Stable salts of novel derivatives of 3,3-diphenylpropylamines

• US 6,858,650 B1
• Filed: 11/15/2000
• Issued: 02/22/2005
• Est. Priority Date: 11/16/1999
• Status: Expired due to Term

• Current Assignee: UCB Pharma GmbH (UCB SA)
• Original Assignee: Schwarz Pharma Ag (Schwarz Pharma)
• Inventors: Meese, Claus
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Tucker, Zachary C.
• Application Number:
  US10/130,214
• Time in Patent Office: 1,560 Days
• Field of Search: 514/530, 514/531, 514/534, 514/548, 514/551, 560/61, 560/122, 560/123, 560/124, 560/138, 560/142, 560/250, 560/37, 560/18, 560/42, 560/140, 564/319
• US Class Current: 514/530
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/06 Anti-spasmodics
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 215/54 linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
• CPC Class Codes: C07C 219/28 having amino groups bound to acyclic carbon atoms of the carbon skeleton
• CPC Class Codes: C07C 229/38 having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton

Abstract

The present invention concerns highly pure, crystalline, stable compounds of novel derivatives of 3,3-diphenylpropylamines in the form of their salts, a method for the manufacture and highly pure, stable intermediate products.

The method is in particular characterized by regio- and chemoselectivity and high yield. Salts of phenolic monoesters of 3,3-diphenylpropylamines are provided, that are particularly well-suited for use in pharmaceutical formulations. Preferred compounds are R-(+)-2-(3-diisopropylamino-1-phenyl-propyl)-4-hydroxymethylphenylisobutyrate ester hydrogen fumarate and R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyrate ester hydrochloride hydrate. Furthermore, stable, crystalline intermediate products that are essential for obtaining the abovementioned salts are provided. A preferred intermediate product is R-(−)-3-(3-diisopropylamino-phenyl-propyl)-4-hydroxy-benzoic acid methyl ester.

Claims

1. Compounds of general formula I

in which R denotes C₁-C₆-alkyl, C₃-C₁₀-cycloalkyl, substituted or unsubstituted phenyl and X⁻

is the acid residue of a physiologically compatible inorganic or organic acid.

2. Compounds in accordance with claim 1, characterised in that X⁻

in each case is an acid ester of hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(−

)-malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+) -tartaric acid, D-(−

)-tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid (N-benzoyl-glycine), aceturic acid (N-aectylglycine), phloretinic acid (3-(4-hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid or orotic acid.

3. Compounds in accordance with claims 1, characterised in that they have general formula 2:

in which R denotes C₁-C₆-alkyl, C₃-C₁₀-cycloalkyl, substituted or unsubstituted phenyl and X⁻

is the acid residue of a physiologically compatible inorganic or organic acid.

4. Compounds in accordance with claim 3, characterised in that X in each case is an acid ester of hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(−

)-malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+)-tartaric acid, D-(−

)-tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid (N-benzoyl-glycine), aceturic acid (N-aectylglycine), phloretinic acid (3-(4-hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid or orotic acid.

5. Compounds in accordance with claims 3, characterised in that they are R-(+)-2-(3-(diisopropylamino-1-phenylpropyl)-4-hydroxymethyl -phenylisobutyrate ester hydrogen fumarate, R-(+)-2-(3-(diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyrate ester-hydrochloride hydrate.

6. Compounds in accordance with claims 3, characterised in that R stands for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-(1-cyclopropyl-methanoyloxy)-phenyl, 4-(1-cyclobutyl-methanoyloxy)-phenyl, 4-(1-cyclohexyl-methanoyloxy)-phenyl or 4-(2,2-dimethyl-propanoyloxy)-phenyl and X⁻

denotes chloride.

21. A method of treating a patient suffering from urinary incontinence, which method comprises the step of administering to said patient an effective amount of a compound according to claim 1.

22. A method of treating a patient suffering from urinary incontinence, which method comprises the step of administering to said patient an effective amount of a compound according to claim 3.

23. A method of treating a patient suffering from urinary incontinence, which method comprises the step of administering to said patient an effective amount of a compound according to claim 5.

24. The method of any one of claims 21-23, wherein the urinary incontinence disorder is urge incontinence.

7. Method for manufacturing compounds of general formula I

in which R denotes C₁-C₆-alkyl, C₃-C₁₀-cycloalkyl, substituted or unsubstituted phenyl and X−

is the acid residue of a physicologically compatible inorganic or organic acid, characterised in that

a) a compound of formula III

is split with a hydrogenation agent to form a compound of Formula V

whereupon

b) the compoud of formula V so obtained is converted with a reducing agent, in order to give a compound of formula VI

which

c) is converted with an acylation agent, in order to obtain a compound of formula A

in which R has the significance stated above, which

d) is converted with a physiologically compatible inorganic or organic acid to form a compound of formula I

in which R denotes C₁-C₆-alkyl, C₃-C₁₀-cycloalkyl, unsubstituted or substituted phenyl and X−

is the acid residue of a physiologically compatible inorganic or organic acid.

8. Method in accordance with claim 7, characterised in that for the manufacture of the compounds of general formula I hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(−

)-malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+)-tartaric acid, D-(−

)-tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid (N-benzoyl-glycine), aceturic acid (N-aectylglycine), phloretinic acid (3-(4-hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid or orotic acid are used.

11. Method in accordance with claims 7, characterised in that as the hydrogenation agent, Raney nickel/H₂ in methanol is preferably used as the solvent.

12. Method in accordance with claims 7, characterised in that for the reducing agent NaBH₄EtOH, preferably LiAlH₄/THF, is used.

13. Method in accordance with claims 7, characterised in that for the acylation agent isobutyrylchloride and for the base triethylamine are used.

9. Method for manufacturing compounds of general formula 2

in which R denotes C₁-C₆-alkyl, C₃-C₁₀-cycloalkyl, substituted or unsubstituted phenyl and X−

is the acid residue of a physiologically compatible inorganic or organic acid, characterised in that

a) a compound of the formula 3

s split with a hydrogenation agent to form a compound of formula 5

whereupon

b) the compound formula 5 so obtained is converted with a reducing agent, in order to give a compound of formula 6

which

c) is converted with an acylation agent, in order to obtain a compound of formula 1

in which R has the significance stated above, which

d) is converted with a physiologically compatible inorganic or organic acid to form a compound of formula 2

in which R denotes C₁-C₆-alkyl, C₃-C₁₀-cycloalkyl, unsubstituted or substituted phenyl and X−

is the acid residue of a physiologically compatible inorganic or organic acid.

10. Method in accordance with claim 9, characterised in that for the manufacture of the compounds of general formula 2 hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-(−

)-malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+)-tartaric acid, D-(−

)-tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (mucic acid), benzoic acid, 4-hydroxybenzoic acid, salicyclic acid, vanillic acid, 4-hydroxycinammic acid, gallic acid, hippuric acid (N-benzoyl-glycine), aceturic acid (N-aectylglycine), phloretinic acid (3-(4-hydroxyphenyl)-propionic acid), phthalic acid, methanesulfonic acid or orotic acid are used.

14. Method in accordance with claims 9, characterised in that a compound of general formula 6 is converted with an equivalent isobutyryl chloride in the presence of triethylamine using one of the respective solvents ethylacetate, dichloromethane, tetrahydrofurane, acetonitrile or toluene regio- and chemoselectively into R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyrate.

15. Method in accordance with claims 9, characterised in that R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyrate ester and fumaric acid or hydrochloric acid are converted with the formation of the respective salt.

16. Method in accordance with claims 9 for the manufacture of R-(+)-2-(3-diisopropylamino-1-phenyl-propyl)-4-hydroxy-methylphenylisobutyrate ester hydrochloride hydrate, characterised in that the phenolic esterification of R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxy-methylphenol (6) is carried out without the addition of an external base, in that solutions of (6) are dropped into solutions of isobutyryl chloride, that contain at least 1 mole equivalent of water, in order to directly obtain a corresponding stable, hydrate-containing hydrochloride.

17. Compound of formula 7

18. A method of manufacture of phenolic monoesters of general formula 1

wherein the method comprises the steps of:

providing a compound of claim 17;

deprotecting the hydroxyl residues of the 4-hydroxy-benzyl alcohol residue; and

acylating the phenol residue.

19. A method of manufacture of salts of phenolic monoesters of general formula 2:

in which R denotes C₁-C₆-alkyl, C₃-C₁₀-cycloalkyl, substituted or unsubstituted phenyl and X⁻

is the acid residue of a physicologically compatible inorganic or organic acid, wherein the method comprises the steps of;

providing a compound of claim 17;

deprotecting the hydroxyl residues of the 4-hydroxy-benzyl alcohol residue; and

acylating the phenol residue.

20. A method of manufacture of R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyrate ester hydrogen fumarate or R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyrate ester hydrochloride hydrate, the method comprising the steps of;

providing a compound of claim 17;

deprotecting the hydroxyl residues of the 4-hydroxy-benzyl alcohol residue; and

acylating the phenol residue.