Pentaerythritol derivatives, their production and use and...

Details Pentaerythritol derivatives, their production and use and... Pentaerythritol derivatives, their production and use and...

1999-06-08

2001-01-30

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S506000, C558S483000, C558S484000

Reexamination Certificate

active

06180664

ABSTRACT:

FIELD OF APPLICATION OF THE INVENTION
The present invention relates to novel pentaerythritol derivatives, to the preparation and use thereof, especially as drugs, and to intermediates for the synthesis thereof.
KNOWN TECHNICAL BACKGROUND
Organic nitric acid esters 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), isosorbide-5-mononitrate (ISMN) (DE-OS-2221080 DE-OS-2751934DE-PS-3028873, DE-OS-2903927, DE-OS-3102947, DE-OS-3124410, EP-A1-045076, EP-A1-057847, EP-A1-059664, EP-A1-064194, EP-A1-067964, EP-A1-143507, U.S. Pat. No. 3,886,186, U.S. Pat. No. 4,065,488, U.S. Pat. No. 4,417,065, U.S. Pat. No. 4,431,829), isosorbide dinitrate (ISDN) (L. Goldberg, Acta Physiolog. Scand. 15, 173 (1948)), propatyl nitrate (Medard, Mem. Poudres 35: 113 (1953)), trolnitrate (FR-PS 984523) or nicorandil (U.S. Pat. No. 4,200,640) and similar compounds are vasodilators, some of which have been used very widely for decades as major drugs in the therapy of the indication angina pectoris or ischaemic heart disease (IHD) (Nitrangin®, Pentalong®, Monolong®, etc.). Other pentaerythrityl nitrates and their preparation have likewise 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, for example SPM 3672 (N-[3-nitratopivaloyl]-L-cysteine ethyl ester) (U.S. Pat. No. 5,284,872) and derivatives thereof or 1,4-dihydropyridine derivatives (WO-A1-92/02503), have a comparable and improved pharmacological efficacy when used in the above-mentioned areas of indication. In addition to the applications of nitrosating substances which have been known for many years, their use for the treatment and prevention of diseases caused by pathologically increased concentrations of sulfur-containing amino acids in body fluids has been described. These pathological conditions, brought about by congenital or acquired defects in the metabolism of these amino acids and characterized by increased blood and urine concentrations of said amino acids (homocystinuria), are collectively described by the term homocysteinaemia (WO-A1-92/18002). Other uses of the above substances have recently been described, for instance as endothelium-protecting agents (DE-A1-4410997), agents for the treatment of pathologically increased intraocular pressure (WO-A1-95/13812), agents for the treatment of dysmenorrhoea, dysfunctional uterine bleeding, premature labour or after-pains by reducing the uterine contractility (WO-A1-95/13802), agents for the treatment of menopausal symptoms (WO-A1-95/13800) or agents for the treatment of erectile dysfunctions (Merfort, M{umlaut over (u)}nch. Med. Wochenschr. 138 (1996), 504-507; Gomaa et al., Br. Med. J. 312 (1996), 1512-1515).
On the one hand, the hitherto known organic nitric acid esters have a number of associated therapeutic disadvantages. Thus, for example, it is necessary to observe the so-called nitrate tolerance, i.e. the decrease in the action of nitrate at high dosage or when administering longer-acting nitric acid esters. Side effects such as headache, vertigo, nausea, feeling of weakness, erythema and the danger of a comparatively large drop in blood pressure with reflex tachycardia have likewise been verified (Mutschler, Arzneimittelwirkungen (Drug actions), Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1991). On the other hand, PETN as an active substance possesses a number of outstanding properties, especially occurrence of the above-mentioned side effects to only a small extent, if at all, justifying the preferential use of this compound as a drug over other organic nitric acid esters (series of publications entitled “Pentaerythrityltetranitrat” (“Pentaerythrityl tetranitrate”), Dr. Dietrich Steinkopff Verlag, Darmstadt, 1994 to 1996).
The galenical processing of organic nitric acid esters to pharmaceutical formulations for the treatment of angina pectoris or ischaemic heart disease are generally known. It is carried out in accordance with the working procedures and rules generally familiar to those skilled in the art of pharmaceutics, the choice of which technologies to apply and which galenical adjuncts to use depending primarily on the active substance to be processed. Questions of its physicochemical properties, the chosen form of administration, the desired duration of action and the avoidance of drug/adjunct incompatibilities are of particular importance here. Especially peroral, parenteral, sublingual or transdermal administration, in the form of tablets, coated tablets, capsules, solutions, sprays or plasters, is described for drugs indicated for angina pectoris or ischaemic heart disease (DD-A5-293492, DE-AS-2623800, DE-OS-3325652, DE-OS-3328094, DE-PS-4007705, DE-OS-4038203, JP patent application 59/10513 (1982)).
A 1-alkyl-2-acetyl ether analogue of phosphatidylcholine of the formula
H
3
C—CO—O—CH(CH
2
—O—(CH
2
)
15
—CH
3
)—CH
2
—O—PO
2
—O—CH
2
—CH
2
—N
+
(CH
3
)
3
,
which is a platelet activation factor, is capable of inducing platelet aggregation and vasodilation even at an extremely low concentration of 0.1 nM in the blood (Stryer, Biochemie (Biochemistry), Spektrum der Wissenschaften, Heidelberg, 1990).
The possibility of using organic nitric acid esters as explosives has likewise been known for a long time (Ullmanns Encyklop{umlaut over (a)}die der technischen Chemie (Ullmanns Encyclopaedia of Chemical Technology), vol. 16, 3rd edition, Urban & Schwarzenber, Munich-Berlin, 1965).
DESCRIPTION OF THE INVENTION
The object of the invention is to provide novel compounds derived from pentaerythritol which have pharmacologically advantageous actions, in particular with the greatest possible retention of the properties characteristic of pentaerythrityl tetranitrate and superior to those of other nitrates.
The object of the invention is achieved by compounds of general formula I:
in which
R
1
, R
2
, R
3
are identical to or different from one another and are CH
2
—ONO
2
, CH
2
—OR
4
or R
5
, at least one of the substituents R
1
to R
3
being R
5
,
R
4
is H or C
1
- to C
6
-alkanoyl,
R
5
is COR
6
,
R
6
is OH, OR
7
, NH
2
, NHR
7
, NR
7
2
, N
+
R
7
3
X, NR
8
, NR
9
R
10
, NR
11
R
12
or NH—NH
2
,
R
7
is linear or branched C
1
- to C
6
-alkyl, linear or branched C
1
- to C
6
-alkenyl, aryl, aralkyl, heteroaryl or heteroaralkyl,
R
8
is C
1
- to C
6
-alkylidene,
R
9
, R
10
are different from one another and are R
7
,
R
11
, R
12
are identical to or different from one another and are NR
7
2
, N
+
R
7
3
X
−
or NR
8
, and
X is a halogen or a group capable of anion formation, ps and therapeutically acceptable salts thereof.
or those in which
R
4
is H or C
1
- to C
6
-alkenoyl, and
R
6
is OH, OR
7
, NH
2
, NHR
7
, NR
7
2
or N
+
R
7
3
X
−
, i.e. especially the esters and mixed esters, amides, hemiamides, amidoesters and ammonium salts.
Other preferred embodiments are compounds having one, two and three hydrophilic groups. This relates in particular to the metal and ammonium salts, esters, amides and hydrazides of carboxylic acids. Particularly preferred compounds are those of formulae VIII to XIII:
especially 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid, 2,2-bis(nitryloxymethyl)malonic acid and 2-carboxy-2-nitryloxmethlmalonic acid.
The readily accessible nitric acid esters of pentaerythritol are used as starting compounds; for the preparation of said esters, reference is made expressly to the process of partial denitration of pentaerythrityl tetranitrate by means of hydrazine (Simecek, Coll. Czech. Chem. Comm. 27 (1962), 363 and U.S. Pat. No. 3,408,383). Another method is the nitration of pentaerythritol to the trinitrate, followed by its hydrazinolysis to pentaerythrityl dinitrate and mononitrate and by chromatographic separation of the mixture formed. Other starting compounds used are 2,2-bis(hydroxymethyl)malonic acid (Gault, Roesch, C. R. Hebd. S{acute over (e)}ances Acad. Sci. (1934

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