Details for Patent: 8,329,900

Title:	Dipeptidyl peptidase inhibitors
Abstract:	Compounds, pharmaceuticals, kits and methods are provided for use with DPP-IV and other S9 proteases that comprise a compound comprising: ##STR00001## wherein M is N or CR.sub.4; Q.sup.1 and Q.sup.2 are each independently selected from the group consisting of CO, SO, SO.sub.2, and C.dbd.NR.sub.9; and each L, X, R.sub.1, R.sub.2, and R.sub.3 are as defined herein.
Inventor(s):	Feng; Jun (Carlsbad, CA), Gwaltney; Stephen L. (San Diego, CA), Stafford; Jeffrey A. (San Diego, CA), Zhang; Zhiyuan (San Diego, CA), Elder; Bruce J. (Wynantskill, NY), Isbester; Paul K. (Castleton, NY), Palmer; Grant J. (Clifton Park, NY), Salsbury; Jonathon S. (Albany, NY), Ulysse; Luckner G. (Albany, NY)
Assignee:	Takeda Pharmaceutical Company Limited (Osaka, JP)
Filing Date:	Oct 30, 2007
Application Number:	11/929,673
Claims:	1. A process for producing a pyrimidin-dione of the formula: ##STR00064## wherein M is CR.sub.4; R.sub.2 is hydrogen or selected from the group consisting of (C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl, hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl, hetero(C.sub.3-12)cycloalkyl, aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl, (C.sub.9-12)bicycloaryl, hetero(C.sub.4-12)bicycloaryl, hetero(C.sub.4-12)bicycloaryl(C.sub.1-5)alkyl, carbonyl (C.sub.1-3)alkyl, thiocarbonyl (C.sub.1-3)alkyl, sulfonyl (C.sub.1-3)alkyl, sulfinyl (C.sub.1-3)alkyl, imino (C.sub.1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, and carbonyl group, each substituted or unsubstituted; R.sub.3 is selected from the group consisting of 3-amino-piperidinyl-1-yl, 3-aminomethyl-pyrrolidin-1-yl, 2-aminoazetidin-1-yl, 3-amino-3-methylpiperidin-1-yl, 3-aminohexahydroazepin-1-yl, piperazin-1-yl, homopiperazin-1-yl, 3-amino-pyrrolidin-1-yl, R-3-aminopiperidin-1-yl, R-3-amino-3-methylpiperidin-1-yl and 3-amino-pyrrolidin-1-yl, each substituted or unsubstituted; R.sub.4 is hydrogen; and -L-X taken together is selected from the group consisting of --(CH.sub.2)-(2-cyano)phenyl; --(CH.sub.2)-(3-cyano)phenyl; --(CH.sub.2)-(2-hydroxy)phenyl; --(CH.sub.2)-(3-hydroxy)phenyl; --(CH.sub.2)-(2-alkenyl)phenyl; --(CH.sub.2)-(3-alkenyl)phenyl; --(CH.sub.2)-(2-alkynyl)phenyl; --(CH.sub.2)-(3-alkynyl)phenyl; --(CH.sub.2)-(2-methoxy)phenyl; --(CH.sub.2)-(3-methoxy)phenyl; --(CH.sub.2)-(2-nitro)phenyl; --(CH.sub.2)-(3-nitro)phenyl; --(CH.sub.2)-(2-carboxy)phenyl; --(CH.sub.2)-(3-carboxy)phenyl; --(CH.sub.2)-(2-carboxamido)phenyl; --(CH.sub.2)-(3-carboxamido)phenyl; --(CH.sub.2)-(2-sulfonamido)phenyl; --(CH.sub.2)-(3-sulfonamido)phenyl; --(CH.sub.2)-(2-tetrazolyl)phenyl; --(CH.sub.2)-(3-tetrazolyl)phenyl; --(CH.sub.2)-(2-aminomethyl)phenyl; --(CH.sub.2)-(3-aminomethyl)phenyl; --(CH.sub.2)-(2-hydroxymethyl)phenyl; --(CH.sub.2)-(3-hydroxymethyl)phenyl; --(CH.sub.2)-(2-phenyl)phenyl; --(CH.sub.2)-(3-phenyl)phenyl; --(CH.sub.2)-(2-halo)phenyl; --(CH.sub.2)-(3-halo)phenyl; --(CH.sub.2)-(2-CONH.sub.2)phenyl; --(CH.sub.2)-(3-CONH.sub.2)phenyl; --(CH.sub.2)-(2-CONH(C.sub.1-7)alkyl)phenyl; --(CH.sub.2)-(3-CONH(C.sub.1-7)alkyl)phenyl; --(CH.sub.2)-(2-CO.sub.2(C.sub.1-7)alkyl)phenyl; --(CH.sub.2)-(3-CO.sub.2(C.sub.1-7)alkyl)phenyl; --(CH.sub.2)-(2-NH.sub.2)phenyl; --(CH.sub.2)-(3-NH.sub.2)phenyl; --(CH.sub.2)-(2-(C.sub.3-7)alkyl)phenyl; --(CH.sub.2)-(3-(C.sub.3-7)alkyl)phenyl; --(CH.sub.2)-(2-(C.sub.3-7)cycloalkyl)phenyl; --(CH.sub.2)-(3-(C.sub.3-7)cycloalkyl)phenyl; --(CH.sub.2)-(2-aryl)phenyl; --(CH.sub.2)-(3-aryl)phenyl; --(CH.sub.2)-(2-heteroaryl)phenyl; --(CH.sub.2)-(3-heteroaryl)phenyl; --(CH.sub.2)-2-bromo-5-fluoro phenyl; --(CH.sub.2)-2-chloro-5-fluoro phenyl; --(CH.sub.2)-2-cyano-5-fluoro phenyl; --(CH.sub.2)-2,5-dichloro phenyl; --(CH.sub.2)-2,5-difluoro phenyl; --(CH.sub.2)-2,5-dibromo phenyl; --(CH.sub.2)-2-bromo-3,5-difluoro phenyl; --(CH.sub.2)-2-chloro-3,5-difluoro phenyl; --(CH.sub.2)-2,3,5-trifluoro phenyl; --(CH.sub.2)-2,3,5,6-tetrafluorophenyl; --(CH.sub.2)-2-bromo-3,5,6-trifluoro phenyl; --(CH.sub.2)-2-chloro-3,5,6-trifluoro phenyl; --(CH.sub.2)-2-cyano-3,5-difluoro phenyl; --(CH.sub.2)-2-cyano-3,5,6-trifluoro phenyl; --(CH.sub.2)-(2-heterocycloalkyl)phenyl; and --(CH.sub.2)-(3-heterocycloalkyl)phenyl, each substituted or unsubstituted; the process comprising the steps of: (i) contacting a compound of the formula A ##STR00065## wherein Hal is halogen; with a compound of the formula B X-L-LG B wherein LG is a leaving group and LX is as defined above; under conditions sufficient to produce a compound of the formula C ##STR00066## (ii) contacting the compound of formula C with a compound of formula D R.sub.2-LG' D wherein LG' is a leaving group; under conditions sufficient to produce a compound of the formula E; ##STR00067## (iii) contacting the compound of formula E with a compound of formula R.sub.3--H under conditions sufficient to produce the pyrimidin-dione. 2. The process of claim 1, wherein the pyrimidin-dione product is further converted to an acid addition salt. 3. The process of claim 2, wherein the acid addition salt is selected from the group consisting of acetate, citrate, hydrochloride, L-lactate, succinate, sulfate, p-toluenesulfonate, benzenesulfonate, benzoate, methanesulfonate, naphthylene-2-sulfonate, propionate, p-toluenesulfonate, hydrobromate, hydroiodate, R-mandelate, and L-tartrate. 4. The process of claim 1, wherein Hal is selected from the group consisting of Br, Cl and F in the compound of formula A. 5. The process of claim 1, wherein the leaving group LG is selected from the group consisting of Br, Cl and I. 6. The process of claim 1, wherein step (ii) further comprises the addition of a base. 7. The process of claim 6, wherein the base is potassium carbonate. 8. The process of claim 1, wherein product E is further purified before subjecting to step (iii). 9. The process of claim 8, wherein the purification of product E is performed by solvent washes and/or by chromatography. 10. The process of claim 1, wherein R.sub.3--H is a secondary amine or an amine hydrochloride. 11. The process of claim 1, wherein step iii) further comprises a purification step of washing of the product with organic solvents or mixture of solvents and/or by column chromatography. 12. The process of claim 1, wherein R.sub.2 is a substituted or unsubstituted (C.sub.1-10)alkyl. 13. The process of claim 1 wherein the pyrimidin-dione is selected from the group consisting of: 2-{6-[3-Amino-piperidin-1-yl]-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-- 1-ylmethyl}-benzonitrile; 2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmeth- yl}-benzonitrile; 6-[3-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-1H-pyrimidine-2,4-dione; 6-[3-Amino-piperidin-1-yl]-1-(2-iodo-benzyl)-1H-pyrimidine-2,4-dione; 6-[3-Amino-piperidin-1-yl]-1-(2-bromo-5-fluoro-benzyl)-3-methyl-1H-pyrimi- dine-2,4-dione; 6-[3-Amino-piperidin-1-yl]-1-(2-chloro-5-fluoro-benzyl)-3-methyl-1H-pyrim- idine-2,4-dione; 6-[3-Amino-piperidin-1-yl]-1-(2-chloro-4-fluoro-benzyl)-3-methyl-1H-pyrim- idine-2,4-dione; 6-[3-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-3-methyl-1H-pyrimidine-2,4-- dione; 2-{6-[Azepan-3(.+-.)-ylamino]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyr- imidin-1-ylmethyl}-benzonitrile (14); 2-{6-[3(.+-.)-Amino-azepan-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimi- din-1-ylmethyl}-benzonitrile; 2-{6-[3-Amino-piperidin-1-yl]-3-(3-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H- -pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H- -pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3-Amino-piperidin-1-yl]-3-(4-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H- -pyrimidin-1-ylmethyl}-benzonitrile; 2-[6-(3-Amino-piperidin-1-yl)-3-(1H-benzoimidazol-2-ylmethyl)-2,4-dioxo-3- ,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile; 2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3-(4-pyrazol-1-yl-benzyl)-3,4-dih- ydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3-(3-pyrrol-1-yl-benzyl)-3,4-dihy- dro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 6-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-py- rimidin-1-ylmethyl]-thiophene-3-carbonitrile; 3-{4-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H- -pyrimidin-1-ylmethyl}-benzoic acid methyl ester; 3-{4-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H- -pyrimidin-1-ylmethyl}-benzoic acid; 6-[3(R)-Amino-piperidin-1-yl]-1-(2,5-di-chloro-benzyl)-3-methyl-1H-pyrimi- dine-2,4-dione; 6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-3,6-di-fluoro-benzyl)-3-methyl-- 1H-pyrimidine-2,4-dione; (R)-2-((6-(3-amino-3-methylpiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro- pyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile; and 6-[3-Amino-piperidin-1-yl]-1,3-bis-(2-bromo-5-fluoro-benzyl)-1H-pyrimidin- e-2,4-dione. 14. The process of claim 1, wherein the pyrimidin-dione is selected from the group consisting of: 2-{6-[3(R)-Amino-piperidin-1-yl]-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimid- in-1-ylmethyl}-benzonitrile; 2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylm- ethyl}-benzonitrile; 6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-1H-pyrimidine-2,4-dione; 6-[3(R)-Amino-piperidin-1-yl]-1-(2-iodo-benzyl)-1H-pyrimidine-2,4-dione; 6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-5-fluoro-benzyl)-3-methyl-1H-pyr- imidine-2,4-dione; 6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-5-fluoro-benzyl)-3-methyl-1H-py- rimidine-2,4-dione; 6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-4-fluoro-benzyl)-3-methyl-1H-py- rimidine-2,4-dione; 6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-3-methyl-1H-pyrimidine-2- ,4-dione; 2-{6-[3(R)-Amino-piperidin-1-yl]-3-(3-cyano-benzyl)-2,4-dioxo-3,- 4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,4-dioxo-3,4-dihydro- -2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3(R)-Amino-piperidin-1-yl]-3-(4-cyano-benzyl)-2,4-dioxo-3,4-dihydro- -2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3-(4-pyrazol-1-yl-benzyl)-3,4-- dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3-(3-pyrrol-1-yl-benzyl)-3,4-d- ihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 6-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H- -pyrimidin-1-ylmethyl]-thiophene-3-carbonitrile; 3-{4-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro- -2H-pyrimidin-1-ylmethyl}-benzoic acid methyl ester; 3-{4-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro- -2H-pyrimidin-1-ylmethyl}-benzoic acid; and 6-[3(R)-Amino-piperidin-1-yl]-1,3-bis-(2-bromo-5-fluoro-benzyl)-1H-pyrimi- dine-2,4-dione. 15. The process of claim 1, wherein the pyrimidin-dione is present in a mixture of stereoisomers. 16. The process of claim 1, wherein the pyrimidin-dione is present as a single stereoisomer.