Compositions and methods for treating bone deficit conditions

• US 6,008,208 A
• Filed: 06/19/1997
• Issued: 12/28/1999
• Est. Priority Date: 10/23/1995
• Status: Expired due to Term

• Current Assignee: Warsaw Orthopedic Incorporated (Medtronic Plc)
• Original Assignee: Zymogenetics LLC (Bristol-Myers Squibb Company), OsteoScreen, Inc.
• Inventors: Orme, Mark W., Mundy, Gregory R., Harris, Scott M., Baindur, Nand, Robbins, Kirk G., Petrie, Charles, Kontoyianni, Maria
• Primary Examiner(s): POWERS, FIONA
• Application Number:
  US08/878,868
• Time in Patent Office: 922 Days
• Field of Search: 514/150, 514/224.2, 514/456
• US Class Current: 514/150
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/549 having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
• CPC Class Codes: A61K 31/655 Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds

Abstract

Compounds containing two aromatic systems covalently linked through a linker containing one or more atoms, or "linker" defined as including a covalent bond per se so as to space the aromatic systems at a distance 1.5-15 Å, are effective in treating conditions associated with bone deficits. The compounds can be administered to vertebrate subjects alone or in combination with additional agents that promote bone growth or that inhibit bone resorption. They can be screened for activity prior to administration by assessing their ability to effect the transcription of a reporter gene coupled to a promoter associated with a bone morphogenetic protein and/or their ability to stimulate calvarial growth in model animal systems.

Claims

1. A method to treat a condition in a vertebrate animal characterized by a deficiency in, or need for, bone growth replacement and/or an undesirable level of bone resorption, which method comprises administering to a vertebrate subject in need of such treatment an effective amount of a compound of the formula:

space="preserve" listing-type="equation">Ar.sup.1 --L--Ar.sup.2

wherein Ar¹ has the formula;

##STR42## wherein R^a is a non-interfering substituent;

m is an integer of 0-4;

each dotted line represents an optional π

-bond;

each Z is independently N, NR, O, S, CR or CR₂, where each R is independently H or alkyl (1-6C);

X is O, S, SO or SO₂ ;

L is a flexible linker; and

Ar² is a substituted or unsubstituted 6-membered aromatic ring.

2. The method of claim 1 wherein L is a flexible conjugated linker.

3. The method of claim 1 wherein L is selected from the group consisting of a covalent bond, --N═

N--, --RC═

CR--, --RC═

N--, --N═

CR--, --NRCO--, --CONR--, --CR₂ O--, and --CR₂ NR-- where each R is independently H or alkyl (1-6C).

4. The method of claim 1 wherein Ar² is ##STR43## where R^b is a non-interfering substituent and n is an integer from 0 to 5.

5. The method of claim 4 wherein Ar² is unsubstituted phenyl.

6. The method of claim 1 wherein said compound is 59-0008 and has the formula:

##STR44##

7. The method of claim 1 wherein said condition is osteoporosis, bone fracture or deficiency, primary or secondary hyperparathyroidism, periodontal disease or defect, metastatic bone disease, osteolytic bone disease, post-plastic surgery, post-prosthetic joint surgery, or post-dental implantation.

8. The method of claim 1 which further comprises administering to said subject one or more agents that promote bone growth or that inhibit bone resorption.

9. The method of claim 8 wherein said agents are selected from the group consisting of bone morphogenetic factors, anti-resorptive agents, osteogenic factors, cartilage-derived morphogenic proteins, growth hormones, and differentiating factors.