US 2006/0052382 A1 · 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes

Abstract

The present invention is directed to 3-amino-4-phenylbutanoic acid derivatives which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DP-IV inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

A compound of structural formula I:

or a pharmaceutically acceptable salt thereof;
wherein
each n is independently 0, 1, or 2;
X is N or CR2;
Ar is phenyl substituted with one to five R3 substituents;
R1 and R2 are each independently selected from the group consisting of
hydrogen,
halogen,
hydroxy,
cyano,
C1-10 alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,
C1-10 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,
C1-10 alkylthio, wherein alkylthio is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,
C2-10 alkenyl, wherein alkenyl is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,
(CH2)nCOOH,
(CH2)nCOOC1-6 alkyl,
(CH2)nCONR4R5, wherein R4 and R5 are independently selected from the group consisting of hydrogen, tetrazolyl, thiazolyl, (CH2)n-phenyl, (CH2)n—C3-6 cycloalkyl, and C1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five halogens and wherein phenyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;
or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said heterocyclic ring is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;
(CH2)n—NR4R5,
(CH2)n—OCONR4R5,
(CH2)n—SO2NR4R5,
(CH2)n—SO2R6,
(CH2)n—NR7SO2R6,
(CH2)n—NR7CONR4R5,
(CH2)n—NR7COR7,
(CH2)n—NR7CO2R6,
(CH2)n—COR6,
(CH2)n—C3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
(CH2)n-aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, cyano, hydroxy, NR7SO2R6, SO2R6, CO2H, C1-6 alkyloxycarbonyl, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
(CH2)n-heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, and
(CH2)n-heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
wherein any methylene (CH2) carbon atom in R1 or R2 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl unsubstituted or substituted with one to five halogens;
each R3 is independently selected from the group consisting of
hydrogen,
halogen,
cyano,
hydroxy,
C1-6 alkyl, unsubstituted or substituted with one to five halogens, and
C1-6 alkoxy, unsubstituted or substituted with one to five halogens;
R6 is independently selected from the group consisting of tetrazolyl, thiazolyl, (CH2)n-phenyl, (CH2)n—C3-6 cycloalkyl, and C1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five halogens and wherein phenyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, and wherein any methylene (CH2) carbon atom in R6 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, C1-4 alkyl, and C1-4 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;
each R7 is hydrogen or R6;
R8, R9 and R10 are each independently selected from the group consisting of
hydrogen,
cyano,
carboxy,
C1-6 alkyloxycarbonyl,
C1-10 alkyl, unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkoxy, carboxy, C1-6 alkyloxycarbonyl, and phenyl-C1-3 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens,
(CH2)n-aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
(CH2)n-heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
(CH2)n-heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
(CH2)n—C3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, and
(CH2)nCONR4R5, wherein R4 and R5 are independently selected from the group consisting of hydrogen, tetrazolyl, thiazolyl, (CH2)n-phenyl, (CH2)n—C3-6 cycloalkyl, and C1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five halogens and wherein phenyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;
or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said heterocyclic ring is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;
wherein any methylene (CH2) carbon atom in R8, R9 or R10 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl unsubstituted or substituted with one to five halogens;
with the proviso that when X is N, R10 , R11, R12 and R13 are hydrogen,
R8 or R9 is
hydrogen;
cyano;
C1-10 alkyl, unsubstituted or substituted with one to five substituents selected from:
(1) halogen,
(2) hydroxy,
(3) phenyl, optionally substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five halogens,
(4) naphthyl, optionally substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five halogens,
(5) CO2H,
(6) CO2C1-6 alkyl,
(7) CONR11R12, wherein R11 and R12 are independently selected from the group consisting of hydrogen, tetrazolyl, phenyl, C3-6 cycloalkyl and C1-6 alkyl, wherein alkyl is optionally substituted with one to six substituents independently selected from halogen and phenyl, wherein the phenyl or C3-6 cycloalkyl being R11 or R12 or the optional phenyl substituent on C1-6 alkyl are optionally substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, said C1-6 alkyl and C1-6 alkoxy being optionally substituted with one to five halogens,
or wherein R11 and R12 are optionally joined to form a ring selected from pyrrolidine, piperidine and morpholine;
phenyl, which is unsubstituted or substituted with one to five substituents independently selected from C1-6 alkyl, C1-6 alkoxy, hydroxy, and halogen, wherein alkyl and alkoxy are optionally substituted with one to five halogens;
naphthyl, which is unsubstituted or substituted with one to five substituents independently selected from C1-6 alkyl, C1-6 alkoxy, hydroxy, and halogen, wherein alkyl and alkoxy are optionally substituted with one to five halogens;
CO2H;
C1-6 alkyloxycarbonyl;
CONR11R12;
or
C3-6 cycloalkyl, which is optionally substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five halogens;
and when X is CR2 and
R2 is
hydrogen, cyano,
C1-10 alkyl, unsubstituted or substituted with one to five halogens,
(CH2)n-phenyl, which is unsubstituted or substituted with one to five substituents independently selected from halogen, cyano hydroxy, R13, OR13, NHSO2R13, SO2R13, CO2H, and C1-6 alkyloxycarbonyl, wherein R13 is C1-6 alkyl, unsubstituted or substituted with one to five halogens;
or
a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising one to four heteroatoms independently selected from N, S and O, the heterocycle being unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen,
C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five halogens;
then in both cases R1 is not
(1) hydrogen,
(2) cyano,
(3) C1-10 alkyl, unsubstituted or substituted with one to five halogens,
(4) (CH2)n-phenyl, which is unsubstituted or substituted with one to five substituents independently selected from halogen, cyano hydroxy, R13, OR13, NHSO2R13, SO2R13, CO2H, and C1-6 alkyloxycarbonyl, wherein R13 is C1-6 alkyl, unsubstituted or substituted with one to five halogens;
or
(5) a 5- or 6-membered heterocycle which may be saturated or unsaturated comprising one to four heteroatoms independently selected from N, S and O, the heterocycle being unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen,
C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five halogens;
and
R11, R12 and R13 are each independently hydrogen or C1-6 alkyl.

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3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes

Life of this patent

3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes

Life of this patent

Abstract

Claims32