Pharmaceutical formulations

Details Pharmaceutical formulations Pharmaceutical formulations

1999-07-06

2001-02-06

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C562S015000, C514S120000, C514S134000

Reexamination Certificate

active

06184214

ABSTRACT:

This invention relates to certain amide derivatives of phosphoenolpyruvate (PEP), particularly amide derivatives their uses particularly in preventing ischemic damage to cells, and a method of synthesis for certain amide derivatives and for PEP.
An ischaemic insult results when the blood flow to an organ of the body is insufficient relative to local needs, such that the resulting oxygen supply is greatly reduced. This can result in ischemic damage to the cells and, if the ischaemia is prolonged, to the eventual death of the organ. Ischemia is usually the result of a disease of the blood vessels, such as the arteries supplying the heart, but is also induced during cardiac surgery, involving coronary artery bypass grafting or valve replacements and also transplant operations, typically heart transplants.
Phosphoenolpyruvate (PEP) is a glycolytic substrate which combines with adenosine diphosphate (ADP) to form pyruvate and adenosine-5′-triphosphate acid (ATP), catalysed by the enzyme pyruvate kinase. It is an exergonic reaction which is irreversible under intracellular conditions, requiring Mg
++
as a cofactor and an alkali-metal cation (e.g. K+) as a physiological activator. The enzyme is activated by increases in glycolytic intermediates such as fructose 1,6-bisphosphate or PEP, or by low ATP concentrations, and is inhibited by high ATP concentrations or when aerobic metabolites such as fatty acids or acetyl CoA are available.
WO83/02391 relates to a pharmaceutical composition for parental administration for preventing and treating ischemic cell damage which comprises a water soluble salt of PEP and a water soluble salt of ATP. Areas of application for the PEP/ATP composition are given as a perfusion and preservation solution for use in open heart surgery and other organ transplants, and for treating ischemic brain and heart damage as a result of heart failure, drowning or drug overdose.
Other scientific publications reporting on the PEP/ATP composition by the same inventors are: Eur. Surg. Res. 15: 200-207 (1983); Thorac. Cardiovasc. Surgeon 34: 104-109, (1986); and Scand. J. Thor. Cardiovasc. Surg. 21: 245-249, (1987). In these papers it is reported that the combination of PEP and ATP in a cardioplegic solution provides better post-ischemic recovery of function (in rat hearts) than PEP alone, but is no better than ATP alone. In J. Reconstructive Microsurgery Vol. 11, no. 6 (November 1995) a PEP/ATP infusion was found to reduce ischemia—repurfusion injury in rabbit skeletal muscle. In another investigation (British J. Plastic Surgery; 42; 675-681 (1989)) it was found that a composition of PEP and ATP or the free radical scavenger SOD, may be useful in the clinical treatment of failing ischemic skin flaps.
PEP has also been suggested to have applications in other areas. Thus, it may be useful in the treatment of physical or mental fatigue (FR-A-3246) in circulatory insufficiencies, as an anticalculus agent (U.S. Pat. No. 4,826,675), as a cosmetic agent in skin preparations, as an anti-tumour agent, and as an agent to enhance the viability of stored blood (EP-A-275198).
In Biochemistry, vol. 11, no. 3 (1972), p338-345, various derivatives of PEP were synthesised and tested as a potential substrate for pyruvate kinase and for enolase. Among the derivatives tested was the dicyclohexylammonium (CHA) salt of &agr;-(Dihydroxyphosphinyloxy)acrylamide, i.e. CH
2
═C[C(O)NH
2
]—OP(O)(OH)
2
:2CHA, but it was found that this salt was neither a pseudosubstrate for pyruvate kinase nor a very good competitive inhibitor with respect to phosphoenolpyruvate in the (tested) pyruvate kinase reaction. The synthesis for the dicyclohexylammonium salt as above was given on page 340. The synthetic method used was as follows:
CH
2
═CH—CN---(H
2
O
2
/NaOH)-->CH
2
-CH—C(O)NH
2
--(HBr)-->BrCH
2
—CH(OH)—C(O)NH
2
---(CrO
3
)--->BrCH
2
—C(O)—C(O)NH
2
--(P(OCH
2
—Ph)
3
)-->CH
2
═C[C(O)NH
2
]—OP (OCH
2
Ph)
2
---(1.H
2
/Pd; 2.2CHA)--->CH
2
═C[C(O)NH
2
]—OP(O)(OH)
2
*2CHA i.e. PEP-amide*2CHA (CHA=cyclohexylamine: C
6
H
11
NH
2
) the actual structure being a salt.
The following other amide derivatives of PEP have been disclosed:
CH
2
═C[C(O)OH]NHP(O) (OH)
2
, Biorganic and Medical Chemistry Letters, no. 3, no. 8, p1615-1618 (1993) (Shani et al); CH
2
═C[C(O)OEt]OP(O) (NMe
2
)
2
, CH
2
═C[C(O)OEt]OP(O)MeNMe
2
CH
2
═C[C(O)OEt]OP(O)OMeNMe
2
; Tetrahedron Letters, Vol. 31, no. 8, p4471 (1990) (Despax et al); CH
2
═C[OP(OH)(OEt)H]C(O)NHR
1
where R
1
=Pr or Ph, J. Am. Chem. Soc., Vol. 106, p4017-4020 (1984) (Kluger et al).
There are various syntheses of PEP given in the prior art, such as given in WO83/02391 (see above), and Russian patent no. 2043358 (application no. 92008062/04). In this latter synthesis PEP is formed by oxidative halophosphorylation of a derivative of propenoic acid with PCl
3
/O
2
, followed by dehalogenation of the product then hydrolysis to PEP.
We have now found analogues of PEP as shown in Figure (1) below which have good pharmacological activity; particularly for the prophylaxis or treatment of conditions associated with ischemia:
wherein Z=represents O
Y=represents NR
1
R
2
wherein
R
1
and R
2
are independently H, alkyl, alkenyl, alkoxy (except where applied to OR
1
) cycloalkyl, aryl, or aralkyl
Z
1
and Z
2
are independently OR
1
and pharmacologically acceptable salts thereof.
The compounds of formula 1 and salts thereof are hereinafter “compounds of the invention”.
A preferred group of compounds are those of formula (2)
wherein R
1
and R
2
are as defined for formula (1).
The more preferred group of compounds within formula (2) is where R
1
and R
2
are independently H or lower (i.e., C
1-5
) alkyl, such as where R
1
is H and R
2
is methyl, R
1
is H and R
2
is ethyl, or where R
1
and R
2
are both methyl or ethyl.
The most preferred compound is the primary amide of formula (2) (i.e. where R
1
and R
2
are both H) and salts thereof, particularly the potassium salt, such as the monopotassium salt. The IUPAC name compound is:
2-(dihydroxyphosphoryloxy)prop-2-enoic amide (otherwise known as pyruvic amide enol phosphate). The structure of this compound is shown in formula 3 and hereafter is referred to as “the compound of formula 3” or “compound 3”.
By alkyl we include straight and branched chain alkyl groups and the term lower alkyl covers straight and branched alkyl groups having from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, and hexyl.
Alkenyl refers to an unsaturated or partially saturated hydrocarbon group containing from 2 to 7 carbon atoms which may be straight or branched.
By alkoxy we mean to include alkoxy groups having up to 6 carbon atoms.
Cycloalkyl refers to a hydrocarbon ring having up to 7 carbon atoms.
Aryl refers to any benzenoid aromatic group but preferably phenyl.
Aralkyl refers to an aryl group substituted with one or more alkyl groups.
Preferably the compounds of the invention are administered along with ATP, particularly in the treatment of conditions associated with ischemia.
Examples of physiologically acceptable salts of the compounds of formula (1) and physiologically acceptable derivatives thereof include salts derived from an appropriate base, such as an alkali metal (for example, sodium and potassium), an alkaline earth (for example, magnesium), ammonium and NX
4
+
(wherein X is C
1-4
alkyl) Physiologically acceptable salts of an amino group include salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids, organic sulphonic acids, such as methanesulphonic, ethanesulphonic, benzenesulphonic and p-toluenesulphonic acids and inorganic acids, such as hydrochloric, sulphuric, phosphoric and sulphamic acids. Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in

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