WO2012035549A2 - An improved process for the synthesis of beta amino acid derivatives - Google Patents

An improved process for the synthesis of beta amino acid derivatives Download PDF

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Publication number
WO2012035549A2
WO2012035549A2 PCT/IN2011/000621 IN2011000621W WO2012035549A2 WO 2012035549 A2 WO2012035549 A2 WO 2012035549A2 IN 2011000621 W IN2011000621 W IN 2011000621W WO 2012035549 A2 WO2012035549 A2 WO 2012035549A2
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independently selected
alkyl
optionally substituted
cycloalkyl
heteroaryl
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PCT/IN2011/000621
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English (en)
French (fr)
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WO2012035549A3 (en
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Rajesh Jain
Jagadeeshwar R Rao
Siripragada Mahender Rao
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Panacea Biotec Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention is related to the field of synthetic medicinal chemistry. It is related to an improved process and intermediate(s) for the synthesis of beta amino acid derivatives of formula I.
  • the compounds of formula I act as DPP-IV inhibitors and are useful in the treatment of Type 2 diabetes.
  • Type 2 diabetes is a progressive, metabolic disorder characterized by two fundamental defects: insulin resistance at peripheral target tissues and pancreatic beta-cell dysfunction. Despite good compliance to treatment, the glycaemic control of type 2 diabetes deteriorates progressively. Hence, new therapeutic agents are continuously being developed to help our diabetes population. Recent studies have shown that early intervention at prediabetes state and beta cell protection with insulin sensitizers may improve the prognosis of diabetes.
  • DPP-IV inhibitors are a novel class of oral hypoglycemic agent with potentials in improving pancreatic beta cell function and the clinical course of type 2 diabetes.
  • Dipeptidyl peptidase IV (DPP-IV) inhibitors including sitagliptin, vildagliptin, alogliptin, and saxagliptin, represent a novel approach in the management of type 2 diabetes.
  • Galvus Vildagliptin
  • EMEA European Medicines Agency
  • Eucreas a new oral treatment released by Novartis, called Eucreas, a combination of vildagliptin and metformin.
  • Onglyza Saxagliptin
  • BMS Bristol-Myers Squibs
  • AZ Astra Zeneca
  • Onglyza has been shown to reduce major adverse cardiovascular events by as much as 55%.
  • the next in the class namely Linagliptin developed by Boehringer Ingelheim was approved in May 2011.
  • Other DPP-IV drugs in pipeline are Alogliptin, SYR-472, Melogliptin, Anagliptin and Teneligliptin.
  • Beta-amino acid based DPP-IV inhibitors have been disclosed in PCT publications, for example, WO-2004043940, WO-2005044195, WO-2006009886, WO-2006023750, WO2006039325, WO-2003004498, WO-2005116029, WO- 2005113510, WO-2006097175, WO-2005120494, WO-2005121131 , WO- 2005123685, WO-2005040095 WO-2007063928, WO-2007054577, WO- 2007053819, WO-2006081151, WO-2004085378 and US patents such as US 7,259,160, US 7,101,871 and US 7,208,498.
  • DPP-IV inhibitors have oral route of administration and oral medication forms the largest segment of therapy among the anti-diabetics, it appears to be a promising therapy. Hence there still exists a need to provide a simple and convenient process for the preparation of DPP-IV inhibitors.
  • the present invention provides an improved, commercially viable and industrially advantageous processes for the synthesis of beta-amino acid based DPP-IV inhibitors.
  • the intermediates and the final end products obtained through the improved processes of this invention are obtained in a superior yield and high purity.
  • the present invention is related to a novel process and intermediate (s) for the synthesis of beta amino acid derivatives of compounds of formula I.
  • the compounds of the present invention are useful as DPP-IV inhibitors.
  • the present invention relates to a process for preparing a compound of general formula I, their pharmaceutically acceptable derivatives, tautomeric forms, stereoisomers including R and S isomers, prodrugs, metabolites, salts or solvates thereof:
  • Ar represents aryl which may be phenyl, which may be unsubstituted or optionally substituted at any available position by R 8 or by one or more substituents selected from but not limited to halogen, CN, hydroxyl, NH 2 , Ci-i 2 alkyl or Ci-i 2 alkoxy, wherein each of Ci--
  • R 2 and R 3 together represents a single oxygen or sulphur atom which is linked to the diazepine ring by a double bond; or R 1 and R 2 together forms a double bond in the diazepine ring and R 3 represents the group -NR a R b ; or R 1 and R 3 together with the nitrogen atom to which R 1 is attached forms a heterocyclic or heteroaryl ring which may additionally contain from one to three hetero atoms independently selected from O, S and N; the ring formed may optionally be substituted with one or more substituents selected from R c or R° and R 2 represent hydrogen or a double bond;
  • R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, CN, C1-12 alkyl, C 2- 12 alkenyl, C 2- 12 alkynyl, d-i 2 alkoxy, Ci-i 2 haloalkyl, Ci-i 2 haloalkoxy, C 2 -i 2 haloalkenyl, C 2 -i 2 haloalkynyl, Ci-i 2 alkylcarbonyl, Cn 2 alkoxycarbonyl, -OR a , -SR a , -N0 2 , -NR a R b , N(R a )(CO)R b , N(R a )(CO)OR b , N(R a )(CO)NR a R b , -(CO)R a , -(CO)NR a R b , -0(CO)R a , -0(CO)NR a R b
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, CN, Cn 2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, Cn 2 alkoxy, C n2 haloalkyl, Cn 2 haloalkoxy, C 2 -i 2 haloalkenyl, C 2 - 12 haloalkynyl, Cn 2 alkylcarbonyl, C 1 - 12 alkoxycarbonyl, -OR a , -SR a , -N0 2 , -NR a R b , N(R a )(CO)R , N(R a )(CO)OR b , N(R a )(CO)NR a R b , -(CO)R a , -(CO)NR a R b , -0(CO)R a , -0(CO)NR a R b ,
  • R 8 is independently selected from hydrogen, halogen, CN, Cn 2 alkyl, Cr 12 haloalkyl, C1-12 alkoxy, Cr 12 haloalkoxy, C 2 -i 2 haloalkenyl, Ci-i 2 alkylcarbonyl, C1-12 alkoxycarbonyl, -OR a , -SR a , -CF 3 , -OCF 3 , -N0 2 , -NR a R b , N(R a )(CO)R b , N(R a )(CO)OR b , N(R a )(CO)NR a R b , -(CO)R a , -(CO)NR a R b , -0(CO)R a , - 0(CO)NR a R b , -C00R 3 , C M cycloalkyl, S(0) m R a , S0 2 NR
  • R a and R b are independently selected from hydrogen, C n2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, C i2 haloalkyl, C 2 -i 2 haloalkenyl, C 2 -
  • R c or R c is independently selected from the group consisting of but not limited to (1 ) hydrogen, (2) halogen, (3) C1-12 alkyl which is linear or branched and which can be unsubstituted or substituted with 1-5 halogens or phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R 12 , OR 12 , NHS0 2 R 12 , S0 2 R 12 , C0 2 H and C0 2 C 1-6 alkyl .
  • the C0 2 Ci-6 alkyl is linear or branched ; (4) aryl which can be unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R 12 , OR 12 , NHS0 2 R 12 , S0 2 R 12 , C0 2 H and C0 2 Ci-6 alkyl .
  • the C0 2 C 1-6 alkyl is linear or branched (5) a 5 or
  • R 9 and R 10 are independently selected from hydrogen, C 1 -12 alkyl, C2-i 2 alkenyl, C 2-12 alkynyl, C 1 - 1 2 haloalkyl, C 2 -i 2 haloalkenyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH 2 ) n -cycloalkyl, (CH 2 ) n -heterocyclyl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, each of which may be optionally substituted with halogen, hydroxyl or C 1 -6 alkoxy, or R 9 and R 10 may be joined together to form a heterocyclic or heteroaryl ring which may contain from one to three heteroatoms independently selected from O, S and N, which may optionally be substituted with one or more substituents independently selected from R c or R c ;
  • R 12 is C 1 -6 alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 groups independently selected from halogen, CO2H, and C0 2 Ci-6 alkyl, wherein the CO2C 1 -6 alkyl is linear or branched;
  • M and L independently represent a hydrogen atom or they may join together to form a ring
  • n' is 0 or 1
  • n can be 1 or 2;
  • n can be 1 , 2, 3 or 4;
  • Ar is as defined above; and PG is an amino protecting groups selected from acetyl, trifluoroacetyl, benzyloxycarbonyl (CBz), t-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), 2,2,2-trichloroethyloxycarbonyl, allyloxycarbonyl and the like;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , M, L and n' are as defined above;
  • step (b) optionally converting the product obtained in step (b) to a salt.
  • the present invention relates to a process for preparing compounds of formula VI or VII, their pharmaceutically acceptable derivatives, tautomeric forms, stereoisomers including R and S isomers, prodrugs, metabolites, salts or solvates thereof:
  • Ar represents aryl which may be phenyl, which may be unsubstituted or optionally substituted at any available position by one or more substituents selected from but not limited to halogen, CN, hydroxyl, NH 2 , Ci-i 2 alkyl or CM 2 alkoxy, wherein each of Ci - 2 alkoxy and Ci-i 2 alkyl may be linear or branched and can be unsubstituted or optionally substituted with 1-5 halogens;
  • R 2 and R 3 together represents a single oxygen or sulphur atom which is linked to the diazepine ring by a double bond; or R 1 and R 2 together forms a double bond in the diazepine ring and R 3 represents the group -NR a R b ; or R 1 and R 3 together with the nitrogen atom to which R 1 is attached forms a heterocyclic or heteroaryl ring which may additionally contain from one to three heteroatoms independently selected from O, S and N; the ring formed may optionally be substituted with one or more substituents selected from R c or R c and R 2 represent hydrogen or a double bond;
  • R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, CN, Cn 2 alkyl, C 2- 12 alkenyl, C 2- 12 alkynyl, Cn 2 alkoxy, Ci-i 2 haloalkyl, C i 2 haloalkoxy, C 2 -i 2 haloalkenyl, C 2 -i 2 haloalkynyl, C1-12 alkylcarbonyl, C1-12 alkoxycarbonyl, -OR a , -SR a , -N0 2 , -NR a R b , N(R a )(CO)R b , N(R a )(CO)OR b , N(R a )(CO)NR a R b , -(CO)R a , -(CO)NR a R b , -0(CO)R a , -0(CO)NR a R b , -
  • cycloalkyl S(0) m R a , S0 2 NR a R b ; cycloalkyl which may be optionally substituted at any available position by one or more substituents independently selected from R c or R c ; aryl which may be optionally substituted at any available position by one or more substituents independently selected from R c or R c ; heteroaryl which may be optionally substituted at any available position by one or more substituents independently selected from R c or R c ; or heterocyclyl which may be optionally substituted at any available position by one or more substituents independently selected from R c or R c ;
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, CN, C n2 alkyl, C 2- 12 alkenyl, C 2- i 2 alkynyl, C1-12 alkoxy, C n2 haloalkyl, Cn 2 haloalkoxy, C 2 --
  • R 8 is independently selected from hydrogen, halogen, CN, C n 2 alkyl, Cn 2 haloalkyl, C n2 alkoxy, C1-12 haloalkoxy, C2-12 haloalkenyl, C1-12 alkylcarbonyl, C i2 alkoxycarbonyl, -OR a , -SR a , -CF 3 , -OCF3, -N0 2 , -NR a R b , N(R a )(CO)R b , N(R a )(CO)OR b , N(R a XCO)NR a R b , -(CO)R a , -(CO)NR a R b , -0(CO)R a , - 0(CO)NR a R b , -C00R 3 , C3-6 cycloalkyl, S(0) m R a , S0 2 NR a
  • R a and R b are independently selected from hydrogen, C1-12 alkyl, C 2- i 2 alkenyl, C 2- 12 alkynyl, Cr 2 haloalkyl, C 2 -i 2 haloalkenyl, C 2 -i 2 haloalkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH 2 )n-cycloalkyl, (CH 2 ) n -heterocyclyl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl; each of which may be optionally substituted with halogen, hydroxyl, C n2 alkyl, C 2-1 2 alkenyl, C 2- i 2 alkynyl, C i2 alkoxy, Cr 12 alkylcarbonyl, C1-12 alkoxycarbonyl, C 3-8 cycloalkyl, d-12 haloalkyl, C n2 haloal
  • R c or R c is independently selected from the group consisting of but not limited to (1 ) hydrogen, (2) halogen, (3) C 1 - 12 alkyl which is linear or branched and which can be unsubstituted or substituted with 1-5 halogens or phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R 12 , OR 12 , NHS0 2 R 12 , S0 2 R 12 , C0 2 H and C0 2 Ci-6 alkyl .
  • the C0 2 Ci-6 alkyl is linear or branched (4) aryl which can be unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R 12 , OR 12 , NHS0 2 R 12 , S0 2 R 12 , C0 2 H and C0 2 C 1-6 alkyl, wherein the C0 2 Ci-6 alkyl is linear or branched (5) a 5 or 6 member
  • R 1 and R 3 together with the nitrogen atom to which R 1 is attached forms a heterocyclic or heteroaryl ring which may additionally contain from one to three heteroatoms independently selected from O, S and N, R c or R c' cannot be C0 2 H.
  • R 9 and R 10 are independently selected from hydrogen, Cn 2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, C n2 haloalkyl, C 2 -i 2 haloalkenyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH 2 ) n -cycloalkyl, (CH 2 ) n -heterocyclyl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, each of which may be optionally substituted with halogen, hydroxyl or C 1 -6 alkoxy, or R 9 and R 10 may be joined together to form a heterocyclic or heteroaryl ring which may contain from one to three heteroatoms independently selected from O, S and N, which may optionally be substituted with one or more substituents independently selected from R c or R c ;
  • R 2 is C-i-6 alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 groups independently selected from halogen, C0 2 H, and C0 2 Ci-6 alkyl, wherein the C0 2 Ci-6 alkyl is linear or branched;
  • X is selected from the group consisting of N and CR 11 ;
  • R 1 is selected from the group consisting of R c or R c ;
  • n can be 1 or 2;
  • n can be 1 , 2, 3 or 4;
  • r can be 1 , 2, 3 or 4.
  • Ar is as defined above;
  • PG is an amino protecting groups selected from acetyl, trifluoroacetyl, benzyloxycarbonyl (CBz), t-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), 2,2,2-trichloroethyloxycarbonyl, allyloxycarbonyl and the like;
  • step (a) removing the protecting group (PG) from the compound obtained in step (a) using deprotecting agents, and
  • step (b) optionally converting the product obtained in step (b) to a salt.
  • the present invention relates to a compound of formula IV, their pharmaceutically acceptable derivatives, tautomeric forms, stereoisomers including R and S isomers, prodrugs, metabolites, salts or solvates thereof:
  • the present invention relates to compounds of formula X, XI and XII and their pharmaceutically acceptable derivatives, tautomeric forms, stereoisomers including R and S isomers, prodrugs, metabolites, salts or solvates thereof:
  • alkyl refers to straight or branched 1 to 12 carbon atoms. These groups may further be substituted with one or more substituents selected from but not limited to, halogen, hydroxyl, oxo, carboxyl, carboxyalkyl, azido, alkenyl, alkynyl, alkoxy, cycloalkyi, cycloalkynyl, acyl acyloxy, aryl, heterocyclyl and heteroaryl.
  • cycloalkyi refers to cyclic alkyl groups constituting 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, for example, fused or spiro systems which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition.
  • Such cycloalkyi groups include, by way of example, single ring structures, for example, cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures, for example, adamantyl, and bicyclo[2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example, indane and the like.
  • Cycloalkyi groups may further be substituted with one or more substituents selected from but not limited to, halogen, hydroxyl, oxo, carboxy, carboxyalkyl, azido, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkynyl, acyl acyloxy, aryl, heterocyclyl, heteroaryl.
  • alkoxy denotes the group O-alkyl wherein alkyi is the same as defined above.
  • aralkyi refers to alkyl-aryl linked through alkyi (wherein alkyi is the same as defined above) portion and the said alkyi portion contains carbon atoms from 1-6 and the aryl is as defined herein, after.
  • alkyi is the same as defined above
  • alkyi portion contains carbon atoms from 1-6 and the aryl is as defined herein, after.
  • aralkyi groups include benzyl and the like.
  • aryl refers to a carbocyclic aromatic group, for example phenyl or naphthyl ring and the like optionally substituted with one or more substituents selected from but not limited to, halogen, hydroxyl, alkyi, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF 3 , COOR d (wherein R d can be hydrogen, alkyi, alkenyl, cycloalkyl, aralkyi, heterocyclylalkyl or heteroarylalkyl), cyano, nitro, carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl.
  • the aryl group may optionally be fused with cycloalkyl group, wherein the said cycloalkyl group may optionally contain heteroatoms selected from O, N and S.
  • aryloxy refers to the group O- aryl wherein aryl is as defined above.
  • heteroaryl refers to an aromatic ring structure or a bicyclic aromatic group with one or more heteroatom(s) independently selected from N, O and S and optionally substituted at any available position by substituent(s) selected from but not limited to halogen, hydroxyl, alkyi, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyi, cyano, nitro, heterocyclyl, or heteroaryl.
  • heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1 ,2,3,-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like.
  • heterocyclyl refers to a cyclic, bicyclic or tricyclic cycloalkyl group, fully or partially unsaturated having 5 to 10 carbon atoms; with one or more heteroatom(s) independently selected from N, O and S, and are optionally benzo- fused or fused with heteroaryl of 5-6 ring members; the rings may be optionally substituted wherein the substituents are selected from but not limited to halogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, or heteroaryl.
  • heterocyclyl groups include but are not limited to oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydroisooxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindonyl, piperidinyl or piperazinyl.
  • Heteroarylalkyl refers to alkyl-heteroaryl group linked through alkyl portion, wherein the alkyl and heteroalkyl are the same as defined previously.
  • Heterocyclylalkyl refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are the same as defined previously.
  • Halogen refers to fluoro, chloro, bromo or iodo.
  • Protecting Group refers to a group which is in a modified form to preclude undesired side reactions at the protected site.
  • protecting group may be used with groups, for example, hydroxyl, amino, carboxyl and examples of such groups are found in T.W. Greene, et al. "Protecting Groups in Organic Synthesis," 3 rd Ed, Wiley, New York, which is incorporated herein by reference.
  • the species of the carboxylic protecting groups, amino protecting groups or hydroxyl protecting groups employed are not critical, as long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed without disrupting the remainder of the molecule.
  • Suitable hydroxyl and amino protecting groups include but are not limited to trimethylsilyl, triethylsilyl, o- nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, f-butyldiphenylsilyl, t- butyldimethylsilyl, acetyl, trifluoroacetyl, benzyloxycarbonyl (CBz), t- butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), 2,2,2- trichloroethyloxycarbonyl, allyloxycarbonyl and the like.
  • carboxyl protecting groups are benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2- naphthyl methyl, allyl, 2-chloroallyl, benzyl, 2,2,2- trichloroethyl, trimethylsilyl, t- butyldimethylsilyl, f-butyldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl, p- methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl, i-butyl and the like.
  • terapéuticaally effective amount means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity, weight, physical condition and responsiveness of the subject to be treated, among other factors.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Coupled agent refers to CDI (1 ,1 ' carbonyl diimidazole), EDC [1- ethyl-3-(3-dimethylaminopropyl) carbodiimide] /HOBT (1-hydroxybenzotriazole); DCC (dicyclohexyl carbodiimide), DMAP (4-dimethylaminopyridine); HATU [0-(7- azabenzotriazole-yl)-N,N,N ⁇ N'-tetramethyluronium hexafluorophosphate; HOAT (1-hydroxy-7-azabenzotriazole); BOP [(benzotriazolyl-l-yloxy)-tris(dimethylamine) phosphonium hexafluorophosphate]; mixed anhydride method using ethyl chloroformate or methyl chloroformate in a suitable solvent such as DMF, DCM, acetonitrile, toluene, THF and the like
  • amino protecting groups include but are not limited to acetyl, trifluoroacetyl, benzyloxycarbonyl (CBz), t-butoxycarbonyl (Boc), 9- fluorenylmethyloxycarbonyl (Fmoc), 2,2,2-trichloroethyloxycarbonyl, allyloxycarbonyl and the like.
  • the appropriate conditions for the removal of the amine protecting groups can be readily selected by those having well known skill in the art.
  • reagents used for deprotecting the amine protecting moiety include but are not limited to use of acidic conditions (trifluoroacetic acid, hydrochloric acid, phosphoric acid, p-toluenesulphonic acid and the like), basic conditions (piperidine and the like) or hydrogenation conditions (palladium on charcoal or platinum and the like).
  • the present invention is related to a novel process and intermediates useful for the synthesis of compounds of formula I.
  • compounds of formula I are derivatives of beta-amino acid. They can be synthesized by many routes. An essential step that would be common in many feasible routes employed for the synthesis of these compounds is the amide bond formation. There could be alternate approaches for the amide bond formation. One of these approaches is by coupling of two fragments, one fragment containing carboxylic acid group and the other containing the secondary nitrogen atom, which can be free or present as a part of a heterocyclic ring, in the presence of suitable coupling agent.
  • the present invention relates to a process for preparing a compound of general formula I or its pharmaceutically acceptable salts,
  • Ar represents aryl which may be phenyl, which may be unsubstituted or optionally substituted at any available position by R 8 or by one or more substituents selected from but not limited to halogen, CN, hydroxyl, NH 2> Ci-i 2 alkyl or Ci-i 2 alkoxy, wherein each of Ci-i 2 alkoxy and Ci-i 2 alkyl may be linear or branched and can be unsubstituted or optionally substituted with 1-5 halogens;
  • R 2 and R 3 together represents a single oxygen or sulphur atom which is linked to the diazepine ring by a double bond; or R 1 and R 2 together forms a double bond in the diazepine ring and R 3 represents the group -NR a R b ; or R 1 and R 3 together with the nitrogen atom to which R 1 is attached forms a heterocyclic or heteroaryl ring which may additionally contain from one to three hetero atoms independently selected from O, S and N; the ring formed may optionally be substituted with one or more substituents selected from R c or R c and R 2 represent hydrogen or a double bond;
  • R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, CN, C1-12 alkyl, C 2- 12 alkenyl, C 2- 12 alkynyl, C1-12 alkoxy, Ci-i 2 haloalkyl, C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, C1-12 alkylcarbonyl, C1-12 alkoxycarbonyl, -OR a , -SR a , -N0 2 , -NR a R b , N(R a )(CO)R b , N(R a )(CO)OR b , N(R a )(CO)NR a R b , -(CO)R a , -(CO)NR a R b , -0(CO)R a , -0(CO)NR a R b , -COOR a , C
  • cycloalkyl which may be optionally substituted at any available position by one or more substituents independently selected from R c or R c ; aryl which may be optionally substituted at any available position by one or more substituents independently selected from R c or R c ; heteroaryl which may be optionally substituted at any available position by one or more substituents independently selected from R c or R c ; or heterocyclyl which may be optionally substituted at any available position by one or more substituents independently selected from R c or R c ;
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, CN, C 1 - 12 alkyl, C 2- i 2 alkenyl, C 2-12 alkynyl, C 1 - 12 alkoxy, d-i 2 aloalkyl, C1-12 haloalkoxy, C2-12 haloalkenyl, C2-12 haloalkynyl, Cn 2 alkylcarbonyl, C i2 alkoxycarbonyl, -OR a , -SR a , -N0 2 , -NR a R b , N(R a )(CO)R , N(R a )(CO)OR b , N(R a )(CO)NR a R b , -(CO)R a , -(CO)NR a R b , -0(CO)R a , -0(CO)NR a R b , -COOR
  • R 8 is independently selected from hydrogen, halogen, CN, C1-12 alkyl, Cn 2 haloalkyl, Cn 2 alkoxy, C1-12 haloalkoxy, C2-12 haloalkenyl, C1-12 alkylcarbonyl, C1-12 alkoxycarbonyl, -OR a , -SR a , -CF 3 , -OCF 3 , -N0 2 , -NR a R b , N(R a )(CO)R b , N(R a )(CO)OR b , N(R a )(CO)NR a R b , -(CO)R a , -(CO)NR a R b , -0(CO)R a , - 0(CO)NR a R b , -C00R 3 , Ca-e cycloalkyl, S(0) m R a , S0 2 NR
  • R a and R b are independently selected from hydrogen, C1-12 alkyl, C 2- 12 alkenyl, C 2- 12 alkynyl, C 2 haloalkyl, C2-12 haloalkenyl, C2-12 haloalkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH 2 ) n -cycloalkyl, (CH 2 ) n -heterocyclyl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl; each of which may be optionally substituted with halogen, hydroxyl, C n2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, Cn 2 alkoxy, C1-12 alkylcarbonyl, C n2 alkoxycarbonyl, Czs cycloalkyl, Cn 2 haloalkyl, C-i-12 haloalk
  • R c or R c is independently selected from the group consisting of but not limited to (1 ) hydrogen, (2) halogen, (3) C1-12 alkyl which is linear or branched and which can be unsubstituted or substituted with 1-5 halogens or phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R 12 , OR 12 , NHS0 2 R 12 , S0 2 R 12 , C0 2 H and C0 2 C 1-6 alkyl .
  • the C0 2 Ci-6 alkyl is linear or branched; (4) aryl which can be unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R 2 , OR 12 , NHS0 2 R 12 , S0 2 R 12 , C0 2 H and C0 2 C 1-6 alkyl .
  • 6 alkyl is linear or branched (5) a 5 or 6 membered heterocyclyl which may be saturated or unsaturated comprising 1-4 heteroatoms independently selected from N, S and O, the heterocycle being unsubstituted or substituted with 1-3 substituents independently selected from oxo, OH, halogen, Ci-6 alkyl, and OCi-6 alkyl, wherein the Ci -6 alkyl and OC 1 -6 alkyl are linear or branched and optionally substituted with 1-5 halogens; (6) (CH 2 ) n -cycloalkyl; (7) (CH 2 )n-heterocyclyl, (8) (CH 2 ) n -aryl, (9) (CH 2 ) n -heteroaryl, (10) C n2 alkylcarbonyl, ( 1 ) C n2 alkoxycarbonyl, (12) CN, (13) -OR 9 , (14) -OCF3, (15) - N0 2, (16
  • R 9 and R 10 are independently selected from hydrogen, Ci-i 2 alkyl, C 2- -
  • R 12 is Ci-6 alkyl, which is linear or branched and which is unsubstituted or substituted with 1-5 groups independently selected from halogen, C0 2 H, and C0 2 Ci-6 alkyl, wherein the CO 2 C 1 -6 alkyl is linear or branched;
  • L independently represent a hydrogen atom or they may join together to form a ring
  • n' is 0 or 1
  • n can be 1 or 2;
  • n can be 1 , 2, 3 or 4;
  • Ar is as defined above;
  • PG is an amino protecting groups selected from acetyl, trifluoroacetyl, benzyloxycarbonyl (CBz), t-butoxycarbonyl (Boc), 9-fluorenylmethyloxy carbonyl (Fmoc), 2,2,2-trichloroethyloxycarbonyl, allyloxycarbonyl and the like;
  • step (b) removing the protecting group (PG) from the compound obtained in step (a) using a deprotecting agent;
  • step (b) optionally converting the product obtained in step (b) to a salt.
  • solvent (s) that can be used in the present invention can be selected form the group comprising Dimethylfomamide (DMF), Dimethyl acetamide (DMAc), Dichloromethane (DCM), acetonitrile (ACN) , toluene, tetrahydrofuran (THF) or mixtures thereof.
  • DMF Dimethylfomamide
  • DMAc Dimethyl acetamide
  • DCM Dichloromethane
  • ACN acetonitrile
  • THF tetrahydrofuran
  • the solvent is acetonitrile and / or Dimethylformamide.
  • base (s) that can be used in the present invention can be selected form the group comprising A/-methylmorpholine (NMM), N,N- diisopropylethylamine (DIPEA) and triethylamine (TEA) or mixtures thereof.
  • the base is A/,A/-diisopropylethylamine.
  • deprotecting agent that can be used in the present invention can be selected form the group comprising trifluoroacetic acid, hydrochloric acid, phosphoric acid, p-toluenesulphonic acid, piperidine, palladium on charcoal and platinum.
  • the deprotecting agent is hydrochloric acid.
  • the present invention relates to a process for preparing compounds of formula VI or VII, their pharmaceutically acceptable derivatives, tautomeric forms, stereoisomers including R and S isomers, prodrugs, metabolites, salts or solvates thereof:
  • Ar represents aryl which may be phenyl, which may be unsubstituted or optionally substituted at any available position by one or more substituents selected from but not limited to halogen, CN, hydroxyl, NH 2 , Ci- 12 alkyl or Ci- 2 alkoxy, wherein each of Ci-i 2 alkoxy and Ci- 12 alkyl may be linear or branched and can be unsubstituted or optionally substituted with 1-5 halogens;
  • R 2 and R 3 together represents a single oxygen or sulphur atom which is linked to the diazepine ring by a double bond; or R 1 and R 2 together forms a double bond in the diazepine ring and R 3 represents the group -NR a R b ; or R 1 and R 3 together with the nitrogen atom to which R 1 is attached forms a heterocyclic or heteroaryl ring which may additionally contain from one to three heteroatoms independently selected from O, S and N; the ring formed may optionally be substituted with one or more substituents selected from R c or R c and R 2 represent hydrogen or a double bond;
  • R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, CN, C 1 - 12 alkyl, C 2-12 alkenyl, C 2- i 2 alkynyl, C n2 alkoxy, Ci ⁇ i 2 haloalkyl, C i 2 haloalkoxy, C 2 -
  • R 6 and R 7 are independently selected from the group consisting of hydrogen, halogen, CN, Ci- 2 alkyl, C 2- 12 alkenyl, C 2- 12 alkynyl, C n2 alkoxy, Ci- 2 haloalkyl, C i2 haloalkoxy, C2-12 haloalkenyl, C 2 -i 2 haloalkynyl, Cn 2 alkylcarbonyl, C n2 alkoxycarbonyl, -OR a , -SR a , -N0 2 , -NR a R b , N(R a )(CO)R b , N(R a )(CO)OR b , N(R a )(CO)NR a R b , -(CO)R a , -(CO)NR a R b , -0(CO)R a , -0(CO)NR a R b , -C00
  • R 8 is independently selected from hydrogen, halogen, CN, C i2 alkyl, C1-12 haloalkyl, Cn 2 alkoxy, C1-12 haloalkoxy, C 2 -i 2 haloalkenyl, C1-12 alkylcarbonyl, C1-12 alkoxycarbonyl, -OR a , -SR a , -CF 3 , -OCF3 , -N0 2 , -NR a R b , N(R a )(CO)R b , N(R a )(CO)OR b , N(R a )(CO)NR a R b , -(CO)R a , -(CO)NR a R b , -0(CO)R a , - 0(CO)NR a R b , -COOR a , C 3-6 cycloalkyl, S(0) m R a , S0
  • R c or R c is independently selected from the group consisting of but not limited to (1 ) hydrogen, (2) halogen, (3) Cn 2 alkyl which is linear or branched and which can be unsubstituted or substituted with 1-5 halogens or phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R 12 , OR 12 , NHS0 2 R 12 , S0 2 R 12 , C0 2 H and C0 2 Ci -6 alkyl .
  • the C0 2 Ci -6 alkyl is linear or branched (4) aryl which can be unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R 12 , OR 12 , NHS0 2 R 12 , S0 2 R 12 , C0 2 H and C0 2 C -6 alkyl, wherein the C0 2 Ci-6 alkyl is linear or branched (5) a 5 or 6 member
  • R 1 and R 3 together with the nitrogen atom to which R 1 is attached forms a heterocyclic or heteroaryl ring which may additionally contain from one to three heteroatoms independently selected from O, S and N, R c or R° ' cannot be C0 2 H.
  • R 9 and R 0 are independently selected from hydrogen, C i2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, C n2 haloalkyl, C 2 -i 2 haloalkenyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, (CH 2 ) n -cycloalkyl, (CH 2 ) n -heterocyclyl, (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, each of which may be optionally substituted with halogen, hydroxyl or C 6 alkoxy, or R 9 and R 10 may be joined together to form a heterocyclic or heteroaryl ring which may contain from one to three heteroatoms independently selected from O, S and N, which may optionally be substituted with one or more substituents independently selected from R c or R c ;
  • R 12 is Ci-6 alkyl, which is linear or
  • X is selected from the group consisting of N and CR 11 ;
  • R 11 is selected from the group consisting of R c or R c ;
  • n can be 1 or 2;
  • n can be 1 , 2, 3 or 4;
  • r can be 1 , 2, 3 or 4.
  • Ar is as defined above;
  • PG is an amino protecting groups selected from acetyl, trifluoroacetyl, benzyloxycarbonyl (CBz), t-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), 2,2,2-trichloroethyloxycarbonyl, allyloxycarbonyl and the like;
  • step (b) removing the protecting group (PG) from the compound obtained in step (a) using deprotecting agents, and c) optionally converting the product obtained in step (b) to a salt.
  • solvent (s) that can be used in the present invention can be selected form the group comprising Dimethylfomamide (DMF), Dimethyl acetamide (DMAc), Dichloromethane (DCM), acetonitrile (ACN) , toluene, tetrahydrofuran (THF) or mixtures thereof.
  • DMF Dimethylfomamide
  • DMAc Dimethyl acetamide
  • DCM Dichloromethane
  • ACN acetonitrile
  • THF tetrahydrofuran
  • the solvent is acetonitrile and/or Dimethylformamide.
  • base (s) that can be used in the present invention can be selected form the group comprising /V-methylmorpholine (NMM), N,N- diisopropylethylamine (DIPEA) and triethylamine (TEA) or mixtures thereof.
  • the base is /V,/V-diisopropylethylamine.
  • deprotecting agent that can be used in the present invention can be selected form the group comprising trifluoroacetic acid, hydrochloric acid, phosphoric acid, p-toluenesulphonic acid, piperidine, palladium on charcoal and platinum.
  • the deprotecting agent is hydrochloric acid.
  • the present invention relates to a compound of formula IV, their pharmaceutically acceptable derivatives, tautomeric forms, stereoisomers including R and S isomers, prodrugs, metabolites, salts or solvates thereof:
  • the compound of formula IV is formed as an intermediate in the process of the present invention.
  • the compound of formula IV is formed as a result of the reaction between the compound of formula II with 1 ,1-carbonyldinidazole, which is then reacted with the compound of formula III or VIII or IX.
  • This said intermediate compound can be optionally isolated or can be used in-situ during the progression of the process.
  • the present invention relates to a compound of formula V, its pharmaceutically acceptable derivatives, tautomeric forms, stereoisomers including R and S isomers, prodrugs, metabolites, salts or solvates thereof:
  • the compound of formula IV and V can exist in the various physical forms say amorphous and crystalline form and also in the form of a single diastereoisomer, racemate, racemic mixture or diastereoisomeric mixture, all of which fall within the scope of compound of Formula IV in accordance with the present invention.
  • the racemic mixtures can be resolved if desired at appropriate stages by methods known to those skilled in the art such as crystallization, chromatography, salt formation or enzymatic resolution to obtain the respective individual enantiomers.
  • the present invention relates to compounds of formula X, XI and XII and their pharmaceutically acceptable derivatives, tautomeric forms, stereoisomers including R and S isomers, prodrugs, metabolites, salts or solvates thereof:
  • Example-1 Synthesis of terf-butyl (R)-1-(2,4,5-trifluorophenyl)-4-(1 H-imidazol-1- yl)-4-oxobutan-2-ylcarbamate (compound of Formula V)
  • (R)-3-[(fert-butyloxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)- butanoic acid (1 g, 0.003 mol) (synthesized in accordance with the procedure given in WO-2009093269, which is incorporated in its entirety herein by reference) in acetonitrile (20 ml), was added N,N-Diisopropylethylamine (1.4 ml, 0.010 mol) and 1 ,1-Carbonyl diimidazole (0.73 g, 0.004 mol) at room temperature.
  • reaction mixture was stirred for 1 h at 40°C. After completion of the reaction water (25 ml) was added and extracted twice with ethyl acetate (2 x 50 ml). The combined ethyl acetate layers was evaporated to obtain 0.54 gm of terf-butyl (R)- 1-(2,4,5-trifluorophenyl)-4-( H-imidazol-1-yl)-4-oxobutan-2-ylcarbamate as a white solid.
  • Example 3 Synthesis of Hydrochloric acid salt of 4-[(R)-3-amino-4-(2,4,5- trifluorophenylJ-butyryll-I .S ⁇ .S-tetrahydro-benzoteltl ⁇ ldiazipin ⁇ -one.
  • Example 6 Synthesis of Hydrochloric acid salt of (R)-4-(3-amino-4-(2,4,5- trifluorophenyl)-butanoyl)-8-Fluoro-4,5-dihydro-1 H-benzo[e][1 ,4]diazipin-2(3H)- one.
  • Example 7 Synthesis of Hydrochloric acid salt of 4-[(R)-3-amino-4-(2,4,5- trifluorophenyl)-butyryl]-1-methyl-8-Fluoro-1,3,4,5-tetrahydro- benzo[e][1 ,4]diazepin-2-one.

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