Analogs of parathyroid hormone

Details Analogs of parathyroid hormone Analogs of parathyroid hormone

1999-09-20

2003-04-08

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S324000

Reexamination Certificate

active

06544949

ABSTRACT:

BACKGROUND OF THE INVENTION
Parathyroid hormone (“PTH”) is a polypeptide produced by the parathyroid glands. The mature circulating form of the hormone is comprised of 84 amino acid residues. The biological action of PTH can be reproduced by a peptide fragment of its N-terminus (e.g. amino acid residues 1 through 34). Parathyroid hormone-related protein (“PTHrP”) is a 139 to 173 amino acid-protein with N-terminal homology to PTH. PTHrP shares many of the biological effects of PTH including binding to a common PTH/PTHrP receptor. Tregear, et al., Endocrinol., 93:1349 (1983). PTH peptides from many different sources, e.g., human, bovine, rat, chicken, have been characterized. Nissenson, et al., Receptor, 3:193 (1993).
PTH has been shown to both improve bone mass and quality. Dempster, et al., Endocrine Rev., 14:690 (1993); and Riggs, Amer. J. Med., 91 (Suppl. 5B):37S (1991). The anabolic effect of intermittently administered PTH has been observed in osteoporotic men and women either with or without concurrent antiresorptive therapy. Slovik, et al., J. Bone Miner. Res., 1:377 (1986); Reeve, et al., Br. Med. J., 301:314 (1990); and Hesch, R-D., et al., Calcif. Tissue Int'l, 44:176 (1989).
SUMMARY OF THE INVENTION
In one aspect, the invention features a peptide of the formula (I),
wherein
A
1
is Ser, Ala, or Dap;
A
3
is Ser, Thr, or Aib;
A
5
is Leu, Nle, Ile, Cha, &bgr;-Nal, Trp, Pal, Acc, Phe or p-X-Phe, in which X is OH, a halogen, or CH
3
;
A
7
is Leu, Nle, Ile, Cha, &bgr;-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH
3
;
A
8
is Met, Nva, Leu, Val, Ile, Cha, Acc, or Nle;
A
11
is Leu, Nle, Ile, Cha, &bgr;-Nal, Trp, Pal, Acc, Phe or p-X-Phe in which X is OH, a halogen, or CH
3
;
A
12
is Gly, Acc, or Aib;
A
15
is Leu, Nle, Ile, Cha, &bgr;-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH
3
;
A
16
is Ser, Asn, Ala, or Aib;
A
17
is Ser, Thr, or Aib;
A
18
is Met, Nva, Leu, Val, Ile, Nle, Acc, Cha, or Aib;
A
19
is Glu or Aib;
A
21
is Val, Acc, Cha, or Met;
A
22
is Acc or Glu;
A
23
is Trp, Acc, or Cha;
A
24
is Leu, Acc, or Cha;
A
27
is Lys, Aib, Leu, hArg, Gln, Acc, or Cha;
A
28
is Leu, Acc, or Cha;
A
29
is Gln, Acc, or Aib;
A
30
is Asp or Lys;
A
31
is Val, Leu, Nle, Acc, Cha, or deleted;
A
32
is His or deleted;
A
33
is Asn or deleted;
A
34
is Phe, Tyr, Amp, Aib, or deleted;
each of R
1
and R
2
is, independently, H, C
1-12
alkyl, C
2-12
alkenyl, C
7-20
phenylalkyl, C
11-20
naphthylalkyl, C
1-12
hydroxyalkyl, C
2-12
hydroxyalkenyl, C
7-20
hydroxyphenylalkyl, or C
11-20
hydroxynaphthylalkyl; or one and only one of R
1
and R
2
is COE
1
in which E
1
is C
1-12
alkyl, C
2-12
alkenyl, C
7-20
phenylalkyl, C
11-20
naphthylalkyl, C
1-12
hydroxyalkyl, C
2-12
hydroxyalkenyl, C
7-20
hydroxy-phenylalkyl, or C
11-20
hydroxynaphthylalkyl; and
R
3
is OH, NH
2
, C
1-12
alkoxy, or NH—Y—CH
2
—Z in which Y is a C
1-12
hydrocarbon moiety and Z is H, OH, CO
2
H, or CONH
2
; provided that at least one of A
5
, A
7
, A
8
, A
11
, A
12
, A
15
, A
18
, A
21
, A
22
, A
23
, A
24
, A
27
, A
28
, A
29
, and A
31
is Acc; or a pharmaceutically acceptable salt thereof.
A preferred embodiment of the immediately foregoing peptide is where A
3
is Ser; A
5
is Ile or Acc; A
7
is Leu, Acc, or Cha; A
8
is Acc, Met, Nva, Leu, Val, Ile, or Nle; A
11
is Leu, Acc, or Cha; A
12
is Acc or Gly; A
15
is Leu, Acc, or Cha; A
16
is Asn or Aib; A
17
is Ser or Aib; A
18
is Acc, Met, or Nle; A
21
is Val or Acc; A
27
is Lys, hArg, Acc, or Cha; A
31
is Val, Leu, Nle, Acc, or Cha; A
32
is His; A
33
is Asn; A
34
is Phe, Tyr, Amp, or Aib; or a pharmaceutically acceptable salt thereof.
A preferred embodiment of the immediately foregoing peptide, designated Group B, is where A
5
is Ile or Ahc; A
7
is Leu, Ahc, or Cha; A
8
is Ahc, Met, or Nle; A
11
is Leu, Ahc, or Cha; A
12
is Ahc or Gly; A
15
is Leu, Ahc, or Cha; A
18
is Met or Ahc; A
21
is Val or Ahc; A
22
is Glu or Ahc; A
23
is Trp, Ahc, or Cha; A
24
is Leu, Ahc, or Cha; A
27
is Lys, hArg, Ahc, or Cha; A
28
is Leu, Ahc, or Cha; A
29
is Gln, Ahc, or Aib; A
31
is Val, Leu, Nle, Ahc, or Cha; R
1
is H; R
2
is H; and R
3
is NH
2
; or a pharmaceutically acceptable salt thereof.
A preferred group of peptides of Group B is where at least one of A
7
, A
11
, A
15
, A
23
, A
24
, A
27
, A
28
, or A
31
is Cha.
Another preferred group of peptides of Group B is where at least one of A
16
, A
17
, A
19
, A
29
, or A
34
is Aib.
Preferred peptides of formula (I) are [Ahc
7,11
]hPTH(1-34)NH
2
; [Ahc
7,11
, Nle
8,18
, Tyr
34
]hPTH(1-34)NH
2
; [Ahc
11
]hPTH(1-34)NH
2
; [Ahc
7,11,15
]hPTH(1-34)NH
2
; [Ahc
7
]hPTH(1-34)NH
2
; [Ahc
23
]hPTH(1-34)NH
2
; [Ahc
24
]hPTH(1-34)NH
2
; [Nle
8,18
, Ahc
27
]hPTH(1-34)NH
2
; [Ahc
28
]hPTH(1-34)NH
2
; [Ahc
31
]hPTH(1-34)NH
2
; [Ahc
24,28,31
]hPTH(1-34)NH
2
; [Ahc
24,28,31
, Lys
30
]hPTH(1-34)NH
2
; [Ahc
28,31
]hPTH(1-34)NH
2
; [Ahc
15
]hPTH(1-34)NH
2
; [Ahc
24,27
, Aib
29
, Lys
30
]hPTH(1-34)NH
2
; [Ahc
24,27
, Aib
29
, Lys
30
, Leu
31
]hPTH(1-34)NH
2
; [Ahc
5
]hPTH(1-34)NH
2
; [Ahc
12
]hPTH(1-34)NH
2
; [Ahc
27
]hPTH(1-34)NH
2
; [Ahc
29
]hPTH(1-34)NH
2
; [Ahc
24,27
]hPTH(1-34)NH
2
; [Ahc
24,27
, Aib
29
]hPTH(1-34)NH
2
; [Ahc
24
, Aib
29
]hPTH(1-34)NH
2
; [Ahc
27
, Aib
29
]hPTH(1-34)NH
2
; [Ahc
18
]hPTH(1-34)NH
2
; [Ahc
8
]hPTH(1-34)NH
2
; [Ahc
18,27
, Aib
29
]hPTH(1-34)NH
2
; or [Ahc
18,24,27
, Aib
29
]hPTH(1-34)NH
2
; [Ahc
22
, Leu
27
, Aib
29
]hPTH(1-34)NH
2
; [Ahc
24
, Leu
27
, Aib
29
]hPTH(1-34)NH
2
; [Ahc
22
]hPTH(1-34)NH
2
; and [Acc
22
, Aib
29
]hPTH(1-34)NH
2
; or a pharmaceutically acceptable salt thereof.
The invention also features peptides of the following formulae: [Cha
22,23
, Glu
25
, Lys
26,30
, Leu
28
, Aib
29
]hPTHrP(1-34)NH
2
; [Cha
22,23
, Glu
25
, Lys
26,30
, Aib
29
]hPTHrP(1-34)NH
2
; [Glu
22,25
, Leu
23,28,31
, Lys
26
, Aib
29
, Nle
30
]hPTHrP(1-34)NH
2
; [Glu
22,25
, Leu
23,28,30,31
, Lys
26
, Aib
29
]hPTHrP(1-34)NH
2
; [Glu
22,25,29
, Leu
23,28,30,31
, Lys
26
]hPTHrP(1-34)NH
2
; [Glu
22,25,29
, Leu
23,28,31
, Lys
26
, Nle
30
]hPTHrP(1-34)NH
2
; [Ser
1
, Ile
5
, Met
8
, Asn
10
, Leu
11,23,28,31
, His
14
, Cha
15
, Glu
22,25
, Lys
26,30
, Aib
29
]hPTHrP(1-34)NH
2
; [Glu
22,25
, Cha
23
, Lys
26
, Leu
28,31
, Aib
29
, Nle
30
]hPTHrP(1-34)NH
2
; [Cha
22,23
, Glu
25
, Lys
26,30
, Leu
28,31
, Aib
29
]hPTHrP(1-34)NH
2
; [Cha
22
, Leu
23,28,31
, Glu
25,29
, Lys
26
, Nle
30
]hPTHrP(1-34)NH
2
; [Cha
7,11,15
]hPTHrP(1-34)NH
2
; [Cha
7,8,15
]hPTHrP(1-34)NH
2
; [Glu
22
, Cha
23
, Aib
25,29
, Lys
26,30
, Leu
28,31
]hPTHrP(1-34)NH
2
; [Glu
22
, Cha
23
, Aib
25,29
, Lys
26
, Leu
28
]hPTHrP(1-34)NH
2
; [Glu
22
, Leu
23,28
, Aib
25,29
, Lys
26
]hPTHrP(1-34)NH
2
; [Aib
29
]hPTHrP(1-34)NH
2
; [Glu
22,25
, Cha
23
, Lys
26
, Leu
28,31
, Aib
29
, Nle
30
]hPTHrP(1-34)NH
2
; [Glu
22,25
, Cha
23
, Lys
26,30
, Aib
29
, Leu
31
]hPTHrP(1-34)NH
2
; [Glu
22,25
, Leu
23,28,31
, Lys
26
, Aib
29,30
]hPTHrP(1-34)NH
2
; [Glu
22,25
, Leu
23,28,31
, Lys
26
, Aib
29
]hPTHrP(1-34)NH
2
; [Glu
22,25
, Leu
23,28,31
, Aib
26,29
, Lys
30
)]hPTHrP(1-34)NH
2
; [Glu
22,25
, Cha
23
, Lys
26,30
, Leu
28,31
, Aib
29
]hPTHrP(1-34)NH
2
; [Glu
22,25
, Cha
23
, Lys
26,30
, Aib
29
]hPTHrP(1-34)NH
2
; [Glu
22,25
, Cha
23
, Lys
26,30
, Leu
28
, Aib
29
]hPTHrP(1-34)NH
2
; or [Leu
27
, Aib
29
]hPTH(1-34)NH
2
; or a pharmaceutically acceptable salt thereof.
The following are examples of the peptides of the invention covered by the above formula: [Glu
22,25
, Leu
23,28
, Lys
26,30
, Aib
29
, Ahc
31
]hPTHrP(1-3

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