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木子8210

银虫 (小有名气)

应助: 0 (幼儿园)
金币: 296.3
散金: 8
红花: 1
帖子: 58
在线: 6.2小时
虫号: 721835
注册: 2009-03-13
专业: 天然药物化学

[求助] 求助，谢谢

Description:
This patent application claims the benefit of priority under 35 U.S.C. §119 of German Patent Application No. 199 55 190.1, filed Nov. 16, 1999. German Patent Application No. 199 55 190.1 is incorporated herein in its entirety by reference.
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 manufacturing these and highly pure, stable, intermediate products.
From document PCT/EP99/03212 novel derivatives of 3,3-diphenylproprylamines are known.
These are valuable prodrugn for the treatment of urinary incontinence and other spasmodic complaints, which overcome the disadvantage of the active substances available to date, namely inadequate absorption of the active substance by biological membranes or the unfavourale metabolism of these.
Furthermore these novel prodrugs have improved pharmacokinetic characteristics compared with Oxybutynin and Tolterodin.
Preferred compounds from the group of these novel derivatives of 3,3-diphenylpropylarines are esters of aliphatic or aromatic carboxylic acids with the general formula A referred to below
in which R denotes C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl or unsubstituted or substituted phenyl. These can occur in their optical isomers form as racemic mixtures and in the form of their individual enantiomers.
Compounds with the structure of formula A do, however, have low solubility in water. This restricts their oral bioavailability.
Finally, monoesters of the structure, as shown in formula A, have a tendency towards intermolecular transesterification. During long periods of storage, therefore, as the content of the compounds with the structure of general formula A drops an increase in diesters and free diol can be detected.
Basically salts of the compounds of general formula A can be obtained if solutions of the compounds of formula A (base component) are purified with solutions of acids in suitable solvents, but the salts obtained in the form of solid matter can prove to be altogether amorphous and/or hygroscopic and cannot be directly crystallized from the normal solvents either. Such salts have inadequate chemical stability to be galenically processed as valuable pharmaceutically active substances.
Surprisingly, it has now been found that the abovementioned disadvantages can be avoided if compounds with the structure of general formula A, once they have been prepared under a special reaction process, are converted with a physiologically compatible inorganic or organic acid with general formula H-X, in which − X represents the respective acid residue, into their respective salt with general formula I.
The problem for the present invention is therefore to provide highly pure, crystalline, stable compounds of novel derivatives of 3,3-diphenylpropylamines in the form of their salts, that avoid the stated disadvantages and are well suited to use in pharmaceutical-technical formulations and can be processed into these.
A further problem for the present invention is to provide a method for manufacturing such highly pure, crystalline, stable compounds in the form of their salts, as well as highly pure, stable intermediate products.
The final problem for the invention is to provide a method for manufacturing the abovementioned compounds with which a high yield of the products of the process and the respective intermediate products can be obtained chemo- or regioselectively.
This problem is solved in that highly pure, crystalline, stable compounds of the 3,3-diphenylpropylamines in the form of their salts with general formula I are provided,
in which R denotes C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, substituted or unsubstituted phenyl and X − is the acid residue of a physiologically compatible inorganic or organic acid.
In accordance with a design of the invention the salts of general formula I can contain the respective acid residue X − of the acids mentioned below:
•
o 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.
Preferred compounds of the present invention are the salts
•
o R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hy droxymethylphenylisobutyrate ester hydrogen fumarate and
o R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hy droxymethylphenylisobutyrate ester hydrochloride hydrate.
Furthermore, compounds are preferred in which R stands for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-(1-cyclo-propyl-methanoyloxy)-phenyl, 4-(1-cyclobutyl-methanoyloxy)-phenyl, 4-(1-cyclohexyl-methanoyloxy)-phenyl or 4-(2,2-dimethyl-propanoyloxy)-phenyl and X denotes chloride.
Particular preference is for [(R)-3-(2-{1-[4-(1-cyclopropyl-methanoyloxy)-phenyl]-methano yloxy}-5-hydroxymethyl-phenyl)-3-phenyl-propyl]-diisopropyl- ammonium chloride, [(R)-3-(2-{1-[4-(1-cyclobutyl-methanoyloxy)-phenyl]-methanoy loxy}-5-hydroxymethyl-phenyl)-3-phenyl-propyl]-diisopropyl-a mmonium chloride, [(R)-3-(2-{1-[4-(1-cyclohexyl-methanoyloxy)-phenyl]-methanoy loxy}-5-hydroxymethyl-phenyl)-3-phenyl-propyl]-diisopropyl-a mmonium chloride, [(R)-3-(2-{1-[4-(2,2-dimethyl-propanoyloxy)-phenyl]-methanoy loxy}-5-hydroxymethyl-phenyl)-3-phenyl-propyl]-diisopropyl-a mmonium chloride, {(R)-3-[2-(1-cyclopropyl-methanoyloxy)-5-hydroxymethyl-pheny l]-3-phenyl-propyl}-diisopropyl-ammonium chloride, {(R)-3-[2-(1-cyclobutyl-methanoyloxy)-5-hydroxymethyl-phenyl ]-3-phenyl-propyl}-diisopropyl-ammonium chloride, {(R)-3-[2-(1-cyclopentyl-methanoyloxy)-5-hydroxymethyl-pheny l]-3-phenyl-propyl}-diisopropyl-ammonium chloride and {(R)-3-[2-(1-cyclohexyl-methanoyloxy)-5-hydroxymethyl-phenyl ]-3-phenyl-propyl}-diisopropyl-ammonium chloride.
In the compounds of the present invention the expression “alkyl” preferably stands for a straight-chain or branched-chain hydrogen group with between 1 and 6 C-atoms. Special preference is for methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl. The expression “cycloalkyl” designates cyclical hydrogen groups, that have between 3 and 10 hydrogen atoms, that may also contain suitable substitutes in place of the hydrogen atoms.
The expression “phenyl” designates a —C 6 H 5 -group that may be substituted or unsubstituted. Suitable substitutes can be, for example, alkyl, alkoxy, halogen, nitro and amine. The expression “alkoxy” has, with respect to the alkyl component, the same meaning as already given above for “alkyl”. Suitable halogens are fluorine, chlorine, bromine and iodine atoms
The present invention also includes methods for manufacturing the compounds in accordance with the invention of general formula I as well as valuable intermediate products.
The method is characterised by chemo- and regioselectivity.
Compounds of General Formula I
in which R denotes C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, substituted or unsubstituted phenyl and X − is the acid residue of a physiologically compatible inorganic or organic acid, are that
•
o a) a compound of formula III
is split with a hydrogenation agent to form a compound of formula V
whereupon
o b) the compound of formula V so obtained is converted with agent, in order to give a compound of formula VI
which
o c) is converted with an acylation agent, in order to obtain 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 C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, unsubstituted or substituted phenyl and X− is the acid residue of a physiologically compatible inorganic or organic acid.
In accordance with the invention, 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-(−

-4-benzyloxy-3-(3-diisopropylamino-1-phenyl-propyl)be nzoic acid methyl ester, the highly pure, crystalline intermediate product R-(−

-3-(3-diisopropylamino-phenyl-propyl)-4-hydroxy-benzo ic acid methyl ester is prepared, which is reduced to R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylp henol, is finally acylated in a suitable manner and is then converted with a physiologically compatible inorganic or organic acid under spontaneous crystallization to the respective highly pure, crystalline, stable salt.
Depending on the acid chloride used, compounds of general formula 1 are obtained,
in which R denotes C 1 -C 6 -alkyl, in particular isopropyl, C 3 -C 10 -cycloalkyl or unsubstituted or substituted phenyl.

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