Pentaerythrite derivatives, the production and use thereof...

Details Pentaerythrite derivatives, the production and use thereof... Pentaerythrite derivatives, the production and use thereof...

2000-02-29

2002-04-02

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S534000, C514S568000, C548S132000, C560S169000, C562S564000

Reexamination Certificate

active

06365611

ABSTRACT:

SCOPE OF THE INVENTION
The invention presented here relates to new pentaerythritol derivatives, their preparation and use and intermediates for synthesis of the same, which are used in particular as pharmaceutical products.
KNOWN TECHNICAL BACKGROUND
Organic nitrates such as glycerol trinitrate (GTN) (Murrel, Lancet: 80, 113, 151 (1879)), pentaerythrityl tetranitrate (PETN) (Risemann et al., Circulation, Vol. XVII, 22 (1958), U.S. Pat. No. 2,370,437), isosorbitol-5-mononitrate (ISMN) (DE-OS-22 21 080, DE-OS-27 51 934, DE-OS-30 28 873, DE-PS-29 03 927, DE-OS-31 02 947, DE-OS-31 24 410, EP-A1-045 076, EP-A1-057 847, EP-A1-059 664, EP-A1-064 194, EP-A1-067 964, EP-A1-143 507, U.S. Pat. Nos. 3,886,186, 4,065,488, 4,417,065, 4,431,829), isosorbitol dinitrate (ISDN) (L. Goldberg, Acta Physiolog. Scand. 15, 173 (1948)), propatyl nitrate (Médard, Mem. Poudres 35: 113 (1953)), trolnitrate (FR-PS-984 523) or nicorandil (U.S. Pat. No. 4,200,640) and similar compounds are vasodilators, some of which have been used for many decades for the selective treatment of angina pectoris and ischaemic heart disease (IHK) with a very wide therapeutic application (Nitrangin®, Pentalong®, Monolong®, etc.). Other pentaerythrityl nitrates and their preparation have also been described (Simecek, Coll. Czech. Chem. Comm. 27 (1962), 363; Camp et al., J. Am. Chem. Soc. 77 (1955), 751). Organic nitrates of a more recent type such as for example SPM 3672 the ethyl ester of (N-[3-nitratopivaloyl]-L-cysteine) (U.S. Pat. No. 5,284,872) and its derivatives are intended to have comparable and improved pharmacological efficacy when used in the areas mentioned above. Furthermore, the preparation of 3-nitryloxy-2,2-bis-(nitryloxymethyl)propionic acid and its methyl ester (Nec. Chem. Prum. (1978), 28 (2), 84) has also been disclosed. The galenic processing of organic nitrates to give pharmaceutical preparations for the treatment of angina pectoris or ischaemic heart disease is generally well recognised. It is performed using methods of operation and rules which are generally familiar to a person skilled in the pharmaceutical field, wherein the choice of technologies to be used and the galenic auxiliary agents to be used are governed in the first instance by the active substance to be processed. In this case questions relating to its chemico-physical properties, in particular the explosive properties which are known to be associated with organic nitrates, which requires the use of special safety precautions and special processing technologies, the form of application chosen, the period of activity required and the avoidance of medicament/auxiliary agent incompatibilities are of particular importance. When using medicaments for angina pectoris or ischaemic heart disease, peroral, parenteral, sublingual or transdermal application in the form of tablets, dragees, capsules, solutions, sprays or patches has been described in particular (DD-A5-293 492, DE-AS-26 23 800, DE-OS-33 25 652, DE-OS-33 28 094, DE-PS-40 07 705, DE-OS-40 38 203, JP application 59/10513 (1982)). In addition to use as a nitrosing substance which has been disclosed for many years, their use for the treatment and prevention of illnesses which are caused by pathologically elevated concentrations of sulfur-containing amino acids in the body fluids has also been described. These conditions, caused by congenital or acquired defects in the metabolism of these amino acids and which are characterised by elevated blood and urine concentrations of said amino acids (homocystinurea), are combined under the expression homocystinanaemia (WO-A1-92/18002). The use of specific organic nitrates as endothelial protective agents (DE-A1-44 10 997) and as agents for the treatment of erectile disfunction (WO-A1-96/32118) has been described recently. Furthermore, it is known that 3-amino-1,2,4-oxadiazol-5-ones are suitable as proactive drugs for hydroxyguanidines (Rehse et al. Arch. Pharm. Pharm. Med. Chem. 329, 535 (1996)). On the one hand, the currently disclosed organic nitrates (esters of nitric acid) are associated with a number of therapeutic disadvantages. Thus, for instance, so-called nitrate tolerance is observed; i.e. the decrease in the effect of nitrate at high dosage or when administering nitrates with a long-term effect. Side effects such as headaches, nausea, dizziness, feeling weak, reddening of the skin and the risk of a large drop in blood pressure with reflectorial tachycardia have also been demonstrated (Mutschler, Arzneimittelwirkungen, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1991). On the other hand, PETN has a number of outstanding properties as an active substance which is the reason for the preferred use of this compound as a pharmaceutical product as compared with other organic nitrates, wherein however restricted bioavailability of this active substance has been observed (set of monographs “Pentaerythrityltetranitrat” Dr. Dietrich Steinkopff Verlag, Darmstadt, 1994 to 1995). Lipophilic organic nitrates are generally active for only a short time due to a relatively rapid metabolic degradation to give less active or inactive biotransformation products (Bonn, “Pharmakokinetik organischer Nitrate” in “Pentaerythrityltetranitrat”, Dr. Dietrich Steinkopff Verlag, Darmstadt, 1995).
DESCRIPTION OF THE INVENTION
The object of the invention is to provide new compounds derived from pentaerythritol with pharmacologically advantageous effects.
The object of the invention is achieved by the new compounds of the formulae (I) and (III)
(O
2
NOCH
2
)
m
C(CH
2
OH)
n
(CH
2
COR
1
)
o
(COR
1
)
p
  (I)
(O
2
NOCH
2
)
m
C(CH
2
OH)
n
(CH
2
COR
3
)
o
(COR
3
)
p
  (III)
wherein R
1
represents a group of the formula (II),
and R
3
represents a group of the formula (IV)
R
2
represents a C
1
to C
20
alkyl group, in particular methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl, n-hexyl, n-octyl, benzyl, cyclohexylmethyl, 4-chlorobenzyl, 4-nitrobenzyl, 2-phenylethyl, 3-phenylpropyl, 3-cyclohexylpropyl, 3-phthalimidylpropyl, 1-naphthylmethyl, cinnamyl, 5-ethoxycarbonylbutyl, 3-aminopropyl, —(CH
2
)
3
CH(NHCOCH
3
)COOH, —(CH
2
)
3
CH(NHCOCH
3
)COOCH
3
, or 1,6-hexane-bis and m to p are integers, for which the following is true: m+n+o+p=4, m≧1 and o and/or p≧1. Compounds in which R
2
represents n-butyl, n-pentyl, n-hexyl, benzyl, 2-phenylether, 3-phenylpropyl, 3-phthalimidylpropyl or 5-ethyoxycarbonylbutyl are preferred.
The starting compounds for synthesising compounds of the formulae (I) and (III) are pentaerythritol or its nitrates, i.e. pentaerythrityl mononitrate (PEMN), pentaerythrityl dinitrate (PEDN), pentaerythyrityl trinitrate (PETriN) and pentaerythrityl tetranitrate (PETN), which are synthetically available in good yields in a manner known per se (Simecek, Coll. Czech. Chem. Comm. 27 (1962), 363; Camp et al., J. Am. Chem. Soc. 77 (1955), 751). The compounds PEMN, PEDN and PETriN are converted into the corresponding tri-, di- or monocarboxylic acids by complete or partial oxidation of any hydroxymethyl groups present, and the corresponding derivatives with nitroxy, hydroxyl and carboxyl functions are optionally obtained from these by partial hydrazinolysis of the corresponding nitrate function. The formation of compounds of the formulae (I) and (III) is performed by methods of synthesis and procedures which are familiar to a person skilled in the art, for example by known ester or amide-forming reactions. Compounds of the formula (IV.1), (FIG. 1), are used as starting materials which are also required and the synthesis of these is described in Rehse et al; Arch. Pharm. Pharm. Med. Chem 329, 535 (1996), wherein reference is now made to the disclosures in this publication, and in which in addition one or two hydrogen atoms in the amino group may be replaced by a suitable leaving group, and also compounds of the formula (V),
in which R
2
is defined in the same way as for formula (I) and R
4
represents H or a suitable leaving group, which are obtainable in good yield from compounds of the formula

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