Process for the preparation of resin-bound cyclic peptides

Details Process for the preparation of resin-bound cyclic peptides Process for the preparation of resin-bound cyclic peptides

1999-11-18

2003-05-27

Low, Christopher S. F. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Synthesis of peptides

C530S317000, C530S324000, C530S328000, C530S330000, C514S017400, C514S018700, C514S019300, C514S011400, C514S012200, C514S014800

Reexamination Certificate

active

06569993

ABSTRACT:

FIELD OF THE INVENTION
This invention is directed to a process for the fragment-based preparation of resin-bound cyclic peptide analogs of parathyroid hormones and analogs of parathyroid hormone-related proteins, which analogs contain at least one bridge between the side chains of two non-adjacent amino acid residues. More particularly, the invention is directed to a process for the solid-phase synthesis of such cyclic peptide analogs, and to peptide fragments useful therefor.
BACKGROUND OF THE INVENTION
Cyclic peptide subunits are present in a wide variety of peptides possessing useful biological activity, including parathyroid hormone analogs and parathyroid hormone-related protein analogs, vasoactive peptide analogs, cholecystokinin analogs, tumor necrosis factor (TNF) derived peptides, calcitonin analogs, somatostatin analogs, cell adhesion modulators, growth hormone releasing factor (GRF) analogs, bradykinin antagonists, analogs of tyrosine activation motifs (TAM Mimics) and amylin agonists. Of particular interest are the cyclic peptide parathyroid hormone (hPTH) analogs and parathyroid hormone-related protein (hPTHrP) analogs.
Human parathyroid hormone (hPTH) is an 84 amino acid protein which is a major regulator of calcium homeostasis. Parathyroid hormone-related protein (hPTHrP) is a 139 to 171 amino acid protein with N-terminal homology to hPTH. The N-terminal fragments of hPTH and hPTHrP, particularly those consisting of amino acids 1-34, retain the full biological activity of the parent hormone.
hPTH(1-34) has the following amino acid sequence:
Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe. (SEQ ID NO: 26)
hPTHrP(1-34) has the following amino acid sequence:
Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Phe-Phe-Leu-His-His-Leu-Ile-Ala-Glu-Ile-His-Thr-Ala. (SEQ ID NO: 27)
The biological activity of hPTH is reflected in the activation of two secondary messenger systems: G-protein coupled adenylyl cyclase (AC) and G-protein coupled and uncoupled protein kinase C (PKC) activity. The N-terminal fragments hPTH(1-34)OH and hPTH(1-31)NH2 have been demonstrated to be anabolic with respect to bone formation in humans and ovariectomized rats, respectively. This increase in bone growth has been demonstrated to be coupled with stimulation of adenylyl cyclase activity. Analogs of these N-terminal fragments have significant therapeutic potential for the treatment of physiological conditions associated with bone cell calcium regulation including hypocalcemia; osteoporosis; osteopenia; and disorders associated with osteoporosis and osteopenia such as hyperparathyroidism, hypoparathyroidism, and Cushings syndrome; glucocorticoid- and immunosuppressant-induced osteopacnia; and bone fracture and bone refracture repair.
It has also been established that deletion of up to six amino acid residues from the N-terminus of hPTH(1-34) markedly decreases the resulting analog's ability to stimulate adenylyl cyclase while having little effect on receptor binding. Thus, analogs of hPTH(1-34) truncated by up to six amino acid residues at the N-teminus inhibit the action of PTH and are useful in the treatment of disorders characterized by an excess of PTH such as hyperparathyrodism and hyperparathyrodism-related hypercalcemia crisis, hypercalcemia of malignancy, renal failure and hypertension.
Acyclic analogs of hPTH(1-27) to (1-34) are disclosed in U.S. Pat. No. 4,086,196. Acyclic analogs of hPTH(1-34) and hPTHrP (1-34) are disclosed in U.S. Pat. No. 5,589,452. [Nle
8
, Nle
18
, Tyr
34
, or Phe
34
]hPTH(1-34) are disclosed in U.S. Pat. No. 4,656,250. [Nle
8
, Nle
18
, Tyr
34
]hPTH(1-34) and N-truncated derivatives thereof are disclosed in U.S. Pat. Nos. 4,771,124 and 4,423,037. Other acyclic analogs of PTH(1-34) are disclosed in U.S. Pat. Nos. 5,723,577 and 5,434,246, WO 97/02834, EPA 561 412-A1, EPA 747 817-A2, WO-94/02510, WO9603437, and WO9511988-A1. Analogs of hPTH(1-28)NH
2
to hPTH(1-31)NH
2
and [Leu
27
]hPTH(1-28)NH
2
to [Leu
27
]hPTH(1-33)NH
2
are decribed in U.S. Pat. No. 5,556,940. Acyclic antagonists of the PTH receptor including N-terminally-truncated analogs of PTH are disclosed in U.S. Pat. Nos. 5,446,130, 5,229,489, 4,771,124 and 4,423,037.
Cyclic and bicyclic analogs of hPTH and hPTHrP have been disclosed. Cyclo(Lys
26
-Asp
30
)[Leu
27
]hPTH(1-34)NH
2
and cyclo(Lys
27
-Asp
30
)hPTH(1-34)NH
2
are disclosed in U.S. Pat. No. 5,556,940. Cyclo(Lys
26
-Asp
30
)[Leu
27
]hPTH(1-31)NH
2
, cyclo(Glu
22
-Lys
26
)[Leu
27
]hPTH(1-31)NH
2
, and cyclo(Lys
27
-Asp
30
)hPTH(1-31)NH
2
are decribed by Barbier, et al.,
J. Med. Chem.
1997, 40, 1373. Monocyclic and bicyclic derivatives of hPTH(1-34) or hPTHrP(1-34) are disclosed in patent documents WO 96/40193, DE19508672-A1, and by A. Bisello, et al., in
Biochemistry
1997, 36, 3293. Cyclo(Lys
13
-Asp
17
)hPTHrP(7-34)NH
2
, a potent antagonist of the PTH receptor, is disclosed by M. Chorev, et al.,
Biochemistry
1991, 30, 5698. Also, Kanmera, et al., has described a series of amide-containing analogs of hPTHrP,
Peptide Chemistry
1993: Okada, Y., ed.; Protein Research Foundation, Osaka, 1994, 321-324.” WO 98/51324 discloses cyclic peptide compounds of formula I
and pharmaceutically acceptable salts and prodrugs thereof wherein
X is selected from the group consisting of
(a) R
1a
—A
0
—A
1
—A
2
—A
3
—A
4
—A
5
—A
6
—A
7
—A
8
—A
9
—,
(b) R
1a
—A
2
—A
3
—A
4
—A
5
—A
6
—A
7
—A
8
—A
9
—,
(c) R
1b
—A
3
—A
4
—A
5
—A
6
—A
7
—A
8
—A
9
—,
(d) R
1a
—A
4
—A
5
—A
6
—A
7
—A
8
—A
9
—,
(e) R
1a
—A
5
—A
6
—A
7
—A
8
—A
9
—,
(f) R
1a
—A
6
—A
7
—A
8
—A
9
—,
(g) R
1a
—A
7
—A
8
—A
9
—,
(h) R
1a
—A
8
—A
9
—,
(i) R
1a
—A
9
—, and
(j) R
1a
—;
Y is selected from the group consisting of
(a) —R
3
,
(b) —A
28
—R
3
,
(c) —A
28
—A
29
—R
3
,
(d) —A
28
—A
29
—A
30
—R
3
,
(e) —A
28
—A
29
—A
30
—A
31
—R
3
,
(e) —A
28
—A
29
—A
30
—A
31
—A
32
—R
3
,
(g) —A
28
—A
29
—A
30
—A
31
—A
32
—A
33
—R
3
, and
(h) —A
28
—A
29
—A
30
—A
31
—A
32
—A
33
—A
34
—R
3
;
R
1a
is H, alkyl, aralkyl or —COR
2
;
R
1b
is R
1a
or a group of formula
R
2
is alkyl, alkenyl, alkynyl, aryl or aralkyl;
R
3
is a group of formula A
35
—OR
4
or A
35
—NR
4
R
5
;
R
4
and R
5
are independently H or lower alkyl;
R
6
and R
9
are independently H or alkyl;
R
7
is alkyl;
R
8
is H, alkyl or COR
2
;
R
10
is H or halogen;
R
11
is alkyl or aralkyl;
m is 1, 2or 3;
n is 3 or 4;
A
0
is absent or a peptide of from one to six amino acid residues;
A
1
is Ser, Ala, Gly or D-Pro, or an equivalent amino acid thereof;
A
2
is Ala, Val or Gly, or an equivalent amino acid thereof;
A
3
is Ala, Ser, Gly or D-Pro, or an equivalent amino acid thereof;
A
4
is Glu, Ala or Gly, or an equivalent amino acid thereof,
A
5
is Ile, His, Ala or Gly, or an equivalent amino acid thereof;
A
6
is Ala, Gln, Gly or D-Pro, or an equivalent amino acid thereof;
A
7
is Ala, Leu, Gly, or an equivalent amino acid thereof;
A
8
is Leu, Nle, Gly or D-Pro, or an equivalent amino acid thereof;
A
9
is His, Ala, D-Pro or Gly, or an equivalent amino acid thereof;
A
10
is Ala, Asn, Asp, Cys, homo-Cys, Glu, Gly, Lys, Orn, Ser, Thr, D-Pro, —NHCH[(CH
2
)
m
NH
2
]CO— or —NHCH [(CH
2
)
n
CO
2
H]CO—;
A
11
is Ala, Gly, Leu or Lys, or an equivalent amino acid thereof;
A
12
is Ala or Gly, or an equivalent amino acid thereof;
A
13
is Ala, Asn, Asp, Cys, homo-Cys, Glu, Gly, Lys, Orn, Ser, Thr, —NHCH[(CH
2
)
m
NH
2
]CO— or —NHCH[(CH
2
)
n
CO
2
H]CO—;
A
14
is Ala, Asn, Asp, Cys, homo-Cys, Glu, Gly, His, Lys, Orn, Ser, Thr, D-Pro, —NHCH[(CH
2
)
m
NH
2
]CO— or —NHCH[(CH
2
)
n
CO
2
H]CO—;
A
15
is Ala, Gly, Ile, D-Pro or Leu, or an equivalent amino acid thereof;
A
16
is Asn, Ala, Gly, D-Pro or Gln, or an equivalent amino acid thereof;
A
17
is Ala, Asn, Asp, Cys, homo-Cys, Glu, Gly, Lys, Orn, Ser, Thr, D-Pro, —NHCH[(CH
2
)
m
NH
2
]CO— or —NHCH[(CH
2
)
n
CO
2
H]CO—;
A
18
is Asp, C

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