# US 5,710,244 A · Derivatized calcitonins

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- Number: US 5,710,244 A
- Document ID: US5710244A
- Status: Granted
- Kind: A
- Application number: 08/176,153
- Filed: 1993-12-30
- Granted: 1998-01-20
- Earliest claimed: 1992-12-31
- Inventors: Virender M. Labroo; Tomikazu Sasaki
- Web page: https://patentgrep.com/patent/US5710244A

## CPC

- C07K 14/57527: {Calcitonin gene related peptide}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/14: for calcium homeostasis (vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04)
- C07K 14/585: Calcitonins
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Derivatized calcitonin molecules, pharmaceutical compositions comprising derivatized calcitonins, and methods of reducing serum calcium in a patient using the derivatized calcitonins are disclosed. The molecules are characterized by a derivatized amino terminus formed by combining a calcitonin with a cyclic, polycyclic or heterocyclic moiety. Multimeric forms of the molecules are also disclosed.

## Claims

### Claim 1

A compound selected from the group consisting of: ##STR19## and pharmaceutically acceptable salts thereof, wherein R is substituted or unsubstituted biaryl, optionally containing 1 or 2 ring nitrogen atoms per ring; or substituted or unsubstituted bis-heterocycloalkyl containing 1 or 2 heteroatoms per ring selected from the group consisting of N, S and O.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R is: ##STR20## wherein X.sub.1 and Y.sub.1 are individually C or N; or ##STR21## wherein X.sub.3 and Y.sub.3 are individually N, O or S; wherein R' is linear C.sub.1 -C.sub.8 alkyl, branched C.sub.1 -C.sub.12 alkyl, nitro, hydroxyl, trifluoromethyl, carboxyl, carboxylamide, sulfhydryl, cyano, halo, alkoxy, ester or H.

### Claim 3 (depends on 2)

A compound according to claim 2, wherein R is: ##STR22##

### Claim 4 (depends on 3)

A compound according to claim 3, wherein R' is CO.sub.2 H or H.

### Claim 5 (depends on 1)

A compound according to claim 1 wherein R is ##STR23## wherein R' is CO.sub.2 H or H.

### Claim 6 (depends on 1)

A compound according to claim 1 wherein R is a fused ring structure containing two or three rings.

### Claim 7 (depends on 1)

A compound according to claim 1 wherein R is selected from the group consisting of: ##STR24##

### Claim 8

Compound of the formula R-N-CT, wherein CT is a calcitonin selected from the group consisting of human, salmon, eel, rat, porcine, bovine, ovine and chicken calcitonins and biologically active derivatives and variants thereof, or a pharmaceutically acceptable salt thereof; N is an amide linkage; and wherein R is substituted or unsubstituted biaryl, optionally containing 1 or 2 ring nitrogen atoms per ring; or substituted or unsubstituted bis-heterocycloalkyl containing 1 or 2 heteroatoms per ring selected from the group consisting of N, S and O.

### Claim 9 (depends on 8)

A compound according to claim 8 wherein R is: ##STR25## wherein X.sub.1 and Y.sub.1 are individually C or N; or ##STR26## wherein X.sub.3 and Y.sub.3 are individually N, O or S; wherein R' is linear C.sub.1 -C.sub.8 alkyl, branched C.sub.1 -C.sub.12 alkyl, nitro, hydroxyl, trifluoromethyl, carboxyl, carboxylamide, sulfhydryl, cyano, halo, alkoxy, ester or H.

### Claim 10 (depends on 9)

A compound according to claim 9 wherein R is: ##STR27##

### Claim 11 (depends on 10)

A compound according to claim 10, wherein R' is CO.sub.2 H or H.

### Claim 12 (depends on 8)

A compound according to claim 8 wherein CT is human or salmon calcitonin.

### Claim 13 (depends on 10)

A compound according to claim 10 wherein R is ##STR28## wherein R' is CO.sub.2 H or H.

### Claim 14 (depends on 8)

A compound according to claim 8 wherein R is a biaryl and each aryl group of the biaryl is a fused ring structure containing two or three rings.

### Claim 15 (depends on 8)

A compound according to claim 8 wherein R is selected from the group consisting of: ##STR29##

### Claim 16

A compound of the formula
X-(R-N-CT).sub.n
wherein X is a monovalent, divalent or trivalent ion of a transition metal; R is a heterocycloalkyl or heteroaryl group; CT is a calcitonin selected from the group consisting of human, salmon, eel, rat, porcine, bovine, ovine and chicken calcitonins and biologically active derivatives and variants thereof; N is an amide linkage; and n=2 or 3; or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 16)

A compound according to claim 16 wherein X is Fe.sup.2+.

### Claim 18 (depends on 16)

A compound according to claim 16 wherein n=3.

### Claim 19 (depends on 16)

A compound according to claim 16 wherein CT is human or salmon calcitonin.

### Claim 20 (depends on 19)

A compound according to claim 19 wherein R is ##STR30## wherein R' is CO.sub.2 H or H.

### Claim 21 (depends on 16)

A compound according to claim 16 wherein R is: ##STR31## wherein R' is CO.sub.2 H or H.

### Claim 22 (depends on 16)

A compound according to claim 16 wherein X is Fe.sup.2+, R is ##STR32## CT is human or salmon calcitonin, and n=3.

### Claim 23 (depends on 16)

A compound according to claim 16 wherein R is selected from the group consisting of: ##STR33##

### Claim 24 (depends on 16)

A compound according to claim 16 wherein R is a fused ring structure containing two or three rings.

### Claim 25 (depends on 8)

A pharmaceutical composition comprising a compound according to claim 8 and a pharmaceutically acceptable carrier.

### Claim 26 (depends on 8)

A method of reducing serum calcium in a patient, comprising administering to said patient an effective amount of a pharmaceutical composition comprising a compound according to claim 8 and a pharmaceutically acceptable carrier.