Patent NZ-508765-A (NZ)
Title: Beta-carboline derivatives and pharmaceuticals thereof that selectively bind somatostatin receptor subtypes
Inventor: GALCERA MARIE-ODILE
IPC: A61K31/444
Filed: 1999-06-08
Abstract: A compound of formula (I) wherein --- represents an optional bond ;X is N or N-R4, where X is N when both optional bonds are present and X is N-R4 when the optional bonds are not present; R1 is H, -(CH2)m-C(O)-(CH2)m-Z1, - (CH2)m-Z1, -(CH2)m-O-Z1 or (C0-6)alkyl-C(O)-NH-(CH2)m-Z3; Z1 is an optionally substituted moiety selected from the group consisting of (C1-12) alkyl, naphthyl, benzo[b]furanyl, thiophene, isoxazolyl, indolyl, benzo[b]thiophene, phenyl, and formulas (a)-(c); R2 is (C1- 12)alkyl, (C0-6)alkyl-C(O)-O-Z5, (C0-6)alkyl-C(O)-NH-(CH2)m- Z3 or optionally substituted phenyl; Z5 is H, (C1-12)alkyl or (CH2)m-aryl; Z3 is amino, (C1-12) alkylamino, N,N-di- (C1-12)alkylamino, -NH-C(O)-O-(CH2)m-phenyl, -NH-C(O)-O- (CH2)m-(C1-6)alkyl or an optionally substituted moiety selected from the group consisting of imidazolyl, pyridinyl and morpholinyl, piperidinyl, piperazinyl, pyrazolidinyl, furanyl and thiophene; R3 is H; R4 is H, -C(=Y)-N(X1X2), C(=O)X2 or X2; Y is O or S; X2 is -(CH2)m-Y1-X3; X3 is H or an optionally substituted moiety selected from the group consisting of (C1-12)alkoxy, aryloxy, (C1-12)alkylamino, N,N-(C1-12)alkyl, (C3-8)cycloalkyl, di-(C1-12)alkylamino, di-(C1-12)alkylamino, -CH-di-(C1-12)alkoxy or phenyl; R5 is (C1-12)alkyl, -(CH2)m-Y1-(CH2)m-phenyl-(X1)m, (C3- 12)cycloalkyl, -(CH2)M-S-(C1-12)alkyl, (C1-12)alkyl-S-S(C1- 12)alkyl, -(CH2)m-(C1-12)alkenyl or an optionally substituted moiety selected from the group consisting of phenyl, furanyl, thiophene, pyrrolyl, pyridinyl and formula (d); Y1 is O, S, NH or a bond; R6 is H or SO2-phenyl; R7 is H, alkyl optionally substituted with alkoxy or dialkylamino; X1 for each occurrence is independently selected from the group consisting of hydrogen, Cl, F, Br, I, NO2, OH, -CF3, -OCF3, (C1-12)alkyl, (C1-12)alkoxy, -S- (C1-6)alkyl, -(CH2)m-amino, -(CH2)m-NH-(C1-6)alkyl, -(CH2)m- N-di-((C1-6)alkyl), -(CH2)m-phenyl and -(CH2)m-NH-(C3- 6)cycloalkyl; m is 0 to 6; and n is 1 to 5. And the compound of formula (II) wherein ---, X, R1, Z1, Z5, Z3, R4, Y, X3, R6, X1, m and n are defined as above; R3 is H, (C1-6)alkyl or optionally substituted phenyl; X2 is H or -(CH2)m-Y1-X3; R5 and R8 are each independently selected from the group consisting of H, (C1-12)alkyl, (C3- 12)cycloalkenyl, -(CH2)m-Y1-(CH2)m-phenyl-(X1)n, (C3- 12)cycloalkyl, -(CH2)m-(C1-12)alkenyl, -(CH2)m-S-(C1- 12)alkyl, (C1-12)alkyl-S-S-(C1-12)alkyl and an optionally substituted moiety selected from the group consisting of phenyl, furanyl, thiophene, pyrrolyl, pyridinyl and formula (e), provided that R5 and R8 are not both H at the same time, or R5 and R8 taken together with the carbon atom to which they are attached to form formulas (f)-(h) or spiro(C4-12)cycloalkyl; A is a bond, -CO- ,-C(O)O-, -C(O)NH- , -C(S)NH-, or -S02-; B is a bond or -(CH2)q-, where q is an integer from 1 to 6; J3 is H, (C1-6)alkyl, optionally substituted phenyl, optionally substituted heteroaryl or N(R9R10), where R9 and R10 are each independently selected from the group consisting of (C1-6) alkyl, and optionally substituted phenyl, or R9 and R10 are taken together with the nitrogen to which they are attached to form a ring having 5 to 8 members including the nitrogen atom that R9 and R10 are attached to, where one of the ring members may optionally be an oxygen atom or NR11 where R11 is (C1- 6)alkyl, -C(O)-(C1-6)alkyl, -C(O)-N(V1V2), -C(S)-N(V1V2), or optionally-substituted-phenyl- (C0-6)alkyl-, where V1 and V2 are each independently H, (C1-6) alkyl or optionally- substituted-phenyl-(C0-6)alkyl; R7 is H, Cl, F, Br, I, CF3, NO2, OH, S02NH2, CN, N3, -OCF3, (C1-C12)alkoxy, -(CH2)m- phenyl-(X')n, -NH-CO-(C1-6)alkyl, -S-phenyl-(X1)n, -O- (CH2)m-phenyl-(X1)n, -O-(CH2)m-NH2, -(CH2)m-C(O)-O-(C1- 6)alkyl, -(CH2)m-C(O)-(C1-6)alkyl, -(C0-12)alkyl-(X1)N; -O- (CH2)m-NH-(C1-6)alkyl, -O-(CH2)m-N-di-((C1-6)alkyl) which can be optionally substituted J1 is N-R6 or S; J2 is N-R1, O or S are described. Also described are pharmaceuticals compositions comprising the compounds for use in treating diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, nephropathy, peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, diarrhea, pancreatitis, gastrointestinal hormone secreting tumors, angiogenesis, inflammatory disorders, allograft rejection, angioplasty, gastrointestinal bleeding, psychiatric disorders and epilepsy for example.