Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Somatostatin ; related peptides
Reexamination Certificate
2000-09-26
2004-03-09
Jones, Dwayne C. (Department: 1614)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Somatostatin ; related peptides
C530S317000, C530S328000, C530S329000, C514S011400, C514S016700
Reexamination Certificate
active
06703481
ABSTRACT:
BACKGROUND OF THE INVENTION
Native somatostatin is comprised of both a 14-amino acid isoform (somatostatin-14) and a 28-amino acid isoform (somatostatin-28). Heiman, et al., Neuroendocrinology, 45:429-436 (1987). Because of the short half-life of the native somatostatin, various somatostatin analogs have been developed, e.g., for the treatment of acromegaly. Raynor, et al., Molecular Pharmacol. 43:838 (1993). Five distinct somatostatin receptors have been identified and characterized. Hoyer, et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 350:441 (1994). Somatostatin produces a variety of effects, including modulation of hormone release, e.g., growth hormone, glucagon, insulin, amylin, and neurotransmitter release. Some of these effects have been associated with its binding to a specific somatostatin receptor. For example, the inhibition of growth hormone has been attributed to the somatostatin type-2 receptor (“SSTR-2”) (Raynor, et al., Molecular Pharmacol. 43:838 (1993); Lloyd, et al., Am. J. Physiol. 268:G102 (1995)) while the inhibition of insulin has been attributed to the somatostatin type-5 receptor (“SSTR-5”) (Coy, et al. 197:366-371 (1993)). The following invention relates to a novel class of somatostatin analogs which are antagonists to somatostatin receptors.
SUMMARY OF THE INVENTION
The invention features a compound of the formula:
wherein
A
1
is a D- or L-isomer of an aromatic amino acid, or is deleted;
A
2
is a D-isomer selected from the group consisting of Cys, Pen, an aromatic amino acid, or an aliphatic amino acid;
A
3
is an aromatic amino acid;
A
4
is Trp or D-Trp;
A
6
is Thr, Thr(Bzl), Gly, Ser, an Eaa, or an aliphatic amino acid;
A
7
is Cys, Pen, or an aromatjkic or an aliphatic amino acid;
A
8
is a D- or L-isomer selected from the group consisting of Thr, Ser, an aromatic amino acid, or an aliphatic amino acid;
each of R
1
and R
2
, is, independently, H or substituted (e.g., one to four times) or unsubstituted lower alkyl, aryl, aryl lower alkyl, heterocycle, heterocycle lower alkyl, E
1
SO
2
or E
1
CO (where E
1
is aryl, aryl lower alkyl, heterocycle, or heterocycle lower alkyl), where said substituent is halo, lower alkyl, hydroxy, halo lower alkyl, or hydroxy lower alkyl; and
R
3
is OH, NH
2
, C
1-12
alkoxy, or NH—Y—CH
2
—Z, wherein Y is a C
1-12
hydrocarbon moiety and Z is H, OH, CO
2
H, or CONH
2
, or R
3
, together with the carbonyl group of A
8
attached thereto, are reduced to form H, lower alkyl, or hydroxy lower alkyl; provided if A
2
is D-Cys or D-Pen, and A
7
is Cys or Pen, then a disulfide bond links the sidechains of A
2
and A
7
, and if A
1
is D-Phe or p-NO
2
-Phe; A
2
is D-Cys; A
3
is Phe or Tyr; A
6
is Thr or Val; and A
7
is Cys; then A
8
is &bgr;-Nal.
In one embodiment, A
2
is D-Cys, A
7
is Cys, and A
4
is D-Trp. In a further embodiment, A
1
is an L-aromatic amino acid. In still a further embodiment, A
1
and A
3
, independently, is &bgr;-Nal, o-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), p-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), m-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), F
5
-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa, or Pal; A
6
is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, &bgr;-Ala, Gaba, or Val; and A
8
is the D- or L-isomer of Thr, Dip, F
5
-Phe, p-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), o-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), m-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), Igl, Tyr(Bzl), or &bgr;-Nal. In yet still another embodiment, A
1
is &bgr;-Nal, Npa, Igl, Phe, p-F-Phe, Trp, p-Cl-Phe, or p-CN-Phe; A
3
is Tyr, Tyr(I), or Pal; A
6
is Val, Tle, Nle, Ile, or Leu; A
8
is p-F-Phe, &bgr;-Nal, Tyr, Dip, p-Cl-Phe, Igl, or p-CN-Phe; R
1
is H, CH
3
CO, 4-(2-hydroxyethyl)-1-piperazinylacetyl, or 4-(2-hydroxyethyl)-1-piperizineethanesulfonyl; R
2
is H; and R
3
is NH
2
.
In another further embodiment, A
1
is a D-aromatic amino acid. In still another further embodiment, A
1
is D-&bgr;-Nal, D-o-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), D-p-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), D-m-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), D-F
5
-Phe, D-Trp, D-Dip, D-2-Pal, D-Tyr(Bzl), D-His, D-Igl, D-Tyr(I), D-Bta, D-Bip, D-Npa, or D-Pal; A
3
is &bgr;-Nal, o-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), p-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), m-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), F
5
-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa, or Pal; A
6
is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, &bgr;-Ala, Gaba, or Val; and A
8
is the D- or L-isomer of Thr, Dip, F
5
-Phe, p-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), o-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), m-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), Tyr(Bzl), Igl, or &bgr;-Nal. In yet still a further embodiment, A
1
is D-&bgr;-Nal, D-Npa, D-Igl, D-Phe, D-p-F-Phe, D-Trp, D-p-Cl-Phe, or D-p-CN-Phe; A
3
is Tyr, Tyr(I), or Pal; A
6
is Val, Tle, Nle, Ile, or Leu; A
8
is p-F-Phe, &bgr;-Nal, Tyr, Dip, p-Cl-Phe, Igl, or p-CN-Phe; R
1
is H, CH
3
CO, 4-(2-hydroxyethyl)-1-piperazinylacetyl, or 4-(2-hydroxyethyl)-1-piperizineethanesulfonyl; R
2
is H; and R
3
is NH
2
.
In still another further embodiment, A
1
is deleted, R
1
is substituted or unsubstituted E
1
CO, and R
2
is H. In still a further embodiment, R
1
is substituted or unsubstituted E
1
CO (where E
1
is phenyl, &bgr;-naphthylmethyl, &bgr;-pyridinylmethyl, or 3-indolylmethyl); A
3
is &bgr;-Nal, o-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), p-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), m-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), F
5
-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa, or Pal; A
6
is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, &bgr;-Ala, Gaba, or Val; and A
8
is the D- or L-isomer of Thr, Dip, F
5
-Phe, p-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), o-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), m-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), Igl, Tyr(Bzl), or &bgr;-Nal. In yet still a further embodiment, R
1
is E
1
CO (where E
1
is 4-hydroxy-phenyl, &bgr;-naphthylmethyl, or phenyl); A
3
is Tyr, Tyr(I), or Pal; A
6
is Val, Tle, Nle, Ile, or Leu; A
8
is p-F-Phe, &bgr;-Nal, Tyr, Dip, p-Cl-Phe, Igl, or p-CN-Phe; R
3
is NH
2
.
In yet still a further embodiment, R
3
, together with the carbonyl group of A
8
attached thereto, are reduced to form H, lower alkyl, or hydroxy lower alkyl. In still another further embodiment, A
1
is the D- or L-isomer of &bgr;-Nal, o-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), p-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), m-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), F
5
-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa, or Pal; A
3
is &bgr;-Nal, o-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), p-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), m-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), F
5
-Phe, Trp, Dip, 2-Pal, Tyr(Bzl), His, Igl, Tyr(I), Bta, Bip, Npa, or Pal; A
6
is Thr, Ser, Tle, Thr(Bzl), Abu, Ala, Ile, Leu, Gly, Nle, &bgr;-Ala, Gaba, or Val; and A
8
is the D- or L-isomer of Thr, Dip, F
5
-Phe, p-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), o-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), m-X-Phe (where X is H, OH, CH
3
, halo, OCH
3
, NH
2
, CN, or NO
2
), Igl, Tyr(Bzl), or &bgr;-Nal. In yet still another further embodiment, A
1
is the D- or L-isomer of &bgr;-Nal, Phe, p-F-Phe, Trp, p-Cl-Phe, or p-CN-Phe; A
3
is Tyr, Tyr(I), or Pal; A
Coy David H.
Morgan Barry
Murphy William
Delacroix-Muirheid C.
Feeney Alan F.
Fish & Richardson
Jones Dwayne C.
Morrill Brian R.
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