US 8,557,776 B2Granted

Compounds and methods for 18F labeled agents

AssigneeBayer Pharma Aktiengesellschaft

InventorsLutz Lehmann, Ananth Srinivasan, Thomas Brumby, Detlef Suelzle, Timo Stellfeld, Keith Graham, Mylene Tania Karramkam, Simon Ametamey

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Abstract

The present invention relates to novel compounds suitable for or already radiolabeled with 18F, methods of making such compounds and use of such compounds for diagnostic imaging. Such labeled compounds are characterized by Formula II, wherein the substituents G, Q, L, Y and U have the meaning as defined in the specification and claims.

Claims23

Dependent claims

A compound of Formula A

wherein
-G is selected from —C≡N and —CF3, wherein the respective substituent can be in ortho, para or meta position in respect of the K group,
-Q is hydrogen,
-L- is —CO— or —SO2—,
Y is a bond or a spacer,
wherein
(a) the spacer is Arg-Ser, Arg-Ava, Lys(Me)2-β-ala, Lys(Me)2-ser, Arg-β-ala, Ser-Ser, Ser-Thr, Arg-Thr, S-alkylcysteine, cysteic acid, thioalkylcysteine (S—S-alkyl) or
wherein k and l are independently selected in the range of from 0 to 4, or
(b) the spacer is a non-amino acid moiety selected from the group consisting of
—NH—(CH2)p—CO—, wherein p is an integer of from 2 to 10,
—NH—(CH2—CH2—O)q—CH2—CH2—CO—, wherein q is an integer of from 0 to 5,
—NH-cycloalkyl-CO— wherein cycloalkyl is selected from C5-C8 cycloalkyl, and
—NH-heterocycloalkyl-(CH2)v—CO— wherein heterocycloalkyl is selected from C5-C8 heterocycloalkyl containing carbon atoms and 1, 2, 3 or 4 oxygen, nitrogen or sulfur heteroatoms and v is an integer of from 1 to 4,
U is a targeting agent comprising
(a) a peptide selected from the group consisting of somatostatin, somatostatin receptor specific peptides, neuropeptide Y, neuropeptide Y1, bombesin, gastrin, gastrin releasing peptide, epidermal growth factor (EGF of various origin), insulin growth factor (IGF) and IGF-1, integrins (α3β1, αvβ3, αvβ5, αIIb3), LHRH agonists and antagonists, transforming growth factors, particularly TGF-α;
angiotensin;
cholecystokinin receptor peptides, cholecystokinin (CCK);
neurotensin, thyrotropin releasing hormone, pituitary adenylate cyclase activating peptide (PACAP), chemokines, substrates and inhibitors for cell surface matrix metalloproteinase, prolactin, tumor necrosis factor, interleukins (IL-1, IL-2, IL-4 or IL-6), interferons, and vasoactive intestinal peptide (VIP);
(b) a peptide selected from the group consisting of peptides having sequence III or IV:
AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-NT1T2 (type A) III, with:
T1=T2=H or
T1=H, T2=OH or
T1=CH3, T2=OH
AA1=Gln, Asn, Phe(4-CO—NH2)
AA2=Trp, D-Trp
AA3=Ala, Ser, Val
AA4=Val, Ser, Thr
AA5=Gly, (N-Me)Gly
AA6=His, His(3-Me), (N-Me)His, (N-Me)His(3-Me)
AA7=Sta, Statine analogs and isomers, 4-Am,5-MeHpA, 4-Am,5-MeHxA, γ-substituted amino acids
AA8=Leu, Cpa, Cba, CpnA, Cha, t-buGly, tBuAla, Met, Nle, iso-Bu-Gly;
or
AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-NT1T2 (type B) IV, with:
T1=T2=H or
T1=H, T2=OH or
T1=CH3, T2=OH
AA1=Gln, Asn or Phe(4-CO—NH2)
AA2=Trp, D-Trp
AA3=Ala, Ser, Val
AA4=Val, Ser. Thr
AA5=βAla, β2- and β3-amino acids as shown herein after
wherein SC represents a side chain found in proteinogenic amino acids and homologs of proteinogenic amino acids,
AA6=His, His(3-Me), (N-Me)His, (N-Me)His(3-Me)
AA7=Phe, Tha, Nal,
AA8=Leu, Cpa, Cba, CpnA, Cha, t-buGly, tBuAla, Met, Nle, iso-Bu-Gly;
or
(c) wherein U is a NR7-peptide, —(CH2)n′-peptide, —O—(CH2)n′-peptide or —S—(CH2)n′-peptide, wherein
n′ is an integer of from 1 to 6,
R7 is hydrogen or unbranched or branched alkyl and
the peptide is defined in (a) or (b);
X− is CF3S(O)2O−, C4F9S(O)2O−, iodide anion, bromide anion, chloride anion, perchlorate anion (ClO4−), phosphate anion, trifluoroacetate anion (CF3—C(O)O−), or the anion of another salt of an inorganic or organic acid,
K is N+(R1)(R2)(R3)X− or W,
wherein
R1, R2 and R3 are each methyl, and
W is 18F,
or a pharmaceutically acceptable salt of an inorganic or organic acid thereof.

53 more elements

A compound selected from

Ia-1:
4-(Trimethylammonium)-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH2 (SEQ ID NO:
103),
Ia-2:
4-(Trimethylammonium)-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His(Me)-Sta-Leu-NH2 (SEQ ID NO:
109),
Ia-3:
4-(Trimethylammonium)-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
110),
Ia-4:
4-(Trimethylammonium)-3-cyano-benzoyl-1,4-cis-Achc-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
111),
Ia-5:
4-(Trimethylammonium)-3-cyano-benzoyl-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
112),
Ia-6:
4-(Trimethylammonium)-3-cyano-benzoyl-AOC-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
113),
Ia-7:
4-(Trimethylammonium)-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Cpa-NH2 (SEQ ID NO:
114),
Ia-8:
4-(Trimethylammonium)-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH2 (SEQ ID NO:
115),
Ia-9:
4-(Trimethylammonium)-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
116),
Ia-10:
4-(Trimethylammonium)-3-cyano-benzoyl-Lys (Me)2-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
117),
Ia-11:
4-(Trimethylammonium)-3-cyano-benzoyl-Lys (Me)2-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
118),
Ia-12:
4-(Trimethylammonium)-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH2 (SEQ ID NO:
119),
Ia-13:
4-(Trimethylammonium)-3-cyano-benzoyl-Ser-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH2 (SEQ ID NO:
120),
Ia-14:
4-(Trimethylammonium)-3-cyano-benzoyl-Lys(Me)2-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-4-AM-5-MeHpA-Leu-NH2 (SEQ ID NO:
121),
Ia-15:
4-(Trimethylammonium)-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
122),
Ia-16:
4-(Trimethylammonium)-3-cyano-benzoyl-Lys(Me)2-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH2 (SEQ ID NO:
123),
Ia-17:
4-(Trimethylammonium)-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His-4-Am,5-MeHpA- -Leu-NH2 (SEQ ID NO:
124),
Ia-18:
4-(Trimethylammonium)-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
125),
Ia-19:
4-(Trimethylammonium)-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
126),
Ia-20:
4-(Trimethylammonium)-3-trifluoromethyl-benzoyl-1,4-cis-Achc-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
127),
Ia-21:
4-(Trimethylammonium)-3-trifluoromethyl-benzoyl-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
128),
Ia-22:
4-(Trimethylammonium)-3-trifluoromethyl-benzoyl-Arg-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH2 (SEQ ID NO:
129),
Ia-23:
4-(Trimethylammonium)-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-4-Am,5-MeHpA-Cpa-NH2 (SEQ ID NO:
130),
Ia-24:
4-(Trimethylammonium)-3-cyano-benzoyl-Ser-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
131),
Ia-25:
4-(Trimethylammonium)-3-cyano-benzoyl-DOA-Gln-Trp-Ala-Val-Gly-His(3Me)Sta-Leu-NH2 (SEQ ID NO:
132),
1a-66:
4-(Trimethylammonium)-3-cyano-benzoyl-Ava-ε-c[Lys-(NMe)Phe-1Nal-D-Trp-Lys-Thr] (SEQ ID NO:
133)
1a-67:
4-(Trimethylammonium)-3-cyano-benzoyl-Ava-β-c[Dpr-Met-(NMe)Phe-Tyr-D-Trp-Lys] (SEQ ID NO:
134)
1a-68:
4-(Trimethylammonium)-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Thr-Arg-Cys-Arg-Tyr-NH2] (SEQ ID NO:
135) or
1a-69:
4-(Trimethylammonium)-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Val-Arg-Cys-Arg-Tyr-NH2] (SEQ ID NO:
136).

84 more elements

A compound selected from the group consisting of

IIA-a-1:
4-[18]Fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH2 (SEQ ID NO:
137),
IIA-a-2:
4-[18]Fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His(Me)-Sta-Leu-NH2 (SEQ ID NO:
138),
IIA-a-3:
4-[18]Fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
139),
IIA-a-4:
4-[18]Fluoro-3-cyano-benzoyl-1,4-cis-Achc-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
140),
IIA-a-5:
4-[18]Fluoro-3-cyano-benzoyl-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
141),
IIA-a-6:
4-[18]Fluoro-3-cyano-benzoyl-AOC-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
142),
IIA-a-7:
4-[18]Fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me)-Sta-Cpa-NH2 (SEQ ID NO:
143),
IIA-a-8:
4-[18]Fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-FA4-Am,5-MeHpA-Leu-NH2 (SEQ ID NO:
144),
IIA-a-9:
4-[18]Fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
145),
IIA-a-10:
4-[18]Fluoro-3-cyano-benzoyl-Lys(Me)2-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
146),
IIA-a-11:
4-[18]Fluoro-3-cyano-benzoyl-Lys(Me)2-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
147),
IIA-a-12:
4-[18]Fluoro-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH2 (SEQ ID NO:
148),
IIA-a-13:
4-[18]Fluoro-3-cyano-benzoyl-Ser-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH2 (SEQ ID NO:
149),
IIA-a-14:
4-[18]Fluoro-3-cyano-benzoyl-Lys(Me)2-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH2 (SEQ ID NO:
(SEQ ID NO:
150),
IIA-a-15:
4-[18]Fluoro-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
151),
IIA-a-16:
4-[18]Fluoro-3-cyano-benzoyl-Lys(Me)2-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH2 (SEQ ID NO:
152),
IIA-a-17:
4-[18]Fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His-4-Am,5-MeHpA-Leu-NH2 (SEQ ID NO:
153),
IIA-a-18:
4-[18]Fluoro-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-LeuNH2 (SEQ ID NO:
154),
IIA-a-19:
4-[18]Fluoro-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
155),
IIA-a-20:
4-[18]Fluoro-3-trifluoromethyl-benzoyl-1,4-cis-Achc-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
156),
IIA-a-21:
4-[18]Fluoro-3-trifluoromethyl-benzoyl-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
157),
IIA-a-22:
4-[18]Fluoro-3-trifluoromethyl-benzoyl-Arg-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH2 (SEQ ID NO:
158),
4-[18]Fluoro-3-cyano-benzoyl-(piperidyl-4-carbonyl)-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
213),
4-[18]Fluoro-3-cyano-benzoyl-(piperazin-1-yl-acetyl)-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 (SEQ ID NO:
214),
4-[18]Fluoro-3-cyano-benzoyl-1,4-trans-Achc-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH2 (SEQ ID NO:
215),
IIA-a-76:
4-[18]Fluoro-3-cyano-benzoyl-Ava-ε-c[Lys-(NMe)Phe-1Nal-D-Trp-Lys-Thr] (SEQ ID NO:
295)
IIA-a-77:
4-[18]Fluoro-3-cyano-benzoyl-Ava-β-c[Dpr-Met-(NMe)Phe-Tyr-D-Trp-Lys] (SEQ ID NO:
296)
IIA-a-78:
4-[18]Fluoro-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Thr-Arg-Cys-Arg-Tyr-NH2 (SEQ ID NO:
299) and
IIA-a-79:
4-[18]Fluoro-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Val-Arg-Cys-Arg-Tyr-NH2 (SEQ ID NO:
300).

82 more elements

A compound of Formula A

wherein
-G is —C≡N or —CF3, wherein the respective substituent —C≡N or CF3 can be in ortho, para or meta position in respect of the K group,
-Q is hydrogen,
-L- is —CO— or —SO2—,
Y is a bond or a spacer,
wherein
(a) the spacer is Arg-Ser, Arg-Ava, Lys(Me)2-β-ala, Lys(Me)2-ser, Arg-β-ala, Ser-Ser, Ser-Thr, Arg-Thr, S-alkylcysteine, cysteic acid, thioalkylcysteine (S—S-alkyl) or
wherein k and l are independently selected in the range of from 0 to 4, or
(b) the spacer is a non-amino acid moiety selected from the group consisting of
—NH—(CH2)p—CO—, wherein p is an integer of from 2 to 10,
—NH—(CH2—CH2—O)q—CH2—CH2—CO—, wherein q is an integer of from 0 to 5,
—NH-cycloalkyl-CO— wherein cycloalkyl is selected from C5-C8 cycloalkyl, and
—NH-heterocycloalkyl-(CH2)v—CO— wherein heterocycloalkyl is selected from C5-C8 heterocycloalkyl containing carbon atoms and 1, 2, 3 or 4 oxygen, nitrogen or sulfur heteroatoms and v is an integer of from 1 to 4,
X− is CF3S(O)2O−, C4F9S(O)2O−, iodide anion, bromide anion, chloride anion, perchlorate anion (ClO4−), phosphate anion, trifluoroacetate anion (CF3—C(O)O−), or the anion of another salt of an inorganic or organic acid,
K is N+(R1)(R2)(R3)X− or W,
wherein
R1, R2 and R3 are each methyl, and
W is a fluorine isotope, and
U is selected from the group consisting of
Gln-Trp-Ala-Val-NMeGly-His-Sta-
SEQ ID NO:
1
Leu-NH2
Gln-Trp-Ala-Val-Gly-His(Me)-Sta-
SEQ ID NO:
2
Leu-NH2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO:
3
Leu-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-
SEQ ID NO:
4
Sta-Leu-NH2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO:
7
Cpa-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO:
8
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO:
12
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-His-4-Am,5-
SEQ ID NO:
17
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-
SEQ ID NO:
23
4-Am,5-MeHpA-Cpa-NH2
Gln-Trp-Ala-Val-NMeGly-His-FA02010-
SEQ ID NO:
27
Cpa-NH2
Gln-Trp-Ala-Val-NMeGly-His-4-Am,5-
SEQ ID NO:
28
MeHpA-tbuGly-NH2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO:
30
tBuGly-NH2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-
SEQ ID NO:
32
4-Am,5-MeHpA-Leu-NH2
Gln-DTrp-Ala-Val-Gly-His-4-Am,5-
SEQ ID NO:
33
MeHpA-tbuGly-NH2
Gln-DTrp-Ala-Val-Gly-His-4-Am-5-
SEQ ID NO:
34
MeHxA-Cpa-NH2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO:
35
Cpa-NH2
Gln-DTrp-Ala-Val-Gly-His-Sta-
SEQ ID NO:
36
tbuAla-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-
SEQ ID NO:
42
Cpa-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-
SEQ ID NO:
43
tBuGly-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO:
46
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO:
48
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-NMeHis-4-Am,5-
SEQ ID NO:
49
MeHpA-Cpa-NH2
Gln-Trp-Ala-Val-Gly-NMeHis(3Me)-4-
SEQ ID NO:
47
Am,5-MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-NMeHis-4-Am,5-
SEQ ID NO:
50
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-NMeGly-HIs-AHMHxA-
SEQ ID NO:
51
Leu-NH2
Gln-Trp-Ala-Val-βAla-NMeHis-Tha-
SEQ ID NO:
52
Cpa-NH2
Gln-Trp-Ala-Val-βAla-NMeHis-Phe-
SEQ ID NO:
53
Cpa-NH2
Gln-Trp-Ala-Val-βAla-NMeHis-Phe-
SEQ ID NO:
54
Leu-NH2
Gln-Trp-Ala-Val-βAla-DHis-Phe-
SEQ ID NO:
55
Leu-NH2
Gln-Trp-Ala-Val-βAla-His-βhLeu-
SEQ ID NO:
56
Leu-NH2
Gln-Trp-Ala-Val-βAla-His-βhIle-
SEQ ID NO:
57
Leu-NH2
Gln-Trp-Ala-Val-βAla-His-βhLeu-
SEQ ID NO:
58
tbuGly-NH2
Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-
SEQ ID NO:
59
Tha-NH2
Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-
SEQ ID NO:
60
Nle-NH2
Gln-Trp-Ala-Val-βAla-NMeHis-Phe-
SEQ ID NO:
61
tbuGly-NH2
Gln-Trp-Ala-Val-βAla-NMeHis-Tha-
SEQ ID NO:
62
tbuGly-NH2
Gln-Trp-Ala-Val-βAla-His(3Me)-Tha-
SEQ ID NO:
63
tbuGly-NH2
Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-
SEQ ID NO:
64
Cpa-NH2
Gln-Trp-Ala-NMeVal-βAla-His-
SEQ ID NO:
65
Phe-Leu-NH2
Gln-Trp-Ala-Val-βAla-His-NMePhe-
SEQ ID NO:
66
Leu-NH2
Gln-DTrp-Ala-Val-βAla-His-Phe-
SEQ ID NO:
67
Leu-NH2
Gln-Trp-DAla-Val-βAla-His-Phe-
SEQ ID NO:
68
Leu-NH2
Gln-Trp-Ala-DVal-βAla-His-Phe-
SEQ ID NO:
69
Leu-NH2
Gln-Trp-Ala-Val-βAla-His-DPhe-
SEQ ID NO:
70
Leu-NH2
Gln-Trp-Ala-Val-βAla-His-βhIle-
SEQ ID NO:
71
tbuGly-NH2
Gln-Trp-Ala-Val-NMeGly-His-4-Am,5-
SEQ ID NO:
72
MeHpA-Cpa-NH2
Gln-Trp-Ala-Val-NMeGly-His-Sta-
SEQ ID NO:
73
Cpa-NH2
Gln-Trp-Ala-Val-NMeGly-His-Sta-
SEQ ID NO:
74
tbuAla-NH2
Gln-Trp-Ala-Val-NMeGly-His-4-Am,5-
SEQ ID NO:
75
MeHpA-tbuAla-NH2
Gln-Trp-Ala-Val-His(Me)-Sta-Leu-NH2
SEQ ID NO:
77
Gln-Trp-Ala-Val-Gly-His(3Me)-
SEQ ID NO:
82
FA4-Am,5-MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO:
90
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-His-4-Am,5-
SEQ ID NO:
91
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-
SEQ ID NO:
101
Am-5-MeHpA-4-amino-5-methyl-
heptanoic acid-Leu-NH2
and
Gln-Trp-Ala-Val-NMeGly-His(3Me)-4-
SEQ ID NO:
102
Am-5-MeHpA-4-amino-5-methyl-
heptanoic acid-Cpa-NH2,
or a pharmaceutically acceptable salt of an inorganic or organic acid thereof.

239 more elements

A peptide sequence selected from

Gln-Trp-Ala-Val-NMeGly-His-Sta-
SEQ ID NO:
1
Leu-NH2
Gln-Trp-Ala-Val-Gly-His(Me)-Sta-
SEQ ID NO:
2
Leu-NH2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO:
3
Leu-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-
SEQ ID NO:
4
Sta-Leu-NH2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO:
7
Cpa-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO:
8
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO:
12
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-His-4-Am,5-
SEQ ID NO:
17
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-
SEQ ID NO:
23
4-Am,5-MeHpA-Cpa-NH2
Gln-Trp-Ala-Val-NMeGly-His-FA02010-
SEQ ID NO:
27
Cpa-NH2
Gln-Trp-Ala-Val-NMeGly-His-4-Am,5-
SEQ ID NO:
28
MeHpA-tbuGly-NH2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO:
30
tBuGly-NH2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-
SEQ ID NO:
32
4-Am,5-MeHpA-Leu-NH2
Gln-DTrp-Ala-Val-Gly-His-4-Am,5-
SEQ ID NO:
33
MeHpA-tbuGly-NH2
Gln-DTrp-Ala-Val-Gly-His-4-Am-5-
SEQ ID NO:
34
MeHxA-Cpa-NH2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO:
35
Cpa-NH2
Gln-DTrp-Ala-Val-Gly-His-Sta-
SEQ ID NO:
36
tbuAla-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-
SEQ ID NO:
42
Cpa-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-
SEQ ID NO:
43
tBuGly-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO:
46
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO:
48
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-NMeHis-4-Am,5-
SEQ ID NO:
49
MeHpA-Cpa-NH2
Gln-Trp-Ala-Val-Gly-NMeHis(3Me)-4-
SEQ ID NO:
47
Am,5-MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-NMeHis-4-Am,5-
SEQ ID NO:
50
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-NMeGly-HIs-AHMHxA-
SEQ ID NO:
51
Leu-NH2
Gln-Trp-Ala-Val-βAla-NMeHis-Tha-
SEQ ID NO:
52
Cpa-NH2
Gln-Trp-Ala-Val-βAla-NMeHis-Phe-
SEQ ID NO:
53
Cpa-NH2
Gln-Trp-Ala-Val-βAla-NMeHis-Phe-
SEQ ID NO:
54
Leu-NH2
Gln-Trp-Ala-Val-βAla-DHis-Phe-
SEQ ID NO:
55
Leu-NH2
Gln-Trp-Ala-Val-βAla-His-βhLeu-
SEQ ID NO:
56
Leu-NH2
Gln-Trp-Ala-Val-βAla-His-βhIle-
SEQ ID NO:
57
Leu-NH2
Gln-Trp-Ala-Val-βAla-His-βhLeu-
SEQ ID NO:
58
tbuGly-NH2
Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-
SEQ ID NO:
59
Tha-NH2
Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-
SEQ ID NO:
60
Nle-NH2
Gln-Trp-Ala-Val-βAla-NMeHis-Phe-
SEQ ID NO:
61
tbuGly-NH2
Gln-Trp-Ala-Val-βAla-NMeHis-Tha-
SEQ ID NO:
62
tbuGly-NH2
Gln-Trp-Ala-Val-βAla-His(3Me)-Tha-
SEQ ID NO:
63
tbuGly-NH2
Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-
SEQ ID NO:
64
Cpa-NH2
Gln-Trp-Ala-NMeVal-βAla-His-
SEQ ID NO:
65
Phe-Leu-NH2
Gln-Trp-Ala-Val-βAla-His-NMePhe-
SEQ ID NO:
66
Leu-NH2
Gln-DTrp-Ala-Val-βAla-His-Phe-
SEQ ID NO:
67
Leu-NH2
Gln-Trp-DAla-Val-βAla-His-Phe-
SEQ ID NO:
68
Leu-NH2
Gln-Trp-Ala-DVal-βAla-His-Phe-
SEQ ID NO:
69
Leu-NH2
Gln-Trp-Ala-Val-βAla-His-DPhe-
SEQ ID NO:
70
Leu-NH2
Gln-Trp-Ala-Val-βAla-His-βhIle-
SEQ ID NO:
71
tbuGly-NH2
Gln-Trp-Ala-Val-NMeGly-His-4-Am,5-
SEQ ID NO:
72
MeHpA-Cpa-NH2
Gln-Trp-Ala-Val-NMeGly-His-Sta-
SEQ ID NO:
73
Cpa-NH2
Gln-Trp-Ala-Val-NMeGly-His-Sta-
SEQ ID NO:
74
tbuAla-NH2
Gln-Trp-Ala-Val-NMeGly-His-4-Am,5-
SEQ ID NO:
75
MeHpA-tbuAla-NH2
Gln-Trp-Ala-Val-His(Me)-Sta-Leu-NH2
SEQ ID NO:
77
Gln-Trp-Ala-Val-Gly-His(3Me)-
SEQ ID NO:
82
FA4-Am,5-MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO:
90
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-His-4-Am,5-
SEQ ID NO:
91
MeHpA-Leu-NH2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-
SEQ ID NO:
101
Am-5-MeHpA-4-amino-5-methyl-
heptanoic acid-Leu-NH2
or
Gln-Trp-Ala-Val-NMeGly-His(3Me)-4-
SEQ ID NO:
102
Am-5-MeHpA-4-amino-5-methyl-
heptanoic acid-Cpa-NH2.

219 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/851,910Filed 7 Sep 2007 · us provisional application
Priority: EP 060901668 Sep 2006
Published: US 2008/0292548 A127 Nov 2008
Granted: 15 Oct 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07K 14/6555
Somatostatins: at least 1 amino acid in D-form
A61K 51/088
Peptides, e.g. proteins , carriers being peptides, polyamino acids, proteins: conjugates with carriers being peptides, polyamino acids or proteins
A61P 35/00
Antineoplastic agents
C07K 14/57545
Hormones: neuropeptide Y

Family

Application60/845,163Us provisional application · filed 18 Sep 2006
US 2008/0292548 A1Pre-grant publication · published 27 Nov 2008
US 8,557,776 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

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Abstract

A compound of Formula A

wherein
-G is selected from —C≡N and —CF3, wherein the respective substituent can be in ortho, para or meta position in respect of the K group,
-Q is hydrogen,
-L- is —CO— or —SO2—,
Y is a bond or a spacer,
wherein
(a) the spacer is Arg-Ser, Arg-Ava, Lys(Me)2-β-ala, Lys(Me)2-ser, Arg-β-ala, Ser-Ser, Ser-Thr, Arg-Thr, S-alkylcysteine, cysteic acid, thioalkylcysteine (S—S-alkyl) or
wherein k and l are independently selected in the range of from 0 to 4, or
(b) the spacer is a non-amino acid moiety selected from the group consisting of
—NH—(CH2)p—CO—, wherein p is an integer of from 2 to 10,
—NH—(CH2—CH2—O)q—CH2—CH2—CO—, wherein q is an integer of from 0 to 5,
—NH-cycloalkyl-CO— wherein cycloalkyl is selected from C5-C8 cycloalkyl, and
—NH-heterocycloalkyl-(CH2)v—CO— wherein heterocycloalkyl is selected from C5-C8 heterocycloalkyl containing carbon atoms and 1, 2, 3 or 4 oxygen, nitrogen or sulfur heteroatoms and v is an integer of from 1 to 4,
U is a targeting agent comprising
(a) a peptide selected from the group consisting of somatostatin, somatostatin receptor specific peptides, neuropeptide Y, neuropeptide Y1, bombesin, gastrin, gastrin releasing peptide, epidermal growth factor (EGF of various origin), insulin growth factor (IGF) and IGF-1, integrins (α3β1, αvβ3, αvβ5, αIIb3), LHRH agonists and antagonists, transforming growth factors, particularly TGF-α;
angiotensin;
cholecystokinin receptor peptides, cholecystokinin (CCK);
neurotensin, thyrotropin releasing hormone, pituitary adenylate cyclase activating peptide (PACAP), chemokines, substrates and inhibitors for cell surface matrix metalloproteinase, prolactin, tumor necrosis factor, interleukins (IL-1, IL-2, IL-4 or IL-6), interferons, and vasoactive intestinal peptide (VIP);
(b) a peptide selected from the group consisting of peptides having sequence III or IV:
AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-NT1T2 (type A) III, with:
T1=T2=H or
T1=H, T2=OH or
T1=CH3, T2=OH
AA1=Gln, Asn, Phe(4-CO—NH2)
AA2=Trp, D-Trp
AA3=Ala, Ser, Val
AA4=Val, Ser, Thr
AA5=Gly, (N-Me)Gly
AA6=His, His(3-Me), (N-Me)His, (N-Me)His(3-Me)
AA7=Sta, Statine analogs and isomers, 4-Am,5-MeHpA, 4-Am,5-MeHxA, γ-substituted amino acids
AA8=Leu, Cpa, Cba, CpnA, Cha, t-buGly, tBuAla, Met, Nle, iso-Bu-Gly;
or
AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-NT1T2 (type B) IV, with:
T1=T2=H or
T1=H, T2=OH or
T1=CH3, T2=OH
AA1=Gln, Asn or Phe(4-CO—NH2)
AA2=Trp, D-Trp
AA3=Ala, Ser, Val
AA4=Val, Ser. Thr
AA5=βAla, β2- and β3-amino acids as shown herein after
wherein SC represents a side chain found in proteinogenic amino acids and homologs of proteinogenic amino acids,
AA6=His, His(3-Me), (N-Me)His, (N-Me)His(3-Me)
AA7=Phe, Tha, Nal,
AA8=Leu, Cpa, Cba, CpnA, Cha, t-buGly, tBuAla, Met, Nle, iso-Bu-Gly;
or
(c) wherein U is a NR7-peptide, —(CH2)n′-peptide, —O—(CH2)n′-peptide or —S—(CH2)n′-peptide, wherein
n′ is an integer of from 1 to 6,
R7 is hydrogen or unbranched or branched alkyl and
the peptide is defined in (a) or (b);
X− is CF3S(O)2O−, C4F9S(O)2O−, iodide anion, bromide anion, chloride anion, perchlorate anion (ClO4−), phosphate anion, trifluoroacetate anion (CF3—C(O)O−), or the anion of another salt of an inorganic or organic acid,
K is N+(R1)(R2)(R3)X− or W,
wherein
R1, R2 and R3 are each methyl, and
W is 18F,
or a pharmaceutically acceptable salt of an inorganic or organic acid thereof.

53 more elements

Facts

Application

11/851,910Filed 7 Sep 2007 · us provisional application

Priority

EP 060901668 Sep 2006

Published

US 2008/0292548 A127 Nov 2008

Granted

15 Oct 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07K 14/6555
Somatostatins: at least 1 amino acid in D-form
A61K 51/088
Peptides, e.g. proteins , carriers being peptides, polyamino acids, proteins: conjugates with carriers being peptides, polyamino acids or proteins
A61P 35/00
Antineoplastic agents
C07K 14/57545
Hormones: neuropeptide Y