WO2000042026B1 - Non-peptide glp-1 agonists - Google Patents

Non-peptide glp-1 agonists

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Publication number
WO2000042026B1
WO2000042026B1 PCT/DK2000/000014 DK0000014W WO0042026B1 WO 2000042026 B1 WO2000042026 B1 WO 2000042026B1 DK 0000014 W DK0000014 W DK 0000014W WO 0042026 B1 WO0042026 B1 WO 0042026B1
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Prior art keywords
lower alkyl
cycloalkyl
aryl
halogen
heterocyclyl
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PCT/DK2000/000014
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French (fr)
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WO2000042026A1 (en
Inventor
Min Teng
Larry Kenneth Truesdale
Dilip Bhumralkar
Dan Kiel
Michael D Johnson
Christine Thomas
Anker Steen Joergensen
Peter Madsen
Preben Houlberg Olesen
Liselotte Bjerre Knudsen
Ingrid Vivika Petterson
De Jong Johannes Cornelis
Carsten Behrens
Janos Tibor Kodra
Jesper Lau
Original Assignee
Novo Nordisk As
Agouron Pharma
Min Teng
Larry Kenneth Truesdale
Dilip Bhumralkar
Dan Kiel
Michael D Johnson
Christine Thomas
Anker Steen Joergensen
Peter Madsen
Preben Houlberg Olesen
Liselotte Bjerre Knudsen
Ingrid Vivika Petterson
De Jong Johannes Cornelis
Carsten Behrens
Janos Tibor Kodra
Jesper Lau
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Application filed by Novo Nordisk As, Agouron Pharma, Min Teng, Larry Kenneth Truesdale, Dilip Bhumralkar, Dan Kiel, Michael D Johnson, Christine Thomas, Anker Steen Joergensen, Peter Madsen, Preben Houlberg Olesen, Liselotte Bjerre Knudsen, Ingrid Vivika Petterson, De Jong Johannes Cornelis, Carsten Behrens, Janos Tibor Kodra, Jesper Lau filed Critical Novo Nordisk As
Priority to AU30335/00A priority Critical patent/AU3033500A/en
Priority to JP2000593594A priority patent/JP2002534512A/en
Priority to EP00900499A priority patent/EP1147094A1/en
Publication of WO2000042026A1 publication Critical patent/WO2000042026A1/en
Publication of WO2000042026B1 publication Critical patent/WO2000042026B1/en

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Abstract

Novel non-peptide GLP-1 agonists, pharmaceutical compositions comprising them, use of the non-peptide GLP-1 agonists for the preparation of pharmaceutical compositions and methods for the treatment and/or prevention of disorders and diseases wherein an activation of the human GLP-1 receptor is beneficial, especially metabolic disorders such as IGT, Type 1 diabetes, Type 2 diabetes and obesity.

Claims

1 oo
AMENDED CLAIMS
[received by the International Bureau on 28 July 2000 (28.07.00); original claims 1-66 replaced by new claims 1-64 (20 pages)]
1 Use of a compound according to the general formula (I):
R'
Figure imgf000003_0001
wherein
R\ R2, R3 and R4 independently are hydrogen, halogen, -CN, -CF3, -NO-,, -OR6, lower alkyl, -SR5, -S(0)2NR5Ra, -S(0)NRsR6, -S(0)2R5, -S(0)Rs, -C(0)NR5Rβ, -CH2OR5, -CH2NR5RS, -NRSR8, -C(0)R5 or -C(0)OR5,
wherein R6 and Rθ independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkeπyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloaikenyl-lower aikyl, cycloaikenyl-lower alkenyl, cycloal- kenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl. heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heteroaryl- lower alkenyl or heteroaryl-lower alkynyl, or R5 and R6 together with the nitrogen atom to which they are bound form a 3 to 8 membered heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or more double bonds, in which the cycloalkyl, cycioalkenyl, heterocyclyl, aryl and heteroaryl rings may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH. -CH-OH, -NO* -CN, -C(0)OH, -O-lower alkyl, -C(0)OCHs, -C(0)NH2. -OCH2C(0)NH2, -NH2, -N(CH3)_, -CH2N(CH3)2, -S02NH2, -OCHF2,
-CF3and -OCF3,
one of X and V is =N-, and the other is =CD- or =N-,
wherein D is hydrogen, halogen, -CN, -CF3, -N02, -OR7, -NR RB, lower alkyl, aryl, -C(0)NR7Rβ, -CH2OR , -CH2NR7R8 or -C(0)OR7, 187 wherein R7 and R6 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkeπyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower aikynyl, cycloaikenyl-lower alkyl, cycloalkeπyl-lower alkenyl, cycloalkeπyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heteroaryl- lower alkenyl or heteroaryl-lower alkynyl, or R7 and Rfl together with the nitrogen atom to which they are bound form a 3 to 8 membered heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or more double bonds, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -N02, -CN, -C(O)0H, -O-lower alkyl, -C(0)OCH3, -C(0)NH2, -OCH2C(0)NH2, -NH2, -N(CH3)2, -CH2N(CH3)2, -S02NH2, -OCHF2, -CF3and -0CF3,
L and M independently are a valence bond, -(CH2)mS(CH2)n-, -(CH2)m0(CH2)--, -(CH2)mS(0)(CH2)n-, -(CH2)mS(0)2(CH2)n-, -(CH2 ,CH=CH(CH2)--, -(CH2)mC-sC(CH2)n-, -(CH2)mCHR9(CH2)n-, -(CH2)mNRB(CH2)π-, -(CH2)mC(0)NR9(CH2)n-, -(CH2)--C(0)0(CH2)--, -S(CH2)mC(0)0(CH2)n-, -S(0)2(CH2)mC(0)0(CH2)n-, -S(0)2(CH2)mC(0)(CH2)n-, -S(0)2NR9<CH2)mC(0)0(CH2)n-, -S(CH2)mC(0)NRβ(CH2)n-, -(CH2)mOC(0)(CH2)n-, -(CH2)mC(0)(CH2)n-, -(CH2)--C(NOR9)(CH2)n-, -(CH2)mNR9S(0)2(CH2)n-, -(CH2)mS(0)2NR9(CH2)--, -(CH2)mCHORB(CH2)n-l -(CH2)mP(0)(OR9)0(CH2)n-, -S(0)2(CH2)mCONRβ(CH2)π-, -S(0)2(CH2)mOC(0)NRβ(CH2)-C(0)0(CH2)r-, -NRB0(CH2)n-1 -NR9NR9βC(0)NR9*(CH2)--, -NR9(CH2)mNR9aC(0)(CH2)n- or -NR9(CRβcRβtl)n-,
wherein R9, R9a and R9 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower aikynyl, cycioalkenyl-lower alkyl, cycloalkeπyl-lower alkenyi, cycloaikenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-iower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heteroaryl- lower alkenyl or heteroaryl-lower alkynyl, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH20H, -N02, -CN, -C(0)OH, -O-lower alkyl, O 00/42026
1.
-C(0)OCH3, -C(0)NH2l -OCH2C(0)NH2, -NH2, -N(CH3)2, -CH2N(CH3)2, -S02NH2, -OCHF- -CF3aπd -OCF3,
Rβcand Rso independently are hydrogen or lower alkyl,
m, n and r independently are 0, 1 , 2, 3 or 4,
A and B independently are hydrogen, halogen, -CF3, -CF2CF3, -CN, -N02, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, hydroxy, in which the cycloalkyl ring may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -N02, -CN, -C(0) H, -O-lower alkyl, -C(0)OCH3, -C(0)NH2, -0CH2C(0)NH2, -NH2, -N(CH3)2, -CH2N(CH3)2, -S02NH2, -OCHF2, -CF3and -OCF3,
or A and B independently are
Figure imgf000005_0001
wherein
p is 1 , 2 or 3,
X' is -N= or -CRU=,
Y' is -N= or -CR1 00/42026
189
T is -N= or -CR,a=,
V' is -N= or -CR17=,
W is -N= or -CR,β=,
G is -CR18aR1Bb-, -N+0\ -NR19-, -O- or -S-,
K is -CR18cR18d-, -NR20, -0- or -S-,
R10, R11, R12, R13, R14, R15, R β, R17, R19, R18a, Rm, R1βc and R1fla independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -0CF2CHF2, -N02, -OR21, -NR21R22, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower aikynyl, cycloaikenyl-lower alkyl, cycloaikenyl- lower alkenyl, cycloaikenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heteroaryl-lower alkenyl or heteroaryl-lower alkynyl, -SCF3, -SR21, -CHF2, -OCHF2, -OS(0)2CF3, -OS(0)2R2\ -NR21S(0)2R22, -S(0)2NR21R22, -S(0)NR21R22, -S(0)2R21, -S(0)R21, -CH2C(0)NR21R22,
Figure imgf000006_0001
-S(O)2NR21(CH)tC(O)0R22, -C(0)NR21(CH)3C(0)OR22 or -C(0)NR21R22 where R12 and R13 furthermore independently may represent oxo, or two of the groups R10 to R1fW when defined in the same ring together may form a bridge -O(CH2)g0- or -CH20(CH2)q0-, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may option- ally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -N02, -CN, -C(0)OH, -O-lower alkyl,
-C(0)OCH3, -C(0)NH2, -OCH2C(0)NH2, -NH2, -N(CH3)2, -CH2N(CHa)2, -Sθ2NH2, -OCHF2,
-CF3and -OCF3,
wherein R2 and R22 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkeπyl-lower alkyl, cycloaikenyl-lower alkenyl, cycloaikenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyi, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heteroaryl- lower alkenyl or heteroaryl-lower alkynyl, or R21 and R22 together with the nitrogen atom to which they are bound form a 3 to 8 membered heterocyclic ring optionally containing one or 00/42026 190
more further heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or more double bonds, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -N02, -CN, -C(0)OH, -O-lower alkyl,
-C(0)OCH3, -C(0)NH2, -OCH2C(0)NH2l -NH2, -N(CH3)2, -CH2N(CH3)2, -S02NH2, -OCHF2, -CF3and -OCF3,
R19 and R20 independently are hydrogen, -OR23, -NR^R2", lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryi, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkeπyl-lower alkyl, cycloaikenyl-lower alkenyl, cycloalkenyl-iower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heteroaryl-lower aikenyl or heteroaryl-lower alkynyl, -C(0)NR23R2* or-C(0)OR23, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -N02, -CN, -C(0)OH, -O-lower alkyl, -C(0)OCH3, -C(0)NH2, -0CH2C(0)NH2, -NH2, -N(CH3)2, -CH2N(CH3)2, -S02NH2l -OCHF2l -CF3aπd -OCF3,
wherein R23 and R2" independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocy yl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkeπyl-lower alkyl, cycloaikenyl-lower alkenyl, cycloal- kenyi-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heteroaryl- lower alkenyl or heteroaryl-lower alkynyl, or R23 and R24 together with the nitrogen atom to which they are bound form a 3 to 8 membered heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or more double bonds, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -N02, -CN, -C(0)OH, -O-lower alkyl, -C(0)OCH3, -C(0)NH2, -OCH2C(0)NH2, -NH2, -N(CH3)2, -CH2N(CH3)3, -S02NH2, -OCHF2, -CF3and -OCF3r
q is 1, 2 or 3, 00/42026 191
Figure imgf000008_0001
or
A and B may be connected and together form a C^-alkylene radical,
with the provisos that
when L represents a group wherein n or r is 0, A is not halogen, -CN or -N02, and
when represents a group wherein n or r is 0, B is not halogen, -CN or -N02,
as well as any optical or geometric isomer or tautomeπc form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prevention of disorders or diseases wherein an activation of the human GLP-1 receptor is beneficial.
2 A compound of the general formula (l-a):
Figure imgf000008_0002
wherein
L is -S(CH2)n-, -S(0)(CH2)π- or -S(0)2(CH2)--, wherein n is 0, 1 2, 3 or 4,
A, and B are as defined for formula (I) in claim 1 ,
with the provisos that
when L is -S(0)2- and -M-B represents hydrogen, A must not be methyl, ethyl, n-propyl, butyl, pheπyl or benzyl, when L is -S- and -M-B represents hydrogen, A must not be methyl, ethyl, n-propyl, butyl, phenyl or benzyl,
as well as any optical or geometric iso er or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
3. A compound of the general formula (l-b):
Figure imgf000009_0001
wherein
L is -S(0)2- or -S(0)2CH,-,
V is -N- or -CH-,
R1 to R4 are as defined for formula (I) in claim 1, wherein two of the groups R1 to R* are hy¬ drogen and the other two are different from hydrogen,
A, M and B are as defined for formula (I) in claim 1 ,
with the provisos that
when V is -N-, R2 and R3 are -Cl, L is -S(0)2- and -M-B represents hydrogen, A must not be methyl, ethyl, n-propyl, butyl, phenyl or benzyl,
when V is -N-, R and R3 are -Cl, L is -S(0)2- and -M-B represents hydrogen, A must not be methyl, 3-nιtrophenylmethyl, -CH2CH2N(CH3)2, phenyl, 4-methylphenylmethyl, ethyl, iso- propyl, benzyl or 4-chlorophenylmethyl,
when V is -N-, R2 and R' are -Cl, L is -S(0)2- and -M-B represents hydrogen, A must not be benzyl, when V is -N-, R1 and R3 are -Cl, L is -S(0)2- and -M-B represents methyl, A must not be methyl or phenyl,
when V is -N-, R1 and R3 are -Cl, L is -S(0)2- and -M-B represents phenyl, A must not be methyl or phenyl,
when V is -N-, R1 and R3 are -Cl, L is -S(0)2- and -M-B represents te/t-butyl, A must not be methyl,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
4. A compound of the general formula (l-c):
Figure imgf000010_0001
wherein
is -N- or -CH-,
L, A, M and B are as defined for formula (I) in claim 1 ,
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
5. A compound of the general formula (l-d):
R2 YlSA
M is a valence bond, -NH- or -N(CH3)-
B is CF3 or lower alkyl, 0/42026 194
R2and R3 are independently halogen, -CF3, -N02 or -C(0)phenyl,
L is a valence bond, -S-, -S(O)-, -S(0)2(CH2)π-, -S(0)2(CH2)2C(0)0(CH2)--, -S(0)2(CH2)2C(0)(CH2)_-, -S(0)2NH(CH2)2C(0)0(CH2)π-, -S(0)2(CH2)4OC(0)NH(CH2)2C(0)0- or -S(0)2(CH2)2CONH(CH2)n-, wherein n is 0, 1, 2, 3 or 4,
A is
lower alkyl, halogen, -CF3, -OH, -N02, cycloalkyl, in which the cycloalkyl ring may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH20H, -NO-, -CN, -C(0)OH, -O-lower alkyl, -C(0)OCH3, -C(0)NH2, -OCH2C(0)NH2, -NH2, -N(CH3)2, -CH2N(CH3)2, -S02NH2, -OCHF2, -CF3and -0CF3,
or A is
195
Figure imgf000012_0001
Figure imgf000012_0002
Figure imgf000012_0003
Figure imgf000012_0004
wherein R", R», R« R« R , R.β| R« R, R._ R1β3 and R1Bare ^ ^^ ^^
(I) in claim 1,
with the provisos that 00/42026 ι n .
196
when R2 and R3 are -Cl and -M-B is methyl, -A-L must not be -Cl,
as well as any optical or geometπc isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 3 or 4, wherein V is -N-
7. A compound according to claim 3, wherein two of the groups R\ R2, Rs and R" are hydro- gen and the other two independently are halogen, -CN, -CF3, -N02, lower alkyl, lower alkoxy,
-S(0)2NR5R6, -S(0)NR6R6, -S(0)2R5, -C(0)NRδR6, -SR5, -C(0)R5 or -C(0)ORs, wherein R5 and Rβ are as defined for formula (I) in claim 1.
8. A compound according to claim 7, wherein two of the groups R', Rz, R5 and R4 are hydro- gen and the other two independently are halogen, -CN, -CF3, lower alkyl, lower alkoxy, -SR5,
-S(0)2Rs, -C(0)OR5, -C(0)Rs, -N02 or -C(0)NRsR6, wherein R5 and R6 are as defined for formula (I) in claim 1.
9 A compound according to claim 87 wherein Rs and Rβ independently are hydrogen, phenyl or lower alkyl, wherein phenyl optionally is substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH. -CH2OH, -N02, -CN, -C(0)OH, -O-lower alkyl, -C(0)OCH3, -C(0)NH2, -OCH2C(0)NH2, -NH2, -N(CH3)2, -CH2N(CH3)2, -S02NH2, -OCHF2, -CF3and -OCF3.
10. A compound according to claim 8, wherein two of the groups R1, R2, R3 and R* are hydrogen and the other two independently are halogen, -CN, -CF3, -N02, -C(0)pheπyl, lower alkyl or lower alkoxy, wherein phenyl optionally is substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -N02, -CN, -C(0)OH, -O-lower alkyl, -C(0)OCH3, -C(0)NH2, -OCH2C(0)NH2, -NH2, -N(CH,)2, -CH2N(CH3)2, -S02NH2, -OCHF2, -CF3 and -OCF3.
11. A compound according to claim 10, wherein two of the groups R\ R2, R3 and R" are hydrogen and the other two independently are halogen, -CF3l -N02 or -C(0)phenyl.
12 A compound according to claim any one of the preceding claims 3 or 7 to 11 , wherein R1 and R4 are both hydrogen. 00/42026
13. A compound according to claim 12, wherein R2 and R3 are both halogen.
14. A compound according to claim 13, wherein R2 and R3 are both chloro.
15. A compound according to claim 12, wherein R2 and R2 are both -N02.
16. A compound according to claim 4, wherein L is a valence bond, -(CH2)mS(CH2)n-, -(CH2)mS(0)(CH2)π-, -(CH2)mS(0)2(CH2)n-, -(CH2)mCHR8(CH2)n-, -S(0)2(CH2)mC(0)0(CH2)--, -S(0)2(CH2)mC(0)(CH2)n-, -S(0)2NRδ(CH2)mC(0)0(CH2)n-,
-S(O)2(CH2)mOC(0)NR9(CH2)-C(0)0(CHz)r- or -S(0)2(CH2)mCONRB(CH2)n-, wherein m, π. r and R8 are as defined for formula (I) in claim 1.
17. A compound according to claim 16, wherein L is a valence bond, -S-, -S(O)-, -S(0)2(CH2)n-, -S(0)2(CH2)2C(0)0(CH2)n-, -S(0)2(CH2)2C(0)(CH2)n-,
-S(0)2NH(CH2)2C(0)0(CH2)π-, -S(0)2(CH2)40C(0)NH(CH2)2C(0)0- or -S(0)2(CH2)2CONH(CH2)n-, wherein n is as defined for formula (i) in claim 1.
18. A compound according to claim 5 or 17, wherein I is a valence bond, -S-, -S(O)-, -S(0)2-, -S(0)2CH2-, -S(0)2(CH2)2-, -S(0)2(CH2)2C(0)0-, -S(0)2(CH2)2C(0)(CH2)2-.
-S(0)2NH(CH2)2C(0)0-, -S(0)2(CH2)4OC(O)NH(CH2)2C(0)0- or -S(0)2(CH2)2CONH(CH2)2-.
19. A compound according to claim 18, wherein L is -S(0)2CH2- or -S(0)2-.
20. A compound according to any one of the preceding claims 2 to 4, wherein A is lower alkyl, halogen, -CF3, -OH, -N02, cycloalkyl, in which the cycloalkyl ring may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -N02, -CN, -C(0)OH, -O-lower alkyl, -C(0)OCH3, -C(0)NH2, -OCH2C(0)NH2) -NH2, -N(CH3)2, -CH2N(CH3)2, -S02NH2, -OCHF2, -CF3 and -OCF3,
or A is 198
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0003
wherein R10, R11, R12, R19, R1\ R15, R1fl, R*7, R1fl, R1βa and R,9 are as defined for formula (I) in claim 1. 199
21. A compound according to claim 5 or 20, wherein A is lower alkyl, halogen, -CF3, -OH, cycloalkyl, in which the cycloalkyl ring may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -N02, -CN, -C(0)OH, -O-lower alkyl, -C(0)OCH3, -C(0)NH2, -OCH2C(0)NH2) -NH2, -N(CH3)2, -CH2N(CH3)2, -S02NH2, -OCHF2, -CF3and -OCF3,
Figure imgf000016_0001
wherein R12 to R19 are as defined for formula (I) in claim 1.
22 A compound according to claim 21, wherein R12 and R13 independently are selected from hydrogen and lower alkyl, R14 to R1β independently are selected from hydrogen, lower alkyl, -N02, halogen. -S(0)2R21, -CONR2lR22, -OCHF2, -S(0)2NR 1(CH)-C(0)OR22, wherein s is 1 or 2, R21 and R22 independently are hydrogen, lower alkyl or pyridyl, and R19 is hydrogen, lower alkyl or phenyl.
23. A compound according to claim 22, wherein A is lower alkyl, halogen, -CF3, -OH, cycloal- kyl,
or A is 200
Figure imgf000017_0001
wherein R14 is -S(0)2CH3, -CONH2, -CONH-pyridyl, -OCHF2 or -S(0)2NH(CH)2C(0)OCH3.
24. A compound according to claim 23, wherein A is lower alkyl.
25. A compound according to any one of the preceding claims 2 to 4, wherein M is a valence bond, -(CH2)mS(CH2)n-, -(CH2) S(0)2(CH2)n-, -(CHz)mNR9(CH2)n-, -NR9(CR9cR9β)n-, -(CH2)mC(0)0(CH2)n-, -NR90(CH2)rl-, -(CH2)mCH=CH(CH2)n-, -NR9NR9aC(0)NR9b(CH2)n-, -O- or -(CH2)mCHR9(CH2)π-, wherein m, n, RB, Rθfl, R9b, R90 and Rβd are as defined for formula (I) in claim 1.
26. A compound according to claim 25, wherein M is a valence bond, -C(0)0-, -CH=CH-, -N(CH3)-, -CH2S(0)2-, -NH-, -CH2CH2-, -N(CH3)0-, NHOCH2-, -S-, -NHCH2CH2NHC(0)-, -NHC(CH3)2-, -CH2S-, -NHCH2-, -NHCH2CH2-, -O- or -CH2-.
27. A compound according to claim 26, wherein M is a valence bond, -C(0)0-, -CH=CH-, -N(CH3)-, -CH2S(0)2-, -NH-, -CH2CH2-, -N(CH3)0-, NHOCH2-, -S-, -NHCH2CH2NHC(0)- or -NHC(CH3)2-.
28. A compound according to claim 27, wherein M is a valence bond, -NH- or -N(CH3)-.
29. A compound according to any one of the preceding claims 2 to 4, wherein B is hydrogen, halogen, -CF3l -CF2CF3, lower alkyl, cycloalkyl, 201 in which the cycloalkyl ring may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -N02, -CN, -C(0)OH, -O-lower alkyl, -C(0)OCH3, -C(0)NH2, -0CH2C(0)NH2, -NH2, -N(CH3)2l -CH2N(CH3)2, -S02NH2, -OCHF2, -CF3and -OCF3,
or B is
Figure imgf000018_0001
wherein R12 to R20 are as defined for formula (I) in claim 1.
30. A compound according to claim 29, wherein B is hydrogen, -CF3, lower alkyl, cycloalkyl, in which the cycloalkyl ring may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -N02, -CN, -C(0)OH, -O-lower alkyl, -C(0)OCH3, -C(0)NH2, -OCH2C(0)NH2l -NH2, -N(CHa)2) -CH2N(CH3)2, -SOzNH2, -OCHF2, -CF3and -OCF3,
or B is
Figure imgf000018_0002
" WO 00/42026 PCT/DKOO/00014
202 wherein R'° to R19 are as defined for formula (I) in claim 1.
31. A compound according to claim 30, wherein RtQ and R11 independently are hydrogen, lower alkyl, halogen. -OCF3, -OCHF2, -CF3 or -N02, R 2 and R13 independently are hydrogen, hydroxy or lower alkyl, R14 to R1e independently are hydrogen, lower alkyl, halogen, -OCF3, -OCHF-, -CF3 or -N02, and R19 is hydrogen or lower alkyl.
32. A compound according to claim 31 , wherein B is hydrogen, -CF3, lower alkyl, cycloalkyl,
Figure imgf000019_0001
33. A compound according to claim 32, wherein B is -CF3 or lower alkyl.
34. A compound according to claim 5 or 33, wherein B is lower alkyl.
35. A compound according to claim 4 of the general formula (IV):
Figure imgf000019_0002
wherein M, B and R14 are as defined for formula (I) in claim 1 or in any one of the preceding claims 26 to 34.
36. A compound according to claim 2 or 35, wherein M is a valence bond and B is -CF3 or lower alkyl.
37. A compound according to claim 2 or 35, wherein M is -NR9-, wherein R* is hydrogen or lower alkyl and B is lower alkyl or
Figure imgf000020_0001
, wherein R14 is hydrogen, lower alkyl, halogen, -OCF3, -OCHF2, -CF3 or -N02.
38. A compound according to any one of the claims 1 to 37 characterised by having a molecular weight of up to 1000, preferably of up to 600.
39. A compound according to any one of the claims 1 to 38 characterised by having an EC50 value as determined by method 1 or 2 according to example 172 of less than 25 μM, preferably of less than 10 μM and more preferred of less than 2 μM.
40. A non-peptide GLP-1 agonist which activates the human GLP-1 receptor.
41. A non-peptide GLP-1 agonist according to claim 40 which activates the human GLP-1 receptor without competing with GLP-1 in a competition binding assay.
42. A non-peptide agonist according to claim 40 or 41 which in a competition binding assay potentiates the binding of GLP-1 to the human GLP-1 receptor.
43. A non-peptide GLP-1 agonist according to any one of the claims 40 to 42 which stabilises an active conformation of the human GLP-1 that is different from the oπe(s) which GLP-1 stabilises.
44. A non-peptide agonist according to any one of the claims 40 to 43 which is a full agonist.
45. A non-peptide agonist according to any one of the claims 40 to 43 which is a partial agonist having an Emax of less than 100%, preferably of less than 90%, more preferably of less than
80%, and even more preferably in the range of 35 to 75% of that of GLP-1 as determined by method 1 or 2 according to example 172.
46. A non-peptide agonist according to any one of the claims 40 to 45 which has at least a 10 fold selectivity towards the human GLP-1 receptor compared to the human glucagon receptor and/or the human GIP receptor. 204
47. A non-peptide GLP-1 agonist according to any one of the claims 40 to 46, where the agonistic effect mediated by the non-peptide GLP-1 agonist can be antagonised by a GLP-1 antagonist.
48. A non-peptide GLP-1 agonist according to claim 47, where the agonistic effect mediated by the non-peptide GLP-1 agonist can be antagonised by 6-(2,5-dichlorobenzyl)-1-hydroxy-2-[2- (4-morphoiinyl)ethyl]-1,6-dihydropyrrolo[3',4',5,6]pyrido[3,4-b]indol-3(2H)-one.
49. A compound according to any one of the claims 2 to 48 for use as a medicament.
50. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the claims 2 to 48 together with one or more pharmaceutically acceptable carriers or excipients.
51. A pharmaceutical composition according to claim 50 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to any one of the claims 2 to 47.
52. Use of a compound as defined in any one of the claims 2 to 48 for the preparation of a medicament for the treatment and/or prevention of disorders or diseases wherein an activation of the human GLP-1 receptor is beneficial
53. Use of a compound as defined in any one of the claims 1 to 48 for the preparation of a medicament for the treatment and/or prevention of a metabolic disorder wherein an activation of the human GLP-1 receptor is beneficial.
54. Use of a compound as defined in any one of the claims 1 to 48 for the preparation of a medicament for the treatment and/or prevention of IGT.
55. Use of a compound as defined in any one of the claims 1 to 48 for the preparation of a medicament for the treatment and/or prevention of Type 2 diabetes.
56. Use according to claim 55 for the preparation of a medicament for the delaying or preven- tion of the progression from IGT to Type 2 diabetes 205
57. Use according to claim 55 for the preparation of a medicament for the delaying or prevention of the progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes
58 Use of a compound as defined in any one of the claims 1 to 48 for the preparation of a medicament for the treatment and/or prevention of Type 1 diabetes.
59. Use according to any one of the claims 52 to 58 in a regimen which additionally comprises treatment with another aπtidiabetic.
60. Use of a compound as defined in any one of the claims 1 to 48 for the preparation of a medicament for the treatment and/or prevention of obesity.
61 Use of a compound as defined in any one of the claims 1 to 48 for the preparation of a medicament for the treatment and/or prevention of obesity in a regimen which additionally comprises treatment with another antiobesity agent.
62. Use of a compound as defined in any one of the claims 1 to 48 for the preparation of a medicament for the treatment and/or prevention of an appetite regulation or energy expendi- ture disorder.
63. A method for the treatment and/or prevention of disorders or diseases wherein an activation of the human GLP-1 receptor is beneficial the method comprising administering to a subject in need thereof an effective amount of a compound as defined in any one of the claims 1 to 48 or a pharmaceutical composition according to claim 50 or 51
64. The method according to claim 63 wherein the effective amount of the compound is in the range of from about 0 05 mg to about 2000 mg, preferably from about 0 1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day.
STATEMENT UNDER ARTICLE 19 (1)
With reference to Article 19 PCT we hereby enclose a new set of claims on the basis of which we wish the international preliminary examination to start.
The new claims have been delimited from the prior art references cited in the International Search Report and the amendments performed are not considered to extent beyond the disclosure in the international application as filed.
Original claim 1 has been amended to a use claim. Said claim is regarded to be novel and inventive as none of the cited references relate to GLP-1 agonists.
New claims 2 to 5 have been delimited from the cited references none of which disclose GLP-1 agonists. Thus, new claim 2 corresponds to original claim 37. Disclaimers have been inserted in order to delimit the claim from the cited references EP 0 018 493 and EP 0 216299.
New claim 3 corresponds to original claim 1 in which the contents of original claims 2, 3, 10 and 20 have been incorporated. Disclaimers have been inserted in order to delimit the claim from the cited references EP 0 018493 and EP 0 216 299.
New claim 4 corresponds to original claim 1 in which the contents of original claims 2, 3 and 16 have been incorporated.
New claim 5 corresponds to oπginal claim 1 in which the contents of original claims 2, 8, 11 , 18, 29 and 34 have been incorporated. A disclaimer has been inserted in order to delimit the claim from the cited Caplus reference 1998.515240
New claim 6 incorporates the provision of original claim 2
New claims 7 to 11 incorporate the provision of original claim 10 Otherwise, they correspond to original claims 4 to 8.
New claim 12 corresponds to original claim 11. 00/42026 207
New claims 13 and 14 correspond to original claims 13 and 14, respectively.
New claims 5 to 35 correspond to original claims 16 to 36, respectively, and new claims 36 to 64 correspond to original claims 38 to 66, respectively.
It is respectfully submitted that the new set of claims are novel and inventive over the cited references.
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