WO2007110084A1 - Pyrazinic acid copper (i) complex - Google Patents

Pyrazinic acid copper (i) complex Download PDF

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Publication number
WO2007110084A1
WO2007110084A1 PCT/EG2006/000024 EG2006000024W WO2007110084A1 WO 2007110084 A1 WO2007110084 A1 WO 2007110084A1 EG 2006000024 W EG2006000024 W EG 2006000024W WO 2007110084 A1 WO2007110084 A1 WO 2007110084A1
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WO
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Patent type
Prior art keywords
complex
amp
treatment
muscle
fatigue
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Application number
PCT/EG2006/000024
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French (fr)
Inventor
Salah Fathi Hussein
Mohamed Abd El Rahman Sidahmed Goher
Original Assignee
Salah Fathi Hussein
Goher Mohamed Abd El Rahman Si
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00Compounds containing elements of Groups 1 or 11 of the Periodic System
    • C07F1/005Compounds containing elements of Groups 1 or 11 of the Periodic System without C-Metal linkages

Abstract

The present invention provides a process for the preparation of a complex of pyrazinic acid and copper (I) chloride, by dissolving the components in a polar solvent, e.g. water, ethanol, acetone and boiling, allowing the mixture to cool, and stand over several hours to yield the complex [CuCl (C4H5N2CO2) ].2H2O. The present invention provides methods for treatment of Fatigue, Infertility, Weakness of muscles, in human requiring such treatment, comprising administering to say a person, an anti-fatigue, etc., effective amount of the complex having the above formula or a pharmaceutical composition comprising the complex together with a pharmaceutically acceptable carrier, diluent and/or excipient. The concentration of the complex (main ingredient) in the pharmaceutical composition depends on. several factors, e.g. type and degree of disease, age of patient, damage of organ or organs.

Description

Myofertolan A Master Key For Incurable

Diseases

Technical Field Drugs

Background

Copper (I) chloride complex of pyrazinic acid is prepared, characterized by elemental analysis, IR, UV- visible spectra and its crystal structure determined by single crystal diffraction methods for the first time. This compound is found to exhibit a very positive influence as a drug in a pharmaceutical acceptable composition for different incurable diseases, e.g. myopathy or weakness of muscles in general, infertility ,etc. To the best of our knowledge this is the first drug having such effect as given in the following parts .

Duchene dystrophy (DD) is an x linked disorder primarily affecting skeletal muscle , caused by lack of dystrophin - the protein product of DD gene located on XP21. These patients are males who suffer from progressive muscle weakness extending to both cardiac and respiratory muscle failure. DD patients die at the age of 25-30 years old of either respiratory and / or cardiac failures. Females are healthy carriers .Several trials for both drug and genetic treatment did not give satisfactory results.

Male infertility is a multi factorial disease process with a number of potential contributing causes . Considering the majority of male infertility cases are due to deficient sperm production of unknown origin , environmental and mutational factors must be evaluated .

The treatment of male factor infertility is a rapidly developing field. Introduction of microsurgical fertilization techniques allows assisted conception units to treat couples who previously would not have benefited from in vitro fertilization techniques . However these techniques are only used for the minority of sub-fertile men in andrological practice. Many subfertile men are still treated pharmacologically or by sperm selection methods to enhance sperm fertilization ability. Numerous pharmacological compound have been described that enhance sperm motility and thus potentially sperm fertilizing capacity. Sperm motility plays an important role in the normal fertilization process. Poor sperm motility (<50% motile sperm with <2+ forward progression according to WHO protocol ) is considered a major factor in diminished rates of fertilization Medical trials for male non obstructive infertility by hormonal replacement, corticosteroids (in immunes infertility) , mutational therapies but results were not satisfactory. Chronic fatigue is world wide complaint affecting the productivity of a good percentage of the population . Chronic fatigue includes unexplained fatigue, chronic fatigue syndrome and fibromyalgia. In all types of fatigue the complex relieved the muscle pain, increased the physical activity and productivity and associated depression.

Cardiomyopathy is this fatal disease where all clinical trials are just symptomatic treatment for heart failure and the hope for these patients are cardiac transplantation.

Disclosure of the Invention

According to one broad form of the invention there is provided a process for the preparation of pyrazinic acid- copper chloride complex by dissolving the components in a polar solvent e.g. acetone, water, ethanol, ...as a red bright microcrystalline powder.

According to another broad form of the invention there is provided a m comprises administering to say human person an effective amount of the complex in a pharmaceutically acceptable composition with other acceptable vitamins, carriers, diluent and or excipient. The concentration of the complex and other components depends on different factors, e.g. type and reason of weakness of the muscles, age of the patient, etc.

According to another broad form of the invention there is provided a method for treatment of Fatigue . The method comprises administering to say a human person the copper chloride-pyrazinic acid complex and /or a pharmaceutically acceptable composition of the complex . The concentration of the complex in the pharmaceutically acceptable form is variable and depends on several factors, e.g. age of the patient, reason of fatigue, etc. According to a further broad form of the invention there is provided a method for treatment of infertility in men, The method comprises administering to say a man the pyrazinic acid complex or apharmaceutically acceptable composition containing the complex, acceptable carrier, diluent, excipient. Solid dosage forms for oral administration may include capsules, tablets, pills and granules, In such solid dosage forms, the pyrazinic acid-copper chloride complex may be admixed with at least one inert diluent

Such dosage forms may also comprise , as is normal practice, additional substances other than inert diluents, e.g. ascorbic acid, other vitamins, etc. In the case of capsules the dosage forms may also comprise buffering agents

Best: mode and other modes for carrying out the invention

An effective amount of a copper chloride -pyrazinic acid complex, to achieve a desired level of improving fatigue, infertility, weakness of muscles, etc., is administered orally to a human person. The composition for this purpose is presented as capsules, tablets ,etc. The specific dose level for a particular person depends on a variety of factors including age, general health, sex, diet, body weight, time of administration, as will be mentioned in details for each case.

Claims

CIAIMS
1. Preparation, physical proper-ties and crystal structure of [CuCl (pyrazinic acid) 2] .2H2O complex
Preparation of the complex
A suspension of copper (I) chloride in aqueous/acetone solution (1:1 v/v) was added drop wisely to pyrazinic acid (31 g) dissolved in boiled acetone (1 L) with continuous boiling and stirring until a clear reddish solution mixture obtained. The final mixture was cooled and allowed to stand over several hours to deposit a red microcrystalline precipitate of the complex. The precipitate was filtered off at the pump and washed several times with acetone and dried in vacuum. Yield is about 65%. Analytical data: Found: C 31.1.; H 3.0, N 14.0; Cl 9.7; Cu 16.6%. Calculated for C10H12 N4CuCl: C 31.2; H 3.2; N 14.1; Cl 9.3 Cu 16.6 %..
Physical proper-ties:
Color : bright red-brown microcrystalline powder Stability: the complex is sufficiently stable when well-dried
Solubility: the complex is insoluble in non polar solvents, e.g. benzene, carbon tetrachloride, etc., and insoluble in polar solvents: water, methanol, ethanol, acetone, but soluble in these solvents upon heating in inert atmosphere, otherwise oxidation takes place. UV-visible spectra: Solid sample mulled in nujol shows an absorption band due to Cu-L Charge Transfer transition at 425 nm.
Infrared spectrum: exhibits &#957; C=O band around 1700 cm-1, and &#957; C-O around 1350 cm-1 (KBr pellets) The composition of the complex formulated as [CuCl (pyrazinic acid) 2]. 2H2O was confirmed by the single crystal diffraction.
X-ray crystallography: empirical formula : C10H12ClCuN4O6, formula weight: 383.24,
Orthorhombic, space group P21212, unit cell dimensions: a = 30.693(6)&#506;, b = 3.6405 (7) &Aring; , c = 6.0918(12) &Aring;, alpha = 90&#730;, beta = 90&#730;, gamma = 90&#730; .volume = 680.7(2) &#506;, Z = 2. Density, calc. = 1.837 itim-1. The X-ray single crystal data were collected on a modified STOE four-circle diffract meter. Crystal size 0.35 x 0.24 x 0.15 mm. Graphite mono achromatized Mo K&#945; radiation ( &#955; = 0.71069 &Aring;) with the w scan technique was used to collect the data set. The accurate unit cell parameters were determined and refined by least-squares method. The structure was solved by direct methods and refined by full-matrix least squares methods on F2, using SHELXTL /PC V 5.03 program package . Goodness of fit on the F2 is 1.258. Maximum and minimum peaks in the final difference Fourier synthesis were 1.030 and - 1.141 e&#506;-3.
The attached figure shows the asymmetric unit along with the labeling scheme
2.Toxicity of the complex
Seventy two rats (250+/-2.0 g b.wt) were randomly located into 12 groups of 6 rats each
Rats were observed for any toxic symptoms or signs of discomfort . Mortality in each group were recorded with
24 hrs.The LD50 was calculated according to Behecens and karbere (1970)
LD50 (I. P.) (oral) =1104.17 mg/kg
LD50 (intrapperitoneally ) 128 mg/Kg
3. Bioavailability studies on rats
Our study on rats Included five groups ,gr.l control, 2 receiving cu ,gr.2 pyrazinic ,gr3 complex with large dose ,&gr.5 receiving complex with small dose. There was no significant difference between control groups and other groups regarding the liver and , kidney functions . Complete blood picture were done for all groups gr. 4&5 receiving the complex showed increase of lymphocytic count ,but not exceeding the normal range suggesting its role in immune function .Lipid profile for all the groups didn't show significant difference.
4. Clinical trials for treatment of weakness of muscles
The complex used in treatment of muscle weakness for different underlying causes (muscle dystrophies post stroke weakness , ..Clinical improvement in DMS patients is dose dependant ,affected by the age ,weight & degree of dystrophy .When the patient reaches the optimum dose onset of improvement in muscle power is observed within hours of drug intake .
5. Clinical trials in Cardiomyopathy
The complex improved all cases of dilated Cardiomyopathy secondary to Duchenne muscle dystrophy And 80% of cases of dilated cardiomyopathy due to other causes . Improvement is shown both clinically and in the ECHO cardiographic measurements .
6. Male Infertility
Our study included 20 patients ,9 patients azospermic, 6 acino- terato- pyospermia , 5 acino- oligo spermia , seven out of nine patients of azospermic count increased to (1.5-3 millions /hpf ) within 6 weeks of treatment and two of them got healthy babies while the other- Two cases showed no response to treatment ,while oligospermia showed doubling of the count within 1 month of treatment .four cases got also healthy babies . All cases showed significant improvement of motility.
7 Clinical trials for treatment of Fatigue in humans
In all types of fatigue the complex relieved the muscle pain , increased the physical activity and productivity and associated depression The drug improves markedly the agonizing fatigue in cases of parkinsonism ,myositis, disseminated sclerosis..
8.Mechanism of action
The drug showed multiple system effect which suggests a common mechanism of action to link between effect on spermatogenesis effect on muscle weakness, on Immune system and improving cardiac muscle in cardio myopathy patients . We hypothysed that the drug may have a role on stimulating the stem cells present in the various organs to differentiate .ODR hypotheses was proved by studying the effect of the drug both invivo and invitro on the stem cell differentiation. Invivo we measured the stem cell count together with CD8 and CD4 cells before, and at regular intervals of medication .There is a significant decrease in stem cell count with an increase in CD4 and CD8 number with no disturbance of CD4/CD8 Its well known that copper is essential for the proper functioning of copper-dependant enzymes, including cytochrome C oxidase (energy production ) , superoxide dismutase (antioxidant protection) , tyrosinase (pigmentation) , dopamine hydroxylase (catecholamine production) , lysyl oxidase (collagen and elastin formation ) , clotting factor v (blood clotting), and ceruloplasmin (antioxidant protection, iron metabolism ,and copper transport) .
PCT/EG2006/000024 2006-03-27 2006-06-25 Pyrazinic acid copper (i) complex WO2007110084A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EG2006030113 2006-03-27
EG2006030113 2006-03-27

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13000704 US20110183951A1 (en) 2006-03-27 2006-06-25 Copper (1) Complex
US12238001 US20090105207A1 (en) 2006-06-25 2008-09-25 Copper (1) Complex

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9756079B2 (en) 2007-05-30 2017-09-05 Cupp Computing As System and method for providing network and computer firewall protection with dynamic address isolation to a device

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002070496A1 (en) * 2001-03-01 2002-09-12 Consiglio Nazionale Delle Ricerche Nitric oxide donors based on metallic centres

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002070496A1 (en) * 2001-03-01 2002-09-12 Consiglio Nazionale Delle Ricerche Nitric oxide donors based on metallic centres

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9756079B2 (en) 2007-05-30 2017-09-05 Cupp Computing As System and method for providing network and computer firewall protection with dynamic address isolation to a device

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