Guanidinealkyl-1,1-bisphosphonic acid derivatives, process for their preparation and their use

• US 5,395,826 A
• Filed: 11/30/1993
• Issued: 03/07/1995
• Est. Priority Date: 12/02/1992
• Status: Expired due to Fees

• Current Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Original Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Inventors: Lang, Hans-Jochen, Naumann, Christoph, Moura, Anne-Marie, Sandow, Jurgen
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): PEABODY, JOHN
• Application Number:
  US08/159,119
• Time in Patent Office: 462 Days
• Field of Search: 558/159, 558/44, 558/61, 558/62, 514/107
• US Class Current: 514/107
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07F 9/3873 containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
• CPC Class Codes: C07F 9/405 containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
• CPC Class Codes: C07F 9/5728 condensed with carbocyclic rings or carbocyclic ring systems

Abstract

Compounds of the tautomeric formula Ia, Ib or Ic, ##STR1## where R is a radical of the formula ##STR2## are effective compounds for the treatment and prophylaxis of degenerative bone disorders. They are used as pharmaceuticals.

Claims

1. A compound of the tautomeric formula Ia, Ib or Ic ##STR19## a physiologically tolerated salt of the compound of the formula Ia, Ib or Ic;

R has the following meaning therein;

I) a radical of the formula V ##STR20## wherein R¹¹ or R¹² has the following meaning;

a) R¹³ --S(O)_n -- or

b) ##STR21## where R¹³ is

     1) (C₁ -C₆)-alkyl,

2) (C₅ -C₇)-cycloalkyl,

3) cyclopentylmethyl,

4) cyclohexylmethyl,

5) phenyl,

6) phenyl substituted once to three times by

6.1 fluorine atom,

6.2 chlorine atom,

6.3 methyl or

6.4 methoxy,

where n is the integer zero, 1 or 2, where R¹⁴ and R¹⁵ are identical or different and have, independently of one another, the following meaning;

1) hydrogen atom,

2) (C₁ -C₆)-alkyl,

3) phenyl,

4) phenyl substituted once or twice by

4.1 fluorine atom,

4.2 chlorine atom,

4.3 methyl or

4.4 methoxy,

5) --(CH₂)_m -phenyl where m is an integer from 1 to 4, or

6) --(CH₂)_m -phenyl where m is an integer from 1 to 4 and the phenyl radical is substituted once or twice by the radicals indicated in 4.1 to 4.4,

and the other substituent R¹¹ or R¹² in each case means

a) hydrogen atom,

b) halogen atom, selected from the group consisting of fluorine, chlorine, bromine or iodine atom,

c) (C.sub. -C₄)-alkyl,

d) (C₂ -C₄)-alkoxy,

e) phenoxy,

f) phenoxy substituted once to three times by

1) fluorine or chlorine atom,

2) methyl or

3) methoxy,

g) R¹³ --S(O)_n, where n is the integer zero, 1 or 2 and R¹³ has the abovementioned meaning, or ##STR22## where R¹⁴ and R¹⁵ have the abovementioned meaning, or II) a radical of the formula VI ##STR23## wherein R²¹, R²², or R²³ has the following meaning;

a) hydrogen atom,

b) halogen atom, selected from the group consisting of fluorine, chlorine, bromine and iodine atom, or

c) (C₁ -C₁₂)-alkyl, where one of the substituents R²¹, R²² or R²³ may also mean

1) N₃,

2) CN,

3) OH,

4) (C₁ -C₁₀)-alkoxy,

5) R²⁴ --C_n H_2n --O_m,

where m is the number zero or 1, n is the number zero, 1, 2 or 3,

R²⁴ is

1) C_p F_2p+1 where

is the number 1, 2 or 3, as long as

n is the number zero or 1,

2) (C₃ -C₁₂)-cycloalkyl,

3) phenyl,

where the ring system in the radicals

     3) to

     6) is unsubstituted or substituted by a radical from the group

3. A compound of the formula Ia, Ib or Ic as claimed in claim 1, or a physiologically tolerated salt of the compound of the formula Ia, Ib or Ic, where R has the following meaning:

I) a radical of the formula V wherein R¹¹ has the following meaning;

a) fluorine atom,

b) chlorine atom,

c) ##STR24## d) R¹³ --S(O)_n --, where n is zero, 1 or 2, or e) phenoxy,

where R¹² has the following meaning;

a) R¹³ --S(O)_n --, where n is zero, 1 or 2, or

b) ##STR25## II) a radical of the formula VI where R²¹, R²² or R²³ has the following meaning;

a) hydrogen atom,

b) halogen atom, selected from the group consisting of fluorine, chlorine and bromine atom, or

c) (C₁ -C₈)-alkyl,

where one of the substituents R²¹, R²² or R²³ may also mean

1) OH,

2) (C₁ -C₆)-alkoxy,

3) R²⁴ --C_n H_2n --O_m,

where

m is the number zero or 1,

n is the number zero, 1, 2 or 3,

R²⁴ means

1) C_p F_2p+1

where

p is the number 1 as long as

n is the number zero or 1,

2) (C₅ -C₇)-cycloalkyl, or

3) phenyl,

where the ring system in the radical

     3) is unsubstituted or substituted by a radical from the group

3.

5. b ) (C₁ -C₅)-alkyl, straight-chain or branched. 3. A compound of the formula Ia, Ib or Ic as claimed in claim 1, where R¹¹ has the following meaning:

a) ##STR26## where R¹⁴ and R¹⁵ are identical or different and have, independently of one another, the following meaning

1) hydrogen atom or

2) (C₁ -C₄)-alkyl, or R¹⁴ and R¹⁵ together form a (C₄ -C₇)-alkyl chain, or

b) R¹³ --S-- where R¹³ is

a ) phenyl, or

phenyl, substituted, by chlorine in the para position,

where R¹² has the following meaning;

a) CH₃ --SO₂ --,

b) H₂ N--SO₂ --,

c) phenoxy or

d) phenoxy, substituted by chlorine in the para position,

R⁵, R⁶, R⁷ and R⁸ are identical or different and have, independently of one another, the following meaning

a) hydrogen atom or

b) (C₁ -C₄)-alkyl,

and physiologically tolerated salts of the compound of the formula Ia, Ib or Ic.

7. A pharmaceutical containing an effective amount of at least one of the compounds of the tautomeric formula Ia, Ib or Ic as claimed in claim 1 and/or at least one of the physiologically tolerated salts of a compound of the tautomeric formula Ia, Ib or Ic, in addition to pharmaceutically acceptable and physiologically tolerated ancillary substances and/or excipients, or diluents.

8. A method for the treatment of degenerative disorders of the bone system, wherein said method comprises administering an effective amount of a pharmaceutical composition of claim 5, wherein said degenerative disorder of the bone system is Paget'"'"'s disease, metastatic osteocarcinoma, hypercalcemia or osteoporosis.

2. 1 fluorine atom,

3.2 chlorine atom,

3.3 CF₃,

3.4 methyl,

3.5 methoxy or

3.6 NR²⁵ R²⁶

where R²⁵ and R²⁶ are identical or different and have, independently of one another, the meaning

3.6.1 hydrogen atom or

3.6.2 (C₁ -C₄)-alkyl, or

R⁵, R⁶, R⁷ and R⁸ are identical or different and have, independently of one another, the following meaning

a) hydrogen atom,

b) (C₁ -C₅)-alkyl, straight-chain or branched, or

c) phenyl.

4. 1 fluorine atom,

3.2 chlorine atom,

3.3 CF₃,

3.4 CH₃ or

3.5 methoxy, or

R⁵, R⁶, R⁷ and R⁸ are identical or different and have, independently of one another, the following meaning

a ) hydrogen atom,

6. Tetraethyl 2-[(3,5-dichlorobenzoyl)-(aminoiminomethyl)amino]ethane-1,1-bisphosphonate and 2-[(3,5-dichlorobenzoyl)-(aminoiminomethyl)amino]ethane-1,1-bisphosphonic acid.