(0)-C,.4 alkyl, CN, C(O)O-0,.4-alkyl or N(C,.4 alkyl)2; alternatively when R and R6 are on adjacent carbon atoms they can be taken together to represent
Figure imgf000030_0002
R2 represents H, C(0)-C,.4-alkyl, C(0)-aryl, C,.4 alkyl, C,.4 alkyl-aryl or aryl ; R3 represents (CH2),.6-NH-C02-(CH2),.3-aryl, H, (CH2),.3-aryl-C(O)-(CH2)0.3- C(CH3)3, (CH2),.6-NH-CO2-(CH2)0.2-C4,4 branched alkyl, (CH2),.6-NH-C(=NH)- NH2, C,.,4 straight chain alkyl, C3.10 branched alkyl, (CH2),.3-S-(CH2),.3-aryl, (CH2),.3-S-(CH2)0.2-CH3, (CH2),.3-aryl, or (CH2),.3-aryl substituted with at least one of OH, O-C,.,0-alkyl, halogen, C,.4-alkyl or C3.,0 branched alkyl; R4 represents a group selected from C,.,4 straight chain alkyl, C3.10 branched alkyl, C5.,4 saturated or partially unsaturated cyclo alkyl, C2.20 branched or straight chain partially unsaturated alkyl, aryl, chromen-4-one, or heteroaryl, said groups substituted with R8, R9 and R10;
R5 is selected from C5.,4 saturated or partially unsaturated cycloalkyl, C,.,4 alkyl, (CH2),.4-aryl, (CH2),.4-COOC,.4 alkyl, halo aryl, aryl-C,.4 alkyl, aryl, C,.4 alkyl morpholino, and C,.4 alkyl-S(0)n-optionally substituted aryl; R8, R9 and R10 independently at each occurance are selected from H, halogen, C,.6 alkyl, C,.4 thio alkyl, thio aryl, OC,.,0 alkyl, NH2, NHC,.6 alkyl, N(C,.6 alkyl)2, C,.4 alkyl aryl, OCF3, OCOOC,.4 alkyl, C5.6 cycloalkyl, C5.6 cycloalkylene, C3.,0 branched alkyl, (CH2)0.3 aryl, and CH(Ph)2; and n represents an integer from 0 to 2; the process comprising:
(a) treating an inert solvent mixture of a compound of Formula 2:
Figure imgf000031_0001
Formula 2, an appropriate base and an optional catalyst, with a compound of Formula 1
Figure imgf000031_0002
.Formula 1 ,
to form a compound of Formula 3
Figure imgf000032_0001
CH, SS .Formula 3,
where R1, R2, R6 and R7 are as defined earlier, and SS represents a solid support; (b) treating a compound of Formula 3 with a protic and inert solvent solution of a mixture of compounds of Formula 4, Formula 5, and Formula 6
Figure imgf000032_0002
.Formula 4,
R4-CHO .Formula 5, and
+
.Formula 6,
in the presence of an optional dehydrating agent and an optional suitable base to form a compound of Formula 7:
Figure imgf000033_0001
.Formula 7,
where R , R2, R3, R , R , R , R and SS are as defined earlier;
(c) optionally treating an inert solvent solution of a compound of Formula 7 with an appropriate base followed by treatment with a mild acid to yield a compound of Formula 8:
Figure imgf000033_0002
.Formula 8,
where R , R', RJ, R4, R , Rb, R7 and SS are as defined earlier; and (d) treating an inert solvent solution of a compound of Formula 7 or Formula 8 with a strong acid to yield a compound of Formula I.
2. A process of Claim 1 wherein step (a) is carried out in the presence of a catalyst.
3. A process of Claim 2 wherein the catalyst is selected from HOBt, 1 - hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide and 4-hydroxy azotriazole.
4. A process of Claim 2 wherein the appropriate base in step (a) is selected from tertiary amines, N-methylmorpholine (NMM), N- ethylmorpholine, N-methylpiperidine, N-ethyl-piperidine, lutidine, pyridine, triethylamine and N,N-diisopropylethylamine (DIPEA).
5. A process of claim 3 wherein, the suitable base in step (b) is selected from 4-methyl morpholine (NMM), N-ethylmorpholine, N-methylpiperidine, N- ethylpipe dine, triethylamine and N,N-diisopropylethylamine (DIPEA).
6. A process of Claim 5 wherein the appropriate base in step (c) is selected from an alkali metal salt of trimethyl silanol and lithium hydroxide, and the mild acid is selected from acetic acid, propionic acid, citric acid, butyric acid and valeric acid.
7. A process of Claim 6 wherein the strong acid in step (d) is selected from TFA, trifluoromethane sulfonic acid, perfluorobutyric acid, hydrochloric acid, hydrobromic acid and hydrofluoric acid.
8. A process of Claim 7 wherein R6, R7 and R1 are independently selected from H, OCH3, CH3, CI and Br; R2 is selected from H and methyl;
R3 represents H, (CH2),.4 alkyl-NH-C02-CH2-Ph, CH3, (CH2),.4-NH-C02-
C(CH3)3, (CH2),.3-NH-C(=NH)NH2, CH2-S-CH2-Ph, (CH2)2-S-CH3, CH(CH3)- ethyl, benzyl, CH2-CH(CH3)2, CH(CH3)2 or 4-(2,2-dimethyl-propionyl)-benzyl;
R4 represents C2.,0 partially unsaturated alkyl, naphthyl or phenyl substituted with at least one substituent selected from the list consisting of OC,.6 alkyl,
OCF3, halogen, O-COO-CH-, phenyl, C,,2 alkyl, pyridyl, cyclohexyl, cyclohexylene, C3.7 branched alkyl, CH(Ph)2, 2-phenyl-propane-1 -yl, CH2-
CH2-Ph; and
R5 represents cyclohexyl, ethyl morpholino, .-butyl, benzyl, CH2-COOMe or
2,6-dimethylphenyl.
A compound of Formula 7:
Figure imgf000035_0001
.Formula 7,
wherein:
R\ R6 and R7 independently at each occurance represent H, 0-C,.4 alkyl, 0- aryl, C,.4 alkyl, halogen, aryl, N02, C(0)-C,.4 alkyl, CN, C(0)0-C,.4-alkyl or N(C„ alkyl)2; alternatively when R1 and R6 are on adjacent carbon atoms they can be taken together to represent
Figure imgf000036_0001
R2 represents H, C(0)-C,.4-alkyl, C(0)-aryl, C,.4 alkyl, C,.4 alkyl-aryl or aryl ;
R3 represents (CH2),.6-NH-C02-(CH2),,-aryl, H, (CH2)„-aryl-C(O)-(CH2)0.3- C(CH3)3, (CH2),.6-NH-CO2-(CH2)0.2-C,,4 branched alkyl, (CH2),5-NH-C(=NH)- NH2, C,.,4 straight chain alkyl, C3.,0 branched alkyl, (CH2),.3-S-(CH2),.3-aryl, (CH2),.3-S-(CH2)0.2-CH3, (CH2),.3-aryl, or (CH2),.3-aryl substituted with at least one of OH, 0-C,..,-alkyl, halogen, C,.4-alkyl or C3.10 branched alkyl;
R4 represents a group selected from C,.14 straight chain alkyl, C3.,0 branched alkyl, C5.,4 saturated or partially unsaturated cyclo alkyl, C2.20 branched or straight chain partially unsaturated alkyl, aryl, chromen-4-one, or heteroaryl, said groups substituted with R8, R9 and R10; R5 is selected from C5.,4 saturated or partially unsaturated cycloalkyl, C,.,4 alkyl, (CH2),.4-aryl, (CH2),.4-COOC,.4 alkyl, halo aryl, aryl-C,.4 alkyl, aryl, C,.4 alkyl morpholino, and C,.4 alkyl-S(0)n-optionally substituted aryl; SS represents a solid support; R8, R9 and R10 independently at each occurance are selected from H, halogen, C,.6 alkyl, C,.4 thio alkyl, thio aryl, OC,.,0 alkyl, NH2, NHC, 6 alkyl, N(C,.6 alkyl)., C,.4 alkyl aryl, OCF3, OCOOC,.4 alkyl, C5.6 cycloalkyl, C5.6 cycloalkylene, C3.,0 branched alkyl, (CH2)0.3 aryl, and CH(Ph)2; and n represents an integer from 0 to 2.
10. A compound of Formula 8:
Figure imgf000037_0001
.Formula 8
wherein:
R1, R6 and R7 independently at each occurance represent H, 0-C1 4 alkyl, O- aryl, C, 4 alkyl, halogen, aryl, N02, C(0)-C, 4 alkyl, CN, C(0)0-C, 4-alkyl or
N(C, 4 alkyl)2; alternatively when R1 and R6 are on adjacent carbon atoms they can be taken together to represent
Figure imgf000037_0002
R2 represents H, C(0)-C, 4-alkyl, C(0)-aryl, C, 4 alkyl, C, 4 alkyl-aryl or aryl ;
R3 represents (CH2), 6-NH-C02-(CH2), 3-aryl, H, (CH2), 3-aryl-C(O)-(CH2)03- C(CH3)3, (CH2)1 6-NH-CO2-(CH2)02-C4 14 branched alkyl, (CH2)1 6-NH-C(=NH)- NH2, C, ,4 straight chain alkyl, C3 10 branched alkyl, (CH2), 3-S-(CH2), 3-aryl, (CH2), 3-S-(CH2)02-CH3, (CH2)1 3-aryl, or (CH2)1 3-aryl substituted with at least one of OH, O-C, ,0-alkyl, halogen, C, 4-alkyl or C3 10 branched alkyl; R4 represents a group selected from C, ,4 straight chain alkyl, C3 10 branched alkyl, C5 14 saturated or partially unsaturated cyclo alkyl, C220 branched or straight chain partially unsaturated alkyl, aryl, chromen-4-one, or heteroaryl, said groups substituted with R8, R9 and R10;
R5 is selected from C5 14 saturated or partially unsaturated cycloalkyl, C, ,4 alkyl, (CH2), .-aryl, (CH2), 4-COOC, 4 alkyl, halo aryl, aryl-C, 4 alkyl, aryl, C, 4 alkyl morpholino, and C, 4 alkyl-S(0)n-optιonally substituted aryl, SS represents a solid support;
R8, R9 and R10 independently at each occurance are selected from H, halogen, C1 6 alkyl, C, 4 thio alkyl, thio aryl, OC, ,0 alkyl, NH2, NHC, 6 alkyl, N(C, 6 alkyl)2, C, 4 alkyl aryl, OCF3, OCOOC, 4 alkyl, C56 cycloalkyl, C56 cycloalkylene, C3 10 branched alkyl, (CH2)03 aryl, and CH(Ph)2; and n represents an integer from 0 to 2.
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