WO2003051848A2 - Imidazolidineacetic acid derivatives - Google Patents

Imidazolidineacetic acid derivatives Download PDF

Info

Publication number
WO2003051848A2
WO2003051848A2 PCT/GB2002/005631 GB0205631W WO03051848A2 WO 2003051848 A2 WO2003051848 A2 WO 2003051848A2 GB 0205631 W GB0205631 W GB 0205631W WO 03051848 A2 WO03051848 A2 WO 03051848A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound according
general formula
pyridyl
aralkyl
Prior art date
Application number
PCT/GB2002/005631
Other languages
French (fr)
Other versions
WO2003051848A3 (en
Inventor
Michael Bryan Roe
André Tartar
Original Assignee
Ferring Bv
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ferring Bv filed Critical Ferring Bv
Priority to AU2002350942A priority Critical patent/AU2002350942A1/en
Publication of WO2003051848A2 publication Critical patent/WO2003051848A2/en
Publication of WO2003051848A3 publication Critical patent/WO2003051848A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to imidazolidineacetic acid derivatives, to a process for the synthesis thereof, and to the use of these compounds in the preparation of pharmaceutically important ethylenediamine derivatives.
  • the key step is the reaction of the ⁇ /-substituted ethylenediamine with (2S)-1-(2- bromoacetyl)pyrrolidine-2-carbonitrile.
  • This step due to non- selective reaction of the nucleophilic a ine groups present in the substrate and in the product with the bromide. This leads to the formation of several side products which are difficult to separate from the desired product and hence to an unacceptably low yield. Therefore, considering the importance of this series of compounds as potential drug therapies for type 2 diabetes, there exists a need for a synthetic route that is selective, higher yielding and amenable to scale-up.
  • the synthesis of ⁇ /-(aminoethyl)glycine derivatives such as NVP- DPP728 is improved by using an imidazolidine derivative rather than an ethylenediamine derivative as the nucleophilic component in the alkylation step.
  • the product of this modified alkylation step is a substituted imidazolidineacetic acid.
  • the present invention comprises these novel imidazolidineacetic acid derivatives.
  • the present invention comprises the use of the compounds for the preparation of pharmaceutically active agents, and particularly ⁇ /-(aminoethyl)glycine derivatives.
  • the present invention comprises a process for the synthesis of these compounds wherein a 1-arylimidazolidine derivative is reacted with a haloacetyl or analogous species, and novel 1-arylimidazolidine derivatives that are useful as starting materials for the preparation of the compounds.
  • the present invention comprises a series of novel imidazolidineacetic acid derivatives according to general formula 1.
  • Ar is an aryl group selected from optionally substituted phenyl and optionally substituted heteroaryl groups.
  • the optional substituents are selected from alkyl groups, acyl groups, OH, O-alkyl, O-acyl, NH 2 , NH-alkyl, N(alkyl) 2 , NH-acyl, N(alkyl)-acyl, N(acyl) 2 , F, CI, Br, I, CF 3l NO 2 , C0 2 H, C0 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 and CN.
  • the aryl group may have up to three such substituents which may be the same or different.
  • the groups R 1 and R 2 may be the same or different, and each is selected from H and alkyl groups. Preferably they are selected from H, methyl and ethyl. More preferably they are both H, both methyl, or one is H and the other is methyl.
  • the group Y is selected from OH, O-alkyl, O-aralkyl, 2-cyano-l-pyrrolidyl (2) and a group according to general formula 3.
  • the group X is selected from OH, O-alkyl, O-aralkyl, O-resin, NH 2 , NH-alkyl, NH-aralkyl, and NH-resin.
  • heteroaryl denotes a five- or six-membered aromatic ring with between one and three heteroatoms selected from oxygen, nitrogen and sulphur.
  • heteroaryl groups include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiaz ⁇ lyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidyl, triazinyl and the like.
  • Oxo tautomers of hydroxy-substituted heteroaryl groups, such as pyridone and pyrone are also considered to be heteroaryl groups.
  • alkyl denotes linear, branched and cyclic saturated hydrocarbon groups with up to eight carbon atoms.
  • alkyl groups include methyl, ethyl, isopropyl, cyclobutyl, neopentyl, cyclobutylethyl and the like.
  • R is hydrogen or a linear, branched or cyclic saturated or unsaturated hydrocarbon group with up to eight carbon atoms.
  • acyl groups include formyl, acetyl, cyclohexylcarbonyl, benzoyl, phenylacetyl and the like.
  • aralkyl denotes an alkyl group substituted with one or more phenyl or heteroaryl groups.
  • aralkyl groups include benzyl, phenethyl, trityi, fluorenylmethyl and the like.
  • the group Ar is selected from optionally substituted phenyl and optionally substituted pyridyl. More preferably, it is optionally substituted pyridyl. More preferably still, it is optionally substituted 2-pyridyl. Yet more preferably it is 5- monosubstituted 2-pyridyl. Most preferably it is 5-cyano-2-pyridyl.
  • the group Y is selected from OH, O-alkyl and O-aralkyl.
  • Y is 2-cyano-l-pyrrolidyl, and more preferably it is (2S)- 2-cyano-1-pyrrolidyl.
  • Y is a group according to general formula 3. More preferably, Y is a group according to general formula 3 and X is selected from OH, O-alkyl, O-aralkyl, NH 2 , NH-alkyl and NH-aralkyl. In another more preferred embodiment X is O- resin or NH-resin. In another more preferred embodiment Y is a group according to general formula 3 in which the absolute configuration is 2S as shown in general formula 3 A
  • Individual preferred compounds within the present invention include: ⁇ /-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-proline;
  • Compounds according to general formula 1 are useful for the preparation of pharmaceutically active agents, and this use is a second aspect of the present invention.
  • the compounds are useful as intermediates in the synthesis of compounds according to general formula 4 disclosed in W098/19998. These compounds are inhibitors of dipeptidyl peptidase IV and are considered to have potential as agents for the treatment of, inter alia, type 2 diabetes and impaired glucose tolerance.
  • Compounds according to general formula 1 can be prepared by the reaction of an imidazolidine according to general formula 5 with an acetic acid derivative according to general formula 6, and this reaction is a third aspect of the present invention.
  • Ar is an aryl group selected from optionally substituted phenyl and optionally substituted heteroaryl groups.
  • the optional substituents are selected from alkyl groups, acyl groups, OH, O-alkyl, O-acyl, NH 2 , NH-alkyl, N(alkyl) 2 , NH-acyl, N(alkyl)-acyl, N(acyl) 2l F, CI, Br, I, CF 3 , N0 2 , C0 2 H, C0 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 and CN.
  • the aryl group may have up to three such substituents which may be the same or different.
  • the group Ar is selected from optionally substituted phenyl and optionally substituted pyridyl. More preferably, it is optionally substituted pyridyl. More preferably still, it is optionally substituted 2-pyridyl. Yet more preferably it is 5-monosubstituted 2-pyridyl. Most preferably it is 5-cyano-2-pyridyl.
  • the group Y is selected from OH, O-alkyl, O-aralkyl, 2-cyano-l-pyrrolidyl (2) and a group according to general formula 3.
  • the group X is selected from OH, O-alkyl, O-aralkyl, O-resin, NH 2 , NH-alkyl, NH-aralkyl, and NH-resin.
  • the group Y is selected from OH, O-alkyl and O-aralkyl.
  • Y is 2-cyano-l-pyrrolidyl, and more preferably it is (2S)-2- cyano-1-pyrrolidyl.
  • Y is a group according to general formula 3. More preferably, Y is a group according to general formula 3 and X is selected from OH, O-alkyl, O-aralkyl, NH 2> NH-alkyl and NH-aralkyl. In another more preferred embodiment X is O-resin or NH-resin.
  • V is a group susceptible to nucleophilic displacement. Suitable groups are CI, Br, I, alkylsulphonates (alkyl-S0 2 -0-), perfluoroalkylsulphonates, optionally substituted benzenesulphonates (Ph(R)-S0 2 -0-, where R represents one or more alkyl, perfluoroalkyl or halogen group), acyloxy groups (acyl-O-) and perfluoroacyloxy groups. Preferred groups are CI, Br, I, methanesulphonate (mesylate), trifluoromethanesulphonate (triflate) and toluenesulphonate (tosylate). More preferably, V is CI or Br
  • Particularly preferred embodiments of the present invention are those that combine two or more of the above preferred features.
  • Individually preferred processes of the presented invention include but are not limited to the process shown:
  • the imidazolidine derivatives according to general formula 5 that serve as starting materials in the process described above can be prepared by the reaction of an ethylenediamine derivative with an aldehyde or ketone.
  • acetic acid derivatives according to general formula 6 that also serve as starting materials in the process are either items of commerce or can be prepared from such items.
  • the present invention comprises compounds according to general formula 5 in which Ar is an optionally substituted heteroaryl group.
  • the optional substituents are selected from alkyl groups, acyl groups, OH, O-alkyl, O-acyl, NH 2 , NH-alkyl, N(alkyl) 2 , NH-acyl, N(alkyl)-acyl, N(acyl) 2 , F, CI, Br, I, CF 3 , N0 2 , C0 2 H, C0 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 and CN.
  • the heteroaryl group may have up to three such substituents which may be the same or different.
  • Ar is an optionally substituted pyridyl group. More preferably it is a 5-monosubstituted 2-pyridyl group. A particularly preferred embodiment is the compound 1-(5-cyano-2-pyridyl)imidazolidine.
  • reaction of an imidazolidine derivative according to general formula 5 with an acetic acid derivative 6 is generally more selective (i.e. it gives fewer side products) and higher yielding than the alkylation of the corresponding ethylenediamine derivative. Accordingly, compounds according to general formula 1 can be readily prepared and easily purified on a commercial scale. Since compounds according to general formula 1 can be transformed into the ethylenediamine derivatives of W098/19998 or analogues thereof, their use represents a significant improvement in the preparation of these ethylenediamine derivatives.
  • Trifluoroacetic acid (125ml) was added to an ice-cold stirred suspension of ferf-butyl (2-(5- cyano-2-pyridylamino)ethyl)carbamate (32. Og, 120mmol) in CH 2 CI 2 (125ml) to give a clear solution. After gas evolution had ceased the cooling bath was removed. After 1.5h the mixture was concentrated and azeotroped with toluene 3 times to afford 6-(2- aminoethylamino)nicotinonitrile trifluoroacetate. The yield was assumed to be quantitative and the material was used directly in the next step.
  • 6-(2-Aminoethylamino)nicotinonitrile trifluoroacetate 120mmol was dissolved in water (1300ml). Aqueous 37% formaldehyde solution (15.5g, 12.5ml, 168mmol) was added and the mixture was stirred for 3 days. The mixture was concentrated then azeotroped with toluene twice and with petroleum ether once. The residue was taken up in Et 2 0/EtOH (50:50, 200ml) and scratched to initiate crystallisation. The mixture was cooled in an ice/water bath for 4h and filtered to afford 1-(5-cyano-2-pyridyl)imidazolidine trifluoroacetate (11.4g, 33%) as a pale yellow crystalline solid.
  • imidazolidine derivatives provides a simple and convenient route to ⁇ /-(aminoethyl)glycine derivatives such as NVP-DPP728.
  • the improved selectivity in the alkylation step reduces the need for lengthy purification procedures, so improving the overall efficiency of the process.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pyrrole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compounds according to general formula (1) are new. They are readily prepared by the reaction of an N-aryl imidazolidine with an acetic acid derivative, and are useful in the synthesis of pharmaceutically active ethylenediamine derivatives. In this general formula, Ar is an aryl group selected from optionally substituted phenyl and optionally substituted heteroaryl groups. The groups R1 and R2 may be the same or different, and each is selected from H and alkyl groups. Preferably they are selected from H, methyl and ethyl. More preferably they are both H, both methyl, or one is H and the other is methyl. The group Y is selected from OH, O-alkyl, O-aralkyl, 2-cyano-1-pyrrolidyl (2) and a group according to general formula (3). The group X is selected from OH, O-alkyl, O-aralkyl, O-resin, NH2, NH-alkyl, NH-aralkyl, and NH-resin.

Description

IM1DAZOL1DINEACETIC ACID DERIVATIVES
The present invention relates to imidazolidineacetic acid derivatives, to a process for the synthesis thereof, and to the use of these compounds in the preparation of pharmaceutically important ethylenediamine derivatives.
BACKGROUND
International Patent Application PCT/EP97/06125 (published as WO98/19998; equivalent to EP 0 937 040 and US 6,011 ,155) discloses, inter alia, a series of Λ/-(aminoethyl)glycine derivatives that are inhibitors of dipeptidyl peptidase IV (DP-IV, CD26, EC.3.4.14.5). One of these (NVP-DPP728) is currently in clinical trials for the treatment of type 2 diabetes. The synthesis of NVP-DPP728 as described in the patent application is shown in Scheme 1.
Scheme 1 - Preparation of NVP-DPP728
Figure imgf000002_0001
NVP-DPP728
The key step is the reaction of the Λ/-substituted ethylenediamine with (2S)-1-(2- bromoacetyl)pyrrolidine-2-carbonitrile. There are problems with this step due to non- selective reaction of the nucleophilic a ine groups present in the substrate and in the product with the bromide. This leads to the formation of several side products which are difficult to separate from the desired product and hence to an unacceptably low yield. Therefore, considering the importance of this series of compounds as potential drug therapies for type 2 diabetes, there exists a need for a synthetic route that is selective, higher yielding and amenable to scale-up.
SUMMARY OF THE INVENTION
We have found that the synthesis of Λ/-(aminoethyl)glycine derivatives such as NVP- DPP728 is improved by using an imidazolidine derivative rather than an ethylenediamine derivative as the nucleophilic component in the alkylation step. The product of this modified alkylation step is a substituted imidazolidineacetic acid. In a first aspect, the present invention comprises these novel imidazolidineacetic acid derivatives. In a second aspect, the present invention comprises the use of the compounds for the preparation of pharmaceutically active agents, and particularly Λ/-(aminoethyl)glycine derivatives. In further aspects the present invention comprises a process for the synthesis of these compounds wherein a 1-arylimidazolidine derivative is reacted with a haloacetyl or analogous species, and novel 1-arylimidazolidine derivatives that are useful as starting materials for the preparation of the compounds.
DETAILED DESCRIPTION OF THE INVENTION
In a first aspect, the present invention comprises a series of novel imidazolidineacetic acid derivatives according to general formula 1.
Figure imgf000003_0001
1
In this general formula, Ar is an aryl group selected from optionally substituted phenyl and optionally substituted heteroaryl groups. The optional substituents are selected from alkyl groups, acyl groups, OH, O-alkyl, O-acyl, NH2, NH-alkyl, N(alkyl)2, NH-acyl, N(alkyl)-acyl, N(acyl)2, F, CI, Br, I, CF3l NO2, C02H, C02-alkyl, CONH2, CONH-alkyl, CON(alkyl)2 and CN. The aryl group may have up to three such substituents which may be the same or different. The groups R1 and R2 may be the same or different, and each is selected from H and alkyl groups. Preferably they are selected from H, methyl and ethyl. More preferably they are both H, both methyl, or one is H and the other is methyl.
The group Y is selected from OH, O-alkyl, O-aralkyl, 2-cyano-l-pyrrolidyl (2) and a group according to general formula 3.
Figure imgf000004_0001
The group X is selected from OH, O-alkyl, O-aralkyl, O-resin, NH2, NH-alkyl, NH-aralkyl, and NH-resin.
Compounds according to general formula 1 in which Y is 2-cyanopyrrolidyl or a group according to general formula 3 have a stereogenic centre ("asymmetric carbon atom") and so can exist as optical isomers. The scope of the present invention includes all such isomers, whether they are in the form of single enantiomers or mixtures of enantiomers (including racemates).
As used herein, the term "heteroaryl" denotes a five- or six-membered aromatic ring with between one and three heteroatoms selected from oxygen, nitrogen and sulphur. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazόlyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidyl, triazinyl and the like. Oxo tautomers of hydroxy-substituted heteroaryl groups, such as pyridone and pyrone are also considered to be heteroaryl groups.
As used herein, the term "alkyl" denotes linear, branched and cyclic saturated hydrocarbon groups with up to eight carbon atoms. Examples of alkyl groups include methyl, ethyl, isopropyl, cyclobutyl, neopentyl, cyclobutylethyl and the like.
As used herein, the term "acyl" denotes a group RC(=0), where R is hydrogen or a linear, branched or cyclic saturated or unsaturated hydrocarbon group with up to eight carbon atoms. Examples of acyl groups include formyl, acetyl, cyclohexylcarbonyl, benzoyl, phenylacetyl and the like.
As used herein, the term "aralkyl" denotes an alkyl group substituted with one or more phenyl or heteroaryl groups. Examples of aralkyl groups include benzyl, phenethyl, trityi, fluorenylmethyl and the like.
As used herein, the term "resin", when used as a chemical entity such as in O-resin and NH-resin, denotes any of the polymeric resins used for solid-phase synthesis of organic molecules.
In a preferred embodiment, the group Ar is selected from optionally substituted phenyl and optionally substituted pyridyl. More preferably, it is optionally substituted pyridyl. More preferably still, it is optionally substituted 2-pyridyl. Yet more preferably it is 5- monosubstituted 2-pyridyl. Most preferably it is 5-cyano-2-pyridyl.
In another preferred embodiment, the group Y is selected from OH, O-alkyl and O-aralkyl.
In another preferred embodiment Y is 2-cyano-l-pyrrolidyl, and more preferably it is (2S)- 2-cyano-1-pyrrolidyl.
In another preferred embodiment Y is a group according to general formula 3. More preferably, Y is a group according to general formula 3 and X is selected from OH, O-alkyl, O-aralkyl, NH2, NH-alkyl and NH-aralkyl. In another more preferred embodiment X is O- resin or NH-resin. In another more preferred embodiment Y is a group according to general formula 3 in which the absolute configuration is 2S as shown in general formula 3A
Figure imgf000005_0001
Individual preferred compounds within the present invention include: Λ/-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-proline;
Λ/-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-proline methyl ester;
Λ/-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-proline benzyl ester;
Λ/-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-proline ferf-butyl ester;
Λ/-(2-(3'-(5"-cyano-2"-pyridyl)imidazoiidine)acetyl)-L-prolineamide; and
(2S)-1-(2'-(3"-(5'"-cyano-2'"-pyridyl)imidazolidine)acetyl)pyrrolidine-2-carbonitrile.
Compounds according to general formula 1 are useful for the preparation of pharmaceutically active agents, and this use is a second aspect of the present invention. In particular, the compounds are useful as intermediates in the synthesis of compounds according to general formula 4 disclosed in W098/19998. These compounds are inhibitors of dipeptidyl peptidase IV and are considered to have potential as agents for the treatment of, inter alia, type 2 diabetes and impaired glucose tolerance.
Figure imgf000006_0001
4
The transformation of compounds according to general formula 1 into these therapeutic agents requires the following processes, which may be performed in any order. (For the sake of clarity these processes are illustrated for the case where R and R2 are both H, but the methods are valid for other embodiments of these two groups.)
i. Conversion of the group Y into the cyanopyrrolidine moiety of 4, if Y in 1 is other than 2-cyanopyrrolidine. This conversion can be achieved in one or more steps using well known chemistry. Examples of these steps are illustrated below.
Figure imgf000006_0002
Figure imgf000007_0001
V O C CouuDplliinnαg agent
Figure imgf000007_0003
Coupling agent
Figure imgf000007_0004
C Coouupplliinnαg
Figure imgf000007_0002
agent
Figure imgf000007_0006
Figure imgf000007_0005
C CoouuDpliinnαg agent
Figure imgf000008_0001
Coupling
Figure imgf000008_0003
H.-DPmro_-MNH_-PResiinn
Figure imgf000008_0004
Liberation of the ethylenediamine functionality from the imidazolidine ring. This may generally be achieved by treatment with aqueous acid, with anhydrous acid in the presence of an aldehyde or ketone scavenger or by treatment with malonic acid and pyridine according to the method of Almeida et al (J. Chem. Soc. Perkin Trans. I, 1988, 1905).
Compounds according to general formula 1 can be prepared by the reaction of an imidazolidine according to general formula 5 with an acetic acid derivative according to general formula 6, and this reaction is a third aspect of the present invention.
Figure imgf000008_0005
In this reaction scheme Ar is an aryl group selected from optionally substituted phenyl and optionally substituted heteroaryl groups. The optional substituents are selected from alkyl groups, acyl groups, OH, O-alkyl, O-acyl, NH2, NH-alkyl, N(alkyl)2, NH-acyl, N(alkyl)-acyl, N(acyl)2l F, CI, Br, I, CF3, N02, C02H, C02-alkyl, CONH2, CONH-alkyl, CON(alkyl)2 and CN. The aryl group may have up to three such substituents which may be the same or different. In a preferred embodiment, the group Ar is selected from optionally substituted phenyl and optionally substituted pyridyl. More preferably, it is optionally substituted pyridyl. More preferably still, it is optionally substituted 2-pyridyl. Yet more preferably it is 5-monosubstituted 2-pyridyl. Most preferably it is 5-cyano-2-pyridyl.
The group Y is selected from OH, O-alkyl, O-aralkyl, 2-cyano-l-pyrrolidyl (2) and a group according to general formula 3.
Figure imgf000009_0001
The group X is selected from OH, O-alkyl, O-aralkyl, O-resin, NH2, NH-alkyl, NH-aralkyl, and NH-resin.
In a preferred embodiment, the group Y is selected from OH, O-alkyl and O-aralkyl. In another preferred embodiment Y is 2-cyano-l-pyrrolidyl, and more preferably it is (2S)-2- cyano-1-pyrrolidyl. In another preferred embodiment Y is a group according to general formula 3. More preferably, Y is a group according to general formula 3 and X is selected from OH, O-alkyl, O-aralkyl, NH2> NH-alkyl and NH-aralkyl. In another more preferred embodiment X is O-resin or NH-resin.
V is a group susceptible to nucleophilic displacement. Suitable groups are CI, Br, I, alkylsulphonates (alkyl-S02-0-), perfluoroalkylsulphonates, optionally substituted benzenesulphonates (Ph(R)-S02-0-, where R represents one or more alkyl, perfluoroalkyl or halogen group), acyloxy groups (acyl-O-) and perfluoroacyloxy groups. Preferred groups are CI, Br, I, methanesulphonate (mesylate), trifluoromethanesulphonate (triflate) and toluenesulphonate (tosylate). More preferably, V is CI or Br
Particularly preferred embodiments of the present invention are those that combine two or more of the above preferred features. Individually preferred processes of the presented invention include but are not limited to the process shown:
Figure imgf000010_0001
Figure imgf000010_0002
Figure imgf000010_0003
Figure imgf000010_0004
Figure imgf000010_0005
Figure imgf000011_0001
Figure imgf000011_0002
Figure imgf000011_0003
The imidazolidine derivatives according to general formula 5 that serve as starting materials in the process described above can be prepared by the reaction of an ethylenediamine derivative with an aldehyde or ketone.
Figure imgf000011_0004
5
The acetic acid derivatives according to general formula 6 that also serve as starting materials in the process are either items of commerce or can be prepared from such items.
Compounds according to general formula 5 in which Ar is an optionally substituted heteroaryl group are themselves novel. Accordingly, in a fourth aspect the present invention comprises compounds according to general formula 5 in which Ar is an optionally substituted heteroaryl group. The optional substituents are selected from alkyl groups, acyl groups, OH, O-alkyl, O-acyl, NH2, NH-alkyl, N(alkyl)2, NH-acyl, N(alkyl)-acyl, N(acyl)2, F, CI, Br, I, CF3, N02, C02H, C02-alkyl, CONH2, CONH-alkyl, CON(alkyl)2 and CN. The heteroaryl group may have up to three such substituents which may be the same or different.
In a preferred embodiment Ar is an optionally substituted pyridyl group. More preferably it is a 5-monosubstituted 2-pyridyl group. A particularly preferred embodiment is the compound 1-(5-cyano-2-pyridyl)imidazolidine.
The reaction of an imidazolidine derivative according to general formula 5 with an acetic acid derivative 6 is generally more selective (i.e. it gives fewer side products) and higher yielding than the alkylation of the corresponding ethylenediamine derivative. Accordingly, compounds according to general formula 1 can be readily prepared and easily purified on a commercial scale. Since compounds according to general formula 1 can be transformed into the ethylenediamine derivatives of W098/19998 or analogues thereof, their use represents a significant improvement in the preparation of these ethylenediamine derivatives.
The present invention is further illustrated in the following non-limiting Examples.
EXAMPLES
Example 1
1-(5-Cyano-2-pyridyl)imidazolidine
Figure imgf000012_0001
Figure imgf000012_0002
1A fe/f-Butyl (2-(5-cvano-2-pyridylamino)ethvDcarbamate
A solution of 6-chloronicotinonitrile (21.7g, 160mmol), potassium hydrogen carbonate (17.6g, 176mmol) and tert-butyl (2-aminoethyl)carbamate (25.8g, 160mmol) in DMF (80ml) was heated to 90°C under N2 for 2.5h. The mixture was cooled, added to saturated NaHC03 solution and extracted with EtOAc. The organic phase was dried over Na2S0 and concentrated until the product started to precipitate. Further product was precipitated by adding petroleum ether. The combined precipitates were collected and washed with cold EtOAc to afford fert-butyl (2-(5-cyano-2-pyridylamino)ethyl)carbamate (27.2g, 65%) as a white solid.
1H NMR (CDCI3, 270MHz): .δ 1.41 (9H, s), 3.30-3.42 (2H, m), 3.44-3.56 (2H, m), 4.92 (1H, br s), 5.72 (1 H, br s), 6.39 (1 H, dd, J=8.9, 0.7Hz), 7.51 (1 H, dd, 8.9, 2.2Hz), 8.30-8.36 (1 H, m) ppm.
1 B 6-(2-Aminoethylamino)nicotinonitrile trifluoroacetate
Trifluoroacetic acid (125ml) was added to an ice-cold stirred suspension of ferf-butyl (2-(5- cyano-2-pyridylamino)ethyl)carbamate (32. Og, 120mmol) in CH2CI2 (125ml) to give a clear solution. After gas evolution had ceased the cooling bath was removed. After 1.5h the mixture was concentrated and azeotroped with toluene 3 times to afford 6-(2- aminoethylamino)nicotinonitrile trifluoroacetate. The yield was assumed to be quantitative and the material was used directly in the next step.
1C 1-(5-Cvano-2-pyridyl)imidazolidine
6-(2-Aminoethylamino)nicotinonitrile trifluoroacetate (120mmol) was dissolved in water (1300ml). Aqueous 37% formaldehyde solution (15.5g, 12.5ml, 168mmol) was added and the mixture was stirred for 3 days. The mixture was concentrated then azeotroped with toluene twice and with petroleum ether once. The residue was taken up in Et20/EtOH (50:50, 200ml) and scratched to initiate crystallisation. The mixture was cooled in an ice/water bath for 4h and filtered to afford 1-(5-cyano-2-pyridyl)imidazolidine trifluoroacetate (11.4g, 33%) as a pale yellow crystalline solid.
1H NMR (d6 DMSO, 270MHz): δ 3.58-3.78 (4H, m), 4.75 (2H, s), 6.78 (1H, d, J=8.9Hz), 8.01 (1H, dd, J=2.2, 8.9Hz), 8.58 (1H, d, J=2.2Hz) ppm. This was dissolved in water and saturated NaHC03 solution was added until the solution was basic. The mixture was extracted with CH2CI2 four times and the combined organic extracts were dried over Na2S04 and concentrated to afford 1-(5-cyano-2-pyridyl)- imidazolidine free base (6.7g, 32%) as a yellow oil.
1H NMR (CDCI3, 270MHz): δ 3.26-3.48 (4H, m), 4.46 (2H, s), 6.28 (1 H, d, J=8.7Hz), 7.57 (1H, dd, J=2.2, 8.7Hz), 8.37 (1H, d, J=2.2Hz) ppm.
Example 2
W-(2-(3' -(5" -cyano-2"-pyridyl)imidazolidine)acetyl)-L-proline tert-butyl ester
Figure imgf000014_0002
2A. Λ/-Bromoacetyl-L-proline terf-butyl ester
A solution of L-proline terf-butyl ester (5.0g, 29mmol), DMAP (15mg) and triethylamine (3.5g, 4.9ml, 35mmol) in CH2CI2 (100ml) was added dropwise to an ice-cold solution of bromoacetyl bromide (6.4g, 2.8ml, 32mmol) in CH2CI2 (75ml). After 90min, EtOAc (800ml) was added and the mixture was filtered and concentrated to give Λ/-bromoacetyl- L-proline terf-butyl ester. The yield was assumed to be quantitative and the material was used directly in the next step. 1H NMR (CDCI3, 270MHz): δ 1.42 (9H, s), 1.80-2.28 (4H, m), 3.48-3.86 (2H, m), 3.71 and 3.79 (total 2H in the ratio 1 :3, each s), 4.08 and 4.33 (total 1H in the ratio 3:1, dd, J=7.2, 14.4Hz and dd, J=3.7, 8.3Hz) ppm.
2B. Λ/-(2-(3 -(5"-cvano-2"-pyridyl)imidazolidine)acetyl)-L-proline terf-butyl ester A solution of Λ/-bromoacetyl-L-proline terf-butyl ester (2.0g, 6.9mmol) in THF (5ml) was added to an ice-cold solution of 1-(5-cyano-2-pyridyl)imidazolidine (1.0g, 5.7mmol) and triethylamine (1.1ml, 0.81 g, δ.Ommol) in THF (10ml). The resulting cloudy mixture was allowed to warm to room temperature and stirred for 24h. The mixture was added to dilute K2C03 solution and extracted with CH2CI2 three times. The combined organic extracts were dried over Na2S04 and concentrated. Chromatography (2.5% MeOH/97.5% CH2CI2) afforded Λ/-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-proline terf-butyl ester (0.77g, 35%) as a golden oil.
1H NMR (CDCI3, 270MHz): δ 1.44 (9H, s), 1.80-2.24 (4H, m), 2.90-3.72 (8H, m), 4.24-4.46 (3H, m), 6.27 (1 H, d, J=8.9Hz), 7.57 (1H, dd, J=8.9,2.0Hz), 8.37 (1H, d, J=2.0Hz, 6"CH) ppm.
MS (ESI) m/z 386.2 (MH+)
Example 3
W-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-proline
Figure imgf000015_0001
A solution of Λ/-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-proline terf-butyl ester
(109mg, 0.28mmol) in CH2CI2 (0.5ml) and trifluoroacetic acid (1ml) was stirred for 2.5h.
The mixture was reduced to dryness to afford Λ/-(2-(3'-(5"-cyano-2"- pyridyl)imidazolidine)acetyl)-L-proline trifluoroacetate salt as a yellow gum. The yield was assumed to be quantitative. 1H NMR (dβ DMSO, 270MHz): δ 1.82-2.02 (3H, m) and 2.08-2.26 (1H, m), 3.30-3.96 (8H, m), 4.20-4.66 (3H, m), 6.79 (1 H, d, J=8.9Hz), 8.03 (1 H, dd, J=2.2, 8.9Hz), 8.59 (1 H, d, J=2.2Hz) ppm.
MS (ESI) m/z 330.2 (MH+).
Example 4 Λ/-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-prolineamide
Figure imgf000016_0001
Figure imgf000016_0002
4A Λ/-Bromoacetyl-L-prolineamide
A solution of L-prolinamide (9.9g, 87mmol), DMAP (15mg) and triethylamine (10.5g, 14.5ml, 104mmol) in CH2CI2 (125ml) was added dropwise to an ice-cold solution of bromoacetyl bromide (19.3g, 8.3ml, 96mmol) in CH2CI2 (75ml) over 1 h. After a further 2h, EtOAc (1500ml) was added and the mixture was filtered and concentrated to give N- bromoacetyl-L-prolineamide (20.4g, 100%).
1H NMR (CDCI3, 270MHz): δ 1.88-2.42 (4H, m), 3.50-3.74 (2H, m), 3.85 (2H, s), 4.44-4.60 (1H, m), 5.56-5.88 (1H, br s), 6.80 (1 H, br s) ppm. 4B. Λ/-(2-(3 -(5,,-cvano-2"-pyridyl)imidazolidine)acetyl)-L-prolineamide A solution of Λ/-bromoacetyl-L-prolineamide (0.79g, 3.34mmol) in THF (5ml) was added to an ice-cold solution of 1-(5-cyano-2-pyridyl)imidazolidine (0.49g, 2.8mmol) and triethylamine (0.54ml, 0.40g, 3.9mmol) in THF (10ml). The resulting cloudy mixture was allowed to warm to room temperature and stirred for 4 days. The mixture was added to dilute K2C03 solution and extracted with CH2CI2 four times. The combined organic extracts were dried over Na2S0 and concentrated. Chromatography (10% MeOH/90% CH2CI2) afforded Λ/-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-prolineamide (0.14g, 15%) as a white foam.
1H NMR (dβ DMSO, 270MHz): 51.78-2.30 (3H, m) and 2.32-2.46 (1H, m), 3.08-3.28 (2H, m), 3.32-3.72 (6H, m), 4.26-4.50 (2H, m), 4.59 (1H, dd, J=2.2, 8.2Hz), 5.47 (1H, br s), 6.29 (1H, d, J=8.9Hz), 6.92 (1H, br s), 7.59 (1H, dd, J=1.7, 8.9Hz), 8.37 (1H, d, J=1.7Hz) ppm.
MS (ESI) m/z 329.2 (MH+).
Example 5 (2S)-1-(2'-(3"-(5'"-cyano-2'"-pyridyl)imidazolidine)acetyl)pyrrolidine-2-carbonitrile
Figure imgf000017_0001
Figure imgf000017_0002
5A (2S)-1-(Bromoacetyl)pyrrolidine-2-carbonitrile
Λ/-Bromoacetyl-L-prolineamine (20.4g, 87mmol) was dissolved in CH2CI2 (120ml) and cooled in an ice/water bath. The cold solution was added to ice-cold trifluoroacetic anhydride (24.6ml, 36.5g, 174mmol) under N2 over 15min. After 2h the mixture was added cautiously to saturated NaHC03 while cooling in an ice/water bath. The phases was separated and the aqueous layer was extracted with CH2CI2. The combined organic phases were washed with water, dried over Na2S0 and concentrated. Chromatography (75% EtOAC/25% petroleum ether) afforded (2S)-1-(bromoacetyl)pyrrolidine-2-carbonitrile (3.94g, 21%) as an orange oil.
1H NMR (CDCI3, 270MHz): δ 2.00-2.50 (4H, m), 3.44-4.02 (2H, m), 3.81 (2H, s), 4.68-4.80 and 4.82-4.90 (total 1H, each m) ppm.
5B (2S)-1-(2'-(3"-(5,"-Cvano-2,"-pyridyl)imidazolidine)acetyl)pyrrolidine-2-carbonitrile
A solution of (2S)-1-(bromoacetyl)pyrrolidine-2-carbonitrile (3.94g, 18.1mmol) in THF
(20ml) was added to an ice-cold solution of 1-(5-cyano-2-pyridyl)imidazolidine (3.16g,
18.1mmol) and triethylamine (2.8ml, 2.0g, 20mmol) in THF (20ml) over 3min. The resulting cloudy mixture was allowed to warm to room temperature and stirred for 6h. The mixture was added to dilute NaHC03 solution and extracted with CH2CI2 four times. The combined organic extracts were dried over Na2S0 and concentrated. Chromatography
(2.5% MeOH/97.5% CH2CI2) afforded (2S)-1-(2'-(3"-(5'"-cyano-2'"-pyridyl)imidazolidine)- acetyl)pyrrolidine-2-carbonitrile (3.4g, 61%) as a white foam.
1H NMR (CDCI3, 270MHz): δ2.04-2.42 (4H, m), 3.18 (2H, t, J=6.7Hz), 3.34-3.76 (6H) 4.26- 4.42 (2H) (each m, 5CH2, 2"CH2, 4"CH2 and 2'CH2), 4.74-4.80 and 4.95-5.04 (total 1H in the ratio 3:1, each m), 6.30 (1H, d, J=8.9Hz), 7.60 (1H, dd, J=2.0, 8.9Hz), 8.38 (1H, d, J=2.0Hz).
MS (ESI) m/z 311.0 (MH+).
Example 6 (2S)-1-(2'-(5"-cyano-2"-pyridylamino)ethylamino)acetyl)pyrrolidine-2-carbonitrile
Figure imgf000019_0001
A solution of (2S)-1-(2'-(3"-(5'"-cyano-2'"-pyridyl)imidazolidine)acetyl)pyrrolidine-2- carbonitrile (3.15g, 10.2mmol) in 10% trifluoroacetic acid (250ml) was stirred for 24h. The mixture was cooled in an ice/water bath and potassium carbonate was added cautiously until saturated, then extracted with CH2CI2 seven times. The combined extracts were dried over Na2SO4 and concentrated. Chromatography (10% MeOH/90% CH2CI2) afforded (2S)-1-(2'-(5"-cyano-2"-pyridylamino)ethylamino)acetyl)pyrrolidine-2-carbonitrile (1.53g, 50%) as a colourless gum.
H NMR at 25°C was consistent with the presence of two rotameric isomers in a ratio of -85:15.
1H NMR (dβ DMSO, 270MHz): .δ 1.84-2.30 (4H, m), 2.71 (2H, t, J=6.2Hz), 3.22-3.48 (5H, m), 3.50-3.66 (1 H, m), 4.73 and 5.13 (1 H, ratio -85:15, dd, J=4.7, 6.4Hz and dd, J=2.5, 6.7Hz), 6.56 (1H, d, J=8.9Hz), 7.50-7.72 (2H, m), 8.36 (1H, d, J=2.0Hz) ppm.
At higher temperatures the NMR signals of the two compounds appeared to coalesce as is typical of rotameric isomers.
1H NMR (dβ DMSO, 270MHz): δ 1.98-2.30 (4H, m), 2.77 (2H, t, J=6.2Hz), 3.30-3.62 (6H, m), 4.62-4.88 (1H, m), 6.57 (1H, d, J=8.9Hz), 7.26 (1H, br s), 7.61 (1H, dd, J=2.2, 8.9Hz),
8.33 (1H, d, J=2.2Hz) ppm. 4N HCI/dioxan (1.3ml, 5.1mmol) was added to a solution of (2S)-1-(2'-(5"-cyano-2"- pyridylamino)ethylamino)acetyl)pyrrolidine-2-carbonitrile (1.53g, 5.13mmol) to afford a white precipitate. The solid was filtered, washed and triturated with Et20 and dried in vacuo over P205 to yield (2S)-1-(2'-(5"-cyano-2"-pyridylamino)ethylamino)acetyl)- pyrrolidine-2-carbonitrile hydrochloride salt (1.40g, 82%) as a white powder. An analytical sample was recystallised from MeOH, m. pt. = 158-163°C.
1H NMR (dβ DMSO, 270MHz): .δ 1.88-2.30 (4H, ), 3.13 (2H, s), 3.32-3.50 (1H, m), 3.52- 3.98 (4H, m), 4.00-4.22 (1H, m), 4.84 (1H, t, J=5.6Hz), 6.64 (1 H, d, J=8.9Hz), 7.76 (1H, dd, J=8.9, 2.1Hz), 8.00 (1 H, br s), 8.43 (1H, d, J=2.1Hz), 9.25 (2H, br s) ppm.
1 C NMR (D20, 68MHz): .5 24.7, 29.6, 38.2, 46.3, 47.0, 47.1, 48.2, 97.3, 111.5, 117.9, 118.7, 141.6, 149.5, 156.8, 165.0 ppm.
MS (ESI) m/z 299.1 (MH+).
As illustrated in the foregoing Examples, the use of imidazolidine derivatives provides a simple and convenient route to Λ/-(aminoethyl)glycine derivatives such as NVP-DPP728. In particular, the improved selectivity in the alkylation step reduces the need for lengthy purification procedures, so improving the overall efficiency of the process.

Claims

1 A compound according to general formula 1 , or a salt thereof
Figure imgf000021_0001
1 wherein:
Ar is selected from optionally substituted phenyl and optionally substituted heteroaryl;
R1 and R2 are independently selected from H and alkyl;
Y is selected from OH, O-alkyl, O-aralkyl, 2-cyano1-pyrrolidyl and a group according to general formula 3
Figure imgf000021_0002
3 and X is selected from OH, O-alkyl, O-aralkyl, O-resin, NH2, NH-alkyl, NH-aralkyl and NH-resin.
2 A compound according to Claim 1 wherein R1 and R2 are independently selected from H, methyl and ethyl.
3 A compound according to Claim 1 or 2 wherein R1 and R2 are independently selected from H and methyl.
4 A compound according to Claim 1 or 2 wherein R1 and R2 are both H.
5 A compound according to Claim 1 or 2 wherein R1 and R2 are both methyl.
6 A compound according to any of Claims 1 to 5 wherein Ar is selected from optionally substituted phenyl and optionally substituted pyridyl. A compound according to any of Claims 1 to 6 wherein Ar is optionally substituted pyridyl.
A compound according to any of Claims 1 to 7 wherein Ar is optionally substituted 2-pyridyl.
A compound according to any of Claims 1 to 8 wherein Ar is 5-monosubst.itut.ed-2- pyridyl.
A compound according to any of Claims 1 to 9 wherein Ar is 5-cyano-2-pyridyl.
A compound according to any of Claims 1 to 10 wherein Y is selected from OH, O-aikyl and O-aralkyl.
A compound according to any of Claims 1 to 10 wherein Y is 2-cyano-l-pyrrolidyl.
A compound according to any of Claims 1 to 10 wherein Y is a group according to general formula 3.
A compound according to any of Claims 1 to 10 or Claim 13 wherein Y is a group according to general formula 3 and X is selected from OH, O-alkyl, O-aralkyl, NH2, NH-alkyl and NH-aralkyl.
A compound according to any of Claims 1 to 10 or Claim 13 wherein Y is a group according to general formula 3 and X is selected from O-resin and NH-resin.
A compound selected from
Λ/-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-proline;
Λ/-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-proline methyl ester;
Λ/-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-proline benzyl ester; Λ/-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-proline terf-butyl ester;
Λ/-(2-(3'-(5"-cyano-2"-pyridyl)imidazolidine)acetyl)-L-prolineamide; and
(2S)-1-(2'-(3"-(5'"-cyano-2'"-pyridyl)imidazolidine)acetyl)pyrrolidine-2-carbonitrile,
or a salt thereof.
A process for the manufacture of a compound according to general formula 1
Figure imgf000023_0001
1 which comprises the reaction of an imidazolidine according to general formula 5 and an acetic acid derivative according to general formula 6
R1 R2
Ar. X ,Y
N NH V o
wherein:
Ar is selected from optionally substituted phenyl and optionally substituted heteroaryl;
R1 and R2 are independently selected from H and alkyl;
V is selected from Br, CI, I, alkylsulphonate, perfluoroalkylsulphonate, optionally substituted benzenesulphonate, acyloxy and perfluoroacyloxy groups;
Y is selected from OH, O-alkyl, O-aralkyl, 2-cyano1-pyrrolidyl and a group according to general formula 3
Figure imgf000024_0001
3 and X is selected from OH, O-alkyl, O-aralkyl, O-resin, NH2, NH-alkyl, NH-aralkyl and NH-resin
A process according to Claim 17 wherein V is selected from CI, Br, I, methanesulphonate, trifluoromethanesulphonate and toluenesulphonate.
A process according to Claim 17 or 18 wherein V is selected from CI and Br.
A process according to any of Claims 17 to 19 wherein Y is selected from OH, O- alkyl and O-aralkyl.
A process according to any of Claims 17 to 19 wherein Y is 2-cyano-l-pyrrolidyl.
A process according to Claim 21 wherein Y is (2S)-2-cyaπo-1-pyrrolidyl.
A process according to any of Claims 17 to 19 wherein Y is a group according to general formula 3.
A process according to any of Claims 17 to 19 and Claim 23 wherein Y is a group according to general formula 3 and X is selected from OH, O-alkyl, O-aralkyl, NH2, NH-alkyl and NH-aralkyl.
A process according to any of Claims 17 to 19 and Claim 23 wherein Y is a group according to general formula 3 and X is selected from O-resin and NH-resin.
A process according to any of Claims 17 to 19 which comprises the reaction of 6- (l-imidazolidinyl)nicotinonitrile with an alkylating agent selected from
Λ/-(chloroacetyl)proline; Λ/-(chloroacetyl)proline methyl ester;
Λ/-(chloroacetyl)proline terf-butyl ester;
Λ/-(chloroacetyI)prolineamide;
(2S)-1-chioroacetylpyrrolidine-2-carbonitrile;
Λ/-(bromoacetyl)proline;
Λ/-(bromoacetyl)proline methyl ester;
/V-(bromoacetyl)proline terf-butyl ester;
Λ/-(bromoacetyl)prolineamide; and
(2S)-1-bromoacetylpyrrolidine-2-carbonitrile.
The use of a compound according to general formula 1
Figure imgf000025_0001
1 wherein:
Ar is selected from optionally substituted phenyl and optionally substituted heteroaryl;
R1 and R2 are independently selected from H and alkyl;
Y is selected from OH, O-alkyl, O-aralkyl, 2-cyano-l-pyrrolidyl and a group according to general formula 3
Figure imgf000026_0001
3 and X is selected from OH, O-alkyl, O-aralkyl, O-resin, NH2, NH-alkyl, NH-aralkyl and NH-resin, which use is as a component in the manufacture of a pharmaceutical agent.
A use according to Claim 27 wherein the pharmaceutical agent is a compound according to general formula 4
Figure imgf000026_0002
4 wherein Ar and Y are as defined in Claim 27.
A compound according to general formula 5, or a salt thereof
Figure imgf000026_0003
5 wherein Ar is optionally substituted phenyl or optionally substituted heteroaryl; and R1 and R2 are independently selected from H and alkyl.
A compound according to claim 29, or salt thereof, wherein the phenyl or heteroaryl group substituent(s) is selected from alkyl groups, acyl groups, OH, O- alkyl, O-acyl, NH2, NH-alkyl, N(alkyl)2, NH-acyl, N(alkyl)-acyl, N(acyl)2, F, CI, Br, I, CF3, N02, C02H, C02-alkyl, CONH2, CONH-alkyl, CON(alkyl)2 and CN.
A compound according to claim 29 or claim 30 with the proviso that when R1 and R2 are both H, Ar is not 4-methoxyphenyl. A compound according to Claim 29, 30 or 31 , or salt thereof, wherein R1 and R2 are both H.
A compound according to any of claims 29 to 32, or salt thereof , wherein Ar is optionally substituted pyridyl.
A compound according to any of claims 29 to 33, or salt thereof , wherein Ar is a 5-m onos u bstituted-2-pyridyl g rou p .
1-(5-Cyano-2-pyridyl)imidazolidine, or a salt thereof.
A process for the manufacture of (2S)-1-(2-(5-cyanopyridyl-2-amino)ethylamino- acetyl)pyrrolidine-2-carbonitrile (NVP-DPP728) that comprises the steps of
(i) reacting 1-(5-cyano-2-pyridyl)imidazolidine with an N-(haloacetyl)- proline, or ester or amide thereof, or with an N-(haloacetyl)pyrrolidine-
2-carbonitriIe; and (ii) optionally modifying the carboxylic acid, ester or amide functionality so as to provide a carbonitrile functional group; and (iii) treating the product so obtained with an acid so as to open the imidazolidine ring and give an ethylenediamine derivative.
PCT/GB2002/005631 2001-12-14 2002-12-12 Imidazolidineacetic acid derivatives WO2003051848A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002350942A AU2002350942A1 (en) 2001-12-14 2002-12-12 Imidazolidineacetic acid derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0129988.2 2001-12-14
GB0129988A GB0129988D0 (en) 2001-12-14 2001-12-14 Imidazolidineacetic acid derivatives

Publications (2)

Publication Number Publication Date
WO2003051848A2 true WO2003051848A2 (en) 2003-06-26
WO2003051848A3 WO2003051848A3 (en) 2003-09-18

Family

ID=9927662

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2002/005631 WO2003051848A2 (en) 2001-12-14 2002-12-12 Imidazolidineacetic acid derivatives

Country Status (3)

Country Link
AU (1) AU2002350942A1 (en)
GB (1) GB0129988D0 (en)
WO (1) WO2003051848A2 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010022690A2 (en) 2008-08-26 2010-03-04 Zentiva, K.S. A method of preparation of highly pure vildagliptin
US7842707B2 (en) 2004-07-23 2010-11-30 Nuada, Llc Peptidase inhibitors
US7960384B2 (en) 2006-03-28 2011-06-14 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
CN104262227A (en) * 2014-09-16 2015-01-07 东北制药集团股份有限公司 Preparation method of (S)-1-(2-chloracetyl)pyrrolidine-2-carbonitrile

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998019998A2 (en) * 1996-11-07 1998-05-14 Novartis Ag N-substituted 2-cyanopyrrolidines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998019998A2 (en) * 1996-11-07 1998-05-14 Novartis Ag N-substituted 2-cyanopyrrolidines

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
C. CHAPUIS ET AL.: "Condensation de diamines-1,2 sur les composés carbonylés. Synthèses d'imidazolidines: mécanisme de réaction" BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE., vol. 3, no. 2, - 1973 pages 977-985, XP002246872 SOCIETE FRANCAISE DE CHIMIE. PARIS., FR ISSN: 0037-8968 *
CHEMICAL ABSTRACTS, vol. 84, no. 17, 26 April 1976 (1976-04-26) Columbus, Ohio, US; abstract no. 115622f, BASSUS, JACQUES ET AL.: "Potential psychotropic compounds. XI. Synthesis and pharmacological activity of new cyclic imidazolidino butyrophenones." XP002246874 & EUR. J. MED: CHEM. - CHIM. THER., vol. 10, no. 4, - 1975 pages 367-372, -& DATABASE CAPLUS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; CA 84:115622, XP002246875 *
NICOLAS WILLAND ET AL.: "Solid and solution phase syntheses of the 2-cyanopyrrolidide DPP-IV inhibitor NVP-DPP728" TETRAHEDRON., vol. 58, no. 28, - 8 July 2002 (2002-07-08) pages 5741-5746, XP002246873 ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM., NL ISSN: 0040-4020 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7842707B2 (en) 2004-07-23 2010-11-30 Nuada, Llc Peptidase inhibitors
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7960384B2 (en) 2006-03-28 2011-06-14 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
WO2010022690A2 (en) 2008-08-26 2010-03-04 Zentiva, K.S. A method of preparation of highly pure vildagliptin
WO2010022690A3 (en) * 2008-08-26 2010-11-11 Zentiva, K.S. A method of preparation of highly pure vildagliptin
CN104262227A (en) * 2014-09-16 2015-01-07 东北制药集团股份有限公司 Preparation method of (S)-1-(2-chloracetyl)pyrrolidine-2-carbonitrile
CN104262227B (en) * 2014-09-16 2018-09-18 东北制药集团股份有限公司 A method of preparing (S) -1- (2- chloracetyls) pyrrolidines -2- formonitrile HCNs

Also Published As

Publication number Publication date
WO2003051848A3 (en) 2003-09-18
GB0129988D0 (en) 2002-02-06
AU2002350942A1 (en) 2003-06-30
AU2002350942A8 (en) 2003-06-30

Similar Documents

Publication Publication Date Title
US4923986A (en) Derivatives of physiologically active substance K-252
JP4502804B2 (en) Azabicyclo-octane and nonane derivatives having DDP-IV inhibitory activity
KR101105607B1 (en) Dipeptidyl Peptidase-IV Inhibiting Compounds, Methods of Preparing the Same, and Pharmaceutical Compositions Containing the Same as Active Agent
TW201823208A (en) N-acyl amino acid compounds and methods of use
CN112135612A (en) Amino acid compounds and methods of use
KR20080004485A (en) Piperidyl-2, 6-dione derivatives used to inhibit cells from releasing tumor necrosis factor
CN107759602B (en) Compound containing conjugated allene structure, pharmaceutical composition and application thereof
WO2003074500A2 (en) N-aminoacetyl-pyrrolidine-2-carbonitriles and their use as ddp-iv inhibitors
TW200524605A (en) Therapeutic agents
AU2021201924B2 (en) Human plasma kallikrein inhibitors
JP2022539579A (en) PLK1 Selective Degradation Inducing Compound
JP7408819B2 (en) Isoindoline derivatives and pharmaceutical compositions and uses thereof
CN114105950B (en) Pyrazole compound and application thereof
WO2018015818A2 (en) Therapeutic inhibitory compounds
WO2003051848A2 (en) Imidazolidineacetic acid derivatives
WO2012165547A1 (en) Method for manufacturing pyrazole derivative
WO1994010157A1 (en) Styrene derivative and salts thereof
JP2005504800A (en) Method for producing pyrimidinone compounds and pharmaceutically acceptable salts thereof
EP0649843B1 (en) Thiazoline derivative
WO2001012601A1 (en) Novel anilide derivatives or salts thereof and drugs containing the same
OA10996A (en) Pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa agonists
AU761721B2 (en) Method for producing enantiomer-free N-methyl-N- ((1S)-1-phenyl- 2-((3S)- 3-hydroxypyrrolidine- 1-yl)ethyl)- 2,2-diphenyl acetamide
WO2018224037A1 (en) Carboxylic acid derivative as at2r receptor antagonist
Paternotte et al. Syntheses and hydrolysis of basic and dibasic ampicillin esters tailored for intracellular accumulation
Mlostoń et al. First synthesis of the N (1)-bulky substituted imidazole 3-oxides and their complexation with hexafluoroacetone hydrate

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP