CA2089959A1 - Use of xanthine derivatives for the treatment of muscle damage after interruption of the blood circulation - Google Patents
Use of xanthine derivatives for the treatment of muscle damage after interruption of the blood circulationInfo
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- CA2089959A1 CA2089959A1 CA002089959A CA2089959A CA2089959A1 CA 2089959 A1 CA2089959 A1 CA 2089959A1 CA 002089959 A CA002089959 A CA 002089959A CA 2089959 A CA2089959 A CA 2089959A CA 2089959 A1 CA2089959 A1 CA 2089959A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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Abstract
Abstract of the disclosure The use of xanthine derivatives for the treatment of muscle damage after interruption of the blood circulation Xanthine derivatives of the formula I
(I) where at least one of the radicals R1 and R3 is a radical of the formula Ia
(I) where at least one of the radicals R1 and R3 is a radical of the formula Ia
Description
HOECHST AXGIENGES~LLSCHAFT HOE 92/F 049 Dr. Th/wo Description The use of xanthine derivatives for the treatment of muscle damage after interruption of the blood circulation A number of oxoalkyl- and hydroxyalkylxanthine~ promote S blood flow and can also be employad for the treatment of disorder~ of muscular energy metabolism as are present, in particular, in cases of mitochondrial myopathy (EP 0 268 585).
Tourniquets axe routinely used in surgery on the extrem-ities in order to obtain an operation area free ~f blood.
Although there are reports that interruptions of blood flow are poRsible for up to three hours, surgeons gener-ally restrict the interruption of blood flow to 90 -120 minutes (Tountas and Bergman, J. Hand. Surg., 1977 2 : 31 ~ 37) because more prolonged i~chemia with sub~e-quent restoration of blood flow leads to a number of types of muscle damage, for example swelling of the muscle fibers, degeneration of the muscle cells, slight sensory and motor damage, destabilization of the membrane of muscle cells, in which case there is disturbance of the intracellular medium, or difficulties in rehabilita-tion. It is known that damage may occur a~ter restoration of blood flow in ischemic tissue in the heart, kidney, intestine and skeletal muscles ( McCord, ~ew England, J. Med., 1985, 312 (3), 159 - 163). To date, no pharma-ceuticals which allow the time of interruption of blood circulation to be prolonged or the disturbances of function caused by the interruption of the blood circula-tion to be significantly reduced are known.
It has now been found that certain xanthine derivatives are suitable for prolonging the tLme of interruption of blood flow, for improving the syndromes which occur after interruption of blood flow and subsequent restoration of blood flow, and for reducing the changes in the intra-compartmental pressure.
20899~9 Interruption of the blood circulation in tissues, organsor extremities occurs, for example, in operations after injuries to the large arteries or vein~, after emergency opexations in case~ of severance of limbs, removal of thrombi or other occlusions in arteries or veins or in tran~plantations, for example of the kidney or heart.
Depending on the duration of the operation, there may then be more or less pronounced disturbances of function of the muscle tissue, which may range from slight dis-turbances to motor deficits, for example paralysis.Partial or brief interruptions of the blood circulation lead as a rule only to reversible damage at the start of the interruption. Intact muscle tissue with a low extra-cellular potassium content and the possibility of com-plete regeneration remains. Surprisingly, experimentalanimals with vascular occlusion in the rear extremities show a rapid recuperation o:E the muscle fibers on treat-ment with the xanthines of the formula I.
The invention therefore relates to the use of at least one xanthine derivative of the formula I
N ~ N
il \ (I) O //~ N--~
in which at least one of the radicals R1 and R3 is a tertiary hydroxyalkyl group of the formula Ia R~
~ ( C H 2 ) n~ C ~ C H3 ~Ia) O H
2 0 ~ 9 in which R4 is an alkyl group with 1, 2 or 3 carbon atoms and n is an integer of 2 - 5 and - if only one of the radicals R1 or R3 is such a tertiary hydroxyalkyl group of the formula Ia - the other radical is a hydrogen atom or an aliphatic hydrocarbon radical R5 which has 1 to 6 car-bon atoms and who~e carbon chain can be interrupted by 1 or 2 oxygen atoms or substituted by an oxo group or by 1 or 2 hydroxyl groups, these oxo and hydroxyl groups being separated by at least 2 carbon atoms from the ring nitrogen, and R2 is an alkyl group with 1 - 4 carbon atoms, for the preparation of pharmaceuticals for the prophylaxis and treatment of muscle damage which may occur af~er interruption of ~he blood circulation.
Xanthine derivatives of the formula I which are preferab-ly used are those in which R2 is methyl or ethyl and/oronly one of the two radicals R1 or R3 is the tertiary hydroxyalkyl group of the formula Ia.
Xanthine derivatives of the formula I which are further-more preferably used are those in which R1 or R3 is t(~-1)-hydroxy-~-1)-methyl]-pentyl, -he~yl or -heptyl.
In addition, xanthine derivatives of the formula I which are preferably u~ed are those in which R1 is t(~
hydroxy-(~-l)-methyl]-pentyl, -hexyl or ~heptyl~ R2 is methyl or ethyl and R3 i6 hydrogen, alkyl or alkoxyalkyl with, in each case, 1 - 4 carbon atoms or hydroxyalkyl with 2 - 5 carbon atoms.
7-Ethoxymethyl-1-(5-hydroxy-5-methylhexyl~3-methylxan-thine is particularly preferably used.
By muscle cells, muscle fibers or muscle tissues are meant all cells, tissues or organs which are capable of contraction, especially smooth or striated muscle tissues, as well as muscle fibers of the heart.
:: 2~99~9 The xanthine derivatives of the formula I are prepared, for axample, by the following process:
Tourniquets axe routinely used in surgery on the extrem-ities in order to obtain an operation area free ~f blood.
Although there are reports that interruptions of blood flow are poRsible for up to three hours, surgeons gener-ally restrict the interruption of blood flow to 90 -120 minutes (Tountas and Bergman, J. Hand. Surg., 1977 2 : 31 ~ 37) because more prolonged i~chemia with sub~e-quent restoration of blood flow leads to a number of types of muscle damage, for example swelling of the muscle fibers, degeneration of the muscle cells, slight sensory and motor damage, destabilization of the membrane of muscle cells, in which case there is disturbance of the intracellular medium, or difficulties in rehabilita-tion. It is known that damage may occur a~ter restoration of blood flow in ischemic tissue in the heart, kidney, intestine and skeletal muscles ( McCord, ~ew England, J. Med., 1985, 312 (3), 159 - 163). To date, no pharma-ceuticals which allow the time of interruption of blood circulation to be prolonged or the disturbances of function caused by the interruption of the blood circula-tion to be significantly reduced are known.
It has now been found that certain xanthine derivatives are suitable for prolonging the tLme of interruption of blood flow, for improving the syndromes which occur after interruption of blood flow and subsequent restoration of blood flow, and for reducing the changes in the intra-compartmental pressure.
20899~9 Interruption of the blood circulation in tissues, organsor extremities occurs, for example, in operations after injuries to the large arteries or vein~, after emergency opexations in case~ of severance of limbs, removal of thrombi or other occlusions in arteries or veins or in tran~plantations, for example of the kidney or heart.
Depending on the duration of the operation, there may then be more or less pronounced disturbances of function of the muscle tissue, which may range from slight dis-turbances to motor deficits, for example paralysis.Partial or brief interruptions of the blood circulation lead as a rule only to reversible damage at the start of the interruption. Intact muscle tissue with a low extra-cellular potassium content and the possibility of com-plete regeneration remains. Surprisingly, experimentalanimals with vascular occlusion in the rear extremities show a rapid recuperation o:E the muscle fibers on treat-ment with the xanthines of the formula I.
The invention therefore relates to the use of at least one xanthine derivative of the formula I
N ~ N
il \ (I) O //~ N--~
in which at least one of the radicals R1 and R3 is a tertiary hydroxyalkyl group of the formula Ia R~
~ ( C H 2 ) n~ C ~ C H3 ~Ia) O H
2 0 ~ 9 in which R4 is an alkyl group with 1, 2 or 3 carbon atoms and n is an integer of 2 - 5 and - if only one of the radicals R1 or R3 is such a tertiary hydroxyalkyl group of the formula Ia - the other radical is a hydrogen atom or an aliphatic hydrocarbon radical R5 which has 1 to 6 car-bon atoms and who~e carbon chain can be interrupted by 1 or 2 oxygen atoms or substituted by an oxo group or by 1 or 2 hydroxyl groups, these oxo and hydroxyl groups being separated by at least 2 carbon atoms from the ring nitrogen, and R2 is an alkyl group with 1 - 4 carbon atoms, for the preparation of pharmaceuticals for the prophylaxis and treatment of muscle damage which may occur af~er interruption of ~he blood circulation.
Xanthine derivatives of the formula I which are preferab-ly used are those in which R2 is methyl or ethyl and/oronly one of the two radicals R1 or R3 is the tertiary hydroxyalkyl group of the formula Ia.
Xanthine derivatives of the formula I which are further-more preferably used are those in which R1 or R3 is t(~-1)-hydroxy-~-1)-methyl]-pentyl, -he~yl or -heptyl.
In addition, xanthine derivatives of the formula I which are preferably u~ed are those in which R1 is t(~
hydroxy-(~-l)-methyl]-pentyl, -hexyl or ~heptyl~ R2 is methyl or ethyl and R3 i6 hydrogen, alkyl or alkoxyalkyl with, in each case, 1 - 4 carbon atoms or hydroxyalkyl with 2 - 5 carbon atoms.
7-Ethoxymethyl-1-(5-hydroxy-5-methylhexyl~3-methylxan-thine is particularly preferably used.
By muscle cells, muscle fibers or muscle tissues are meant all cells, tissues or organs which are capable of contraction, especially smooth or striated muscle tissues, as well as muscle fibers of the heart.
:: 2~99~9 The xanthine derivatives of the formula I are prepared, for axample, by the following process:
3-Alkylxanthines of the formula II
A -N ~ ~ (II) o ~ N N
in which R2 is an alkyl group with 1 to 4 carbon atoms, A is a hydrogen atom, R5 or the radical of the formula Ia and B is a hydrogen atom, R5, benzyl or diphenylmethyl radical, but where at least one of these radicals A and B i~ a hydrogen atom, are alkylate~ in the presence of at least one basic condensing agent or in the form of theix salts in position 1 and/or 7, in one step or ~tepwise, with appropriate alkylating agents of the formula III
X Q (III) in which X is a halogen atom or a sulfonic ester or pho~phoric ester group and Q is a tertiary hydroxyalkyl group of the formula Ia, R5, benzyl or diphenylmethyl xadical, with ~ubsequent reductive elLmination of the radical B
when this is a benzyl or diphe~ylmethyl group, ort where appropriate, hydrolytic elLmination of an alkoxymethyl or alkoxyalkoxymethyl radical from the position of the radical B and reduction of the keto group to the alcohol functionality when A or B i~ n oxoalkyl radical, at a 2~ 5 ~
reaction temperature between 0C and the boiling point of the particular reaction medium used.
The abovementioned reactionq take place under standard conditions in a known manner tEP 0 268 585, US 4 833 146).
The starting materials for the reactions are known or can be easily prepared by methods known from the literature (EP 0 268 585).
The invention also relates to phanmaceuticals which contain at least an effective amount of a xanthine derivative of the formula I, in addition to pharmaceutic-ally suitable and physiologically tolerated excipients, diluents and/or other active and ancillary substances.
The pharmaceuticals according to the invention are administered parenterally, orally, rectally or, where appropriate, also topically. The administration takes place before, during or after an interruption in the blood circulation.
The invention also relates to processes for the prepara-tion o~ a pharmaceutical wherein at least one ~anthinederivative of the formula I is converted with a physio-logically acceptable vehicle a~d other suitable active, additional or ancillary substances into a form ~uitable for administration.
~xamples of suitable solid or liquid pharmaceutical formulations are granule~, powders, coated tablets, tablets, (micro)capsules~ suppositories, syrups, 801u-tions, suspensions, emulsion~, drops or injectable solutions as well as productæ with protracted release of active substance, in the preparation of which convention-al aids such as excipients, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, .
:
.
2 ~ 8 ~
flavorings, sweeteners or solubilizers are used. Examplea of ancillary substances which are frequently used and which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactalbumin, gelatin, ~tarch, cellulose and its deriva-tives, animal and vegetable oils, polyethylene glycols and solvents such as, for example, sterile water and monohydric or po].yhydric alcohols, for example glycerol.
Because of the pharmacological propertie~ of the xanthine derivatives, these compounds can be used in all opera-tions in hospital or outpatient procedures which are associated with use of a tourniquet and thus interruption of the blood circulation in the muscle tissue, for example for vascular injuries in which there is prolonged bloodlessnes~ in the extremities, uch as clamping of the aorta, embolus removal by surgical means or delayed treatment of severed large blood vessels. They can furthermore be employed to reduce the damage which may occur af~er restoration of blood flow to muscle fibers of the heart, or ensure the survival of muscle or skin grafts permeated by blood vessels.
The pharmaceutical product~. are preferably prepared and administered in dosage units, where each unit contains as active constituent a defined dose of at least one xan-thine derivative of the formula I. In the case of solid dosage units such as tablets, capsules, coated tablets or suppositories, this dose is up to about 1000 mg, but preferably about 100 - 600 mg, and in the case of injec-tion solutions in ampule form is up to 300 mg, preferably 20 200 mg.
Indicated ~or the treatment of a patient (70 kg) whose blood circulation has been interrupted is an intravenous infusion treatment of 100 - 2000 mg per day in early phaseR and an oral administration of 400 mg 3 times a day in the later rehabilitation phase, especially of 2û899~9 7-ethoxymethyl-1-(5-hydroxy-5-methylhexyl)-3-methyl-xanthine.
However, higher or lower doses are also appropriate in some circ~6tances. ~he administration of the dose can take place either by a single administration in the form of a single dosage unit or of several smaller dosage units, or by multiple admini~tration of divided doses at particular intervals.
Finally, the xanthine derivatives of the formula I and/or their appropriate salts can also be formulated together with other suitable active substances, for example active substances which trap free oxygen radicals, for example, 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, superoxide dismutase, dimethyl sulfoxide or mannitol, heparin, ascorbic acid or deferoxamine, to prepare the abovemen-tioned pharmaceutical formulations.
Example 1:
Preparation of 7-ethoxymethyl-1-(5-hydroxy-5-methyl-hexyl)-3-methylxanthine (Compound 1) a) 7-Ethoxymeth~1-3-methylxanthine O CH2-O-~H2-CH3 H N ~\1~ ~
o i~\ N N
83 g (0.5 mol) of 3-methylxanthine are dissolved in a hot solution of 20 g (Q.5 mol) of sodium hydroxide in 400 ml of water. After filtration, the filtrate is concentrated under reduced pressure, methanol is distilled over , . . ~ ., ~
, ` 208~9~9 ~everal times/ and then the sodium salt is dried under hi~h vacuum. ~he dried salt is suspended in 1.3 l of dimethylformamide and, while stirring, 47.3 g (0.5 mol) of etho~ymethyl chloride are added to the suspension, which is then stirred at 110C for 18 hours. It i~
subsequently filtered hot, the ~iltrate is evaporated in vacuo, the residue is dissolved in 500 ml of 2 N sodium hydroxide solution, and extraction with chloroform is carried out to remove the 1,7 dialkylated 3-methyl-xanthine which is formed as by-product. The aqueous alkaline solution is hd~usted to pH 9 with 2 N hydro-chloric acid while stirri~g, the crystals which form are separated off, and the crystals are washed initially with water until free of chloride and then with methanol and dried in vacuo.
Yield- 77.6 g (69.2 % of theory) Melting point: 263 - 264C
CgHl2N403 (MW = 224.2) b) 7-Ethoxymethyl-1 (5-hydroxy-5-methylhexyl~-3-methylxanthine CH3 CH2-O-CH2-cH3 H,C-C- ( CH2 )~-N/~
C H o N N
11.2 g ~O.OS mol) of 7-ethoxymethyl-3-methylxanthine in 300 ml of dimethylformamide are mi~ed with 7.5 g (0.054 mol) of potassium carbonate and 8.2 g (0.054 mol) of l-chloro-5-hydroxy-5~methylhexane and heated at 110C
while stirring for 5 hours. The mixture is filtered hot with suction, the filtrate is concentrated in vacuo, the residue is taken up in chloroform, the solution is washed first with 1 N sodium hydro~ide solution and then with .~ ~
g water until neutral and is dried over sodi~m sulfate, the solvent is removed by distillation under reduced pres-sure, and the residue i8 recrystallized from diisopropyl ether with the addition of ethyl acetate and petroleum ether.
Yield: 14.1 g (83.3 ~ of theory) Melting point: 102 - 103C
Cl5H26N404 (MW = 33a.4) Analysis: Calculated: C 56.79 % H 7.74 % N 16.56 %
Found: C 56.76 % H 7.8~ ~ N 16.59 Example 2:
Preparation of a pharmaceutical An iniectable pharmaceutical is prepared as follows:
10 g of the compound from Example l are di~solved in water by stirring and 810wly heating, and the volume is finally made up to 1000 ml with water. The resulting solution is filtered through a 0.2 ~m membrane filter and dispensed into ampules containing 5 or 10 ml which, after sealing, are sterilized at 120C for 15 minutes.
Tablets which contain 250 mg of the compound from Example 1 are prepared in a conventional way by mixing 200 g of the compound from Example I, 150 g of lactose, 30 g of starch, 10 g of crospovidone, lO g of talc, 2 g of colloidal silicon dioxide and 1.5 g of magnesium stearate. The tablets receive a coating of an aqueous suspension composed of 40 g of hydroxypropylmethylcellu-lose, 2 g of polyethylene glycol with an avexage molecul-ar weight of ~000, 3.5 g of ~itanium dioxide, 3 g of talc and 451.5 g of water. About 5 to 10 mg of solids are applied as coating to each tablet.
Example 3:
Two groups of eight adult male South African long-tailed monkeys (Cercopithecus pygerythrus) are investigated. The .
-' ' ' ~
20~99~9 anesthesia of the animals is induced with 15 mg/kg ketamine (Warner Lambert) intramuscularly and is main-tained with thiopentone sodium (25 mg~kg, May of Baker) intravenously. One rear extremity is emptied of blood by S a pneumatic tourniquet and an Esmarch bandage. The interruption of the blood circulation is maintained for three hours, and then the interruption is terminated and the animals are able to awake from the anesthesia. The removal of samples of muscle tissue takes place under anesthesia (15 mg!kg ketamine).
20 mg/kg compound 1 is adminiæt~red intravenously to the animals over 30 minutes before the interruption of the blood circulation.
Muscle preparation:
The removed muscle tissue is immediately frozen in isopentane at -183C. The muscle tissue is prepared as described by Dubowitz (Dubowitz et al. Muscle Biopsy A
Practical Approach, London, Bailliere Tindall, 1985, pp. 82 - 128). Microscopic sections are stained with muscle fi~er ATPase at pH 9.4 for 30 minutes, embedded and examined under a light microscope. The diameters of at least 200 muscle fibers are evaluated with a computer-ized video image analyzer.
The average diameter of each type of muscle fiber is indicated in Table 1.
2~89~9 Table 1 Before inter- Interruption After After ruption of of the 3 hrs 6 hrs the blood blood circulation circulation Muscle Fiber Type 1 Control 34.45 34.07 39.2 38.85 Compound 1 36.50 36.28 39.89~ 43.42 Muscle Fiber Type 2a Control 39.99 37.05 41.91 44.08 Compound 1 45.09 44.75 48.55~ 53.37 Before interruption Interruptlon of After 12 After 18 After 24 of the blood the blood hours hours hours circulation circulatlon Muscle Fiber Type 1 Control 34.45 33.63 37.03' 37.99' 40.26' Compound 1 36.50 33.21 35.79 34.68 33.00 .
: Muscle Fiber Type 2a Control 39.99 45.86 49.98' 51.55- 54.62' Compound 1 45.09 38.69 42.28 41.31 40.24 . ~ ~ _ .. ._.__ ___ _.___ --T . . . , _ .' .
.
-` ~0899S~
The values identified by ~ differ significantly from the values before the interruption of the blood circulation;
p < 0.05.
The values in Table 1 show that the muscle tissues of the animals treated with compound 1 reveal a significantly reduced swelling of the muscle fibers of Type 1 and 2a after 18 - 24 hours restoration of blood flow.
-
A -N ~ ~ (II) o ~ N N
in which R2 is an alkyl group with 1 to 4 carbon atoms, A is a hydrogen atom, R5 or the radical of the formula Ia and B is a hydrogen atom, R5, benzyl or diphenylmethyl radical, but where at least one of these radicals A and B i~ a hydrogen atom, are alkylate~ in the presence of at least one basic condensing agent or in the form of theix salts in position 1 and/or 7, in one step or ~tepwise, with appropriate alkylating agents of the formula III
X Q (III) in which X is a halogen atom or a sulfonic ester or pho~phoric ester group and Q is a tertiary hydroxyalkyl group of the formula Ia, R5, benzyl or diphenylmethyl xadical, with ~ubsequent reductive elLmination of the radical B
when this is a benzyl or diphe~ylmethyl group, ort where appropriate, hydrolytic elLmination of an alkoxymethyl or alkoxyalkoxymethyl radical from the position of the radical B and reduction of the keto group to the alcohol functionality when A or B i~ n oxoalkyl radical, at a 2~ 5 ~
reaction temperature between 0C and the boiling point of the particular reaction medium used.
The abovementioned reactionq take place under standard conditions in a known manner tEP 0 268 585, US 4 833 146).
The starting materials for the reactions are known or can be easily prepared by methods known from the literature (EP 0 268 585).
The invention also relates to phanmaceuticals which contain at least an effective amount of a xanthine derivative of the formula I, in addition to pharmaceutic-ally suitable and physiologically tolerated excipients, diluents and/or other active and ancillary substances.
The pharmaceuticals according to the invention are administered parenterally, orally, rectally or, where appropriate, also topically. The administration takes place before, during or after an interruption in the blood circulation.
The invention also relates to processes for the prepara-tion o~ a pharmaceutical wherein at least one ~anthinederivative of the formula I is converted with a physio-logically acceptable vehicle a~d other suitable active, additional or ancillary substances into a form ~uitable for administration.
~xamples of suitable solid or liquid pharmaceutical formulations are granule~, powders, coated tablets, tablets, (micro)capsules~ suppositories, syrups, 801u-tions, suspensions, emulsion~, drops or injectable solutions as well as productæ with protracted release of active substance, in the preparation of which convention-al aids such as excipients, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, .
:
.
2 ~ 8 ~
flavorings, sweeteners or solubilizers are used. Examplea of ancillary substances which are frequently used and which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactalbumin, gelatin, ~tarch, cellulose and its deriva-tives, animal and vegetable oils, polyethylene glycols and solvents such as, for example, sterile water and monohydric or po].yhydric alcohols, for example glycerol.
Because of the pharmacological propertie~ of the xanthine derivatives, these compounds can be used in all opera-tions in hospital or outpatient procedures which are associated with use of a tourniquet and thus interruption of the blood circulation in the muscle tissue, for example for vascular injuries in which there is prolonged bloodlessnes~ in the extremities, uch as clamping of the aorta, embolus removal by surgical means or delayed treatment of severed large blood vessels. They can furthermore be employed to reduce the damage which may occur af~er restoration of blood flow to muscle fibers of the heart, or ensure the survival of muscle or skin grafts permeated by blood vessels.
The pharmaceutical product~. are preferably prepared and administered in dosage units, where each unit contains as active constituent a defined dose of at least one xan-thine derivative of the formula I. In the case of solid dosage units such as tablets, capsules, coated tablets or suppositories, this dose is up to about 1000 mg, but preferably about 100 - 600 mg, and in the case of injec-tion solutions in ampule form is up to 300 mg, preferably 20 200 mg.
Indicated ~or the treatment of a patient (70 kg) whose blood circulation has been interrupted is an intravenous infusion treatment of 100 - 2000 mg per day in early phaseR and an oral administration of 400 mg 3 times a day in the later rehabilitation phase, especially of 2û899~9 7-ethoxymethyl-1-(5-hydroxy-5-methylhexyl)-3-methyl-xanthine.
However, higher or lower doses are also appropriate in some circ~6tances. ~he administration of the dose can take place either by a single administration in the form of a single dosage unit or of several smaller dosage units, or by multiple admini~tration of divided doses at particular intervals.
Finally, the xanthine derivatives of the formula I and/or their appropriate salts can also be formulated together with other suitable active substances, for example active substances which trap free oxygen radicals, for example, 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, superoxide dismutase, dimethyl sulfoxide or mannitol, heparin, ascorbic acid or deferoxamine, to prepare the abovemen-tioned pharmaceutical formulations.
Example 1:
Preparation of 7-ethoxymethyl-1-(5-hydroxy-5-methyl-hexyl)-3-methylxanthine (Compound 1) a) 7-Ethoxymeth~1-3-methylxanthine O CH2-O-~H2-CH3 H N ~\1~ ~
o i~\ N N
83 g (0.5 mol) of 3-methylxanthine are dissolved in a hot solution of 20 g (Q.5 mol) of sodium hydroxide in 400 ml of water. After filtration, the filtrate is concentrated under reduced pressure, methanol is distilled over , . . ~ ., ~
, ` 208~9~9 ~everal times/ and then the sodium salt is dried under hi~h vacuum. ~he dried salt is suspended in 1.3 l of dimethylformamide and, while stirring, 47.3 g (0.5 mol) of etho~ymethyl chloride are added to the suspension, which is then stirred at 110C for 18 hours. It i~
subsequently filtered hot, the ~iltrate is evaporated in vacuo, the residue is dissolved in 500 ml of 2 N sodium hydroxide solution, and extraction with chloroform is carried out to remove the 1,7 dialkylated 3-methyl-xanthine which is formed as by-product. The aqueous alkaline solution is hd~usted to pH 9 with 2 N hydro-chloric acid while stirri~g, the crystals which form are separated off, and the crystals are washed initially with water until free of chloride and then with methanol and dried in vacuo.
Yield- 77.6 g (69.2 % of theory) Melting point: 263 - 264C
CgHl2N403 (MW = 224.2) b) 7-Ethoxymethyl-1 (5-hydroxy-5-methylhexyl~-3-methylxanthine CH3 CH2-O-CH2-cH3 H,C-C- ( CH2 )~-N/~
C H o N N
11.2 g ~O.OS mol) of 7-ethoxymethyl-3-methylxanthine in 300 ml of dimethylformamide are mi~ed with 7.5 g (0.054 mol) of potassium carbonate and 8.2 g (0.054 mol) of l-chloro-5-hydroxy-5~methylhexane and heated at 110C
while stirring for 5 hours. The mixture is filtered hot with suction, the filtrate is concentrated in vacuo, the residue is taken up in chloroform, the solution is washed first with 1 N sodium hydro~ide solution and then with .~ ~
g water until neutral and is dried over sodi~m sulfate, the solvent is removed by distillation under reduced pres-sure, and the residue i8 recrystallized from diisopropyl ether with the addition of ethyl acetate and petroleum ether.
Yield: 14.1 g (83.3 ~ of theory) Melting point: 102 - 103C
Cl5H26N404 (MW = 33a.4) Analysis: Calculated: C 56.79 % H 7.74 % N 16.56 %
Found: C 56.76 % H 7.8~ ~ N 16.59 Example 2:
Preparation of a pharmaceutical An iniectable pharmaceutical is prepared as follows:
10 g of the compound from Example l are di~solved in water by stirring and 810wly heating, and the volume is finally made up to 1000 ml with water. The resulting solution is filtered through a 0.2 ~m membrane filter and dispensed into ampules containing 5 or 10 ml which, after sealing, are sterilized at 120C for 15 minutes.
Tablets which contain 250 mg of the compound from Example 1 are prepared in a conventional way by mixing 200 g of the compound from Example I, 150 g of lactose, 30 g of starch, 10 g of crospovidone, lO g of talc, 2 g of colloidal silicon dioxide and 1.5 g of magnesium stearate. The tablets receive a coating of an aqueous suspension composed of 40 g of hydroxypropylmethylcellu-lose, 2 g of polyethylene glycol with an avexage molecul-ar weight of ~000, 3.5 g of ~itanium dioxide, 3 g of talc and 451.5 g of water. About 5 to 10 mg of solids are applied as coating to each tablet.
Example 3:
Two groups of eight adult male South African long-tailed monkeys (Cercopithecus pygerythrus) are investigated. The .
-' ' ' ~
20~99~9 anesthesia of the animals is induced with 15 mg/kg ketamine (Warner Lambert) intramuscularly and is main-tained with thiopentone sodium (25 mg~kg, May of Baker) intravenously. One rear extremity is emptied of blood by S a pneumatic tourniquet and an Esmarch bandage. The interruption of the blood circulation is maintained for three hours, and then the interruption is terminated and the animals are able to awake from the anesthesia. The removal of samples of muscle tissue takes place under anesthesia (15 mg!kg ketamine).
20 mg/kg compound 1 is adminiæt~red intravenously to the animals over 30 minutes before the interruption of the blood circulation.
Muscle preparation:
The removed muscle tissue is immediately frozen in isopentane at -183C. The muscle tissue is prepared as described by Dubowitz (Dubowitz et al. Muscle Biopsy A
Practical Approach, London, Bailliere Tindall, 1985, pp. 82 - 128). Microscopic sections are stained with muscle fi~er ATPase at pH 9.4 for 30 minutes, embedded and examined under a light microscope. The diameters of at least 200 muscle fibers are evaluated with a computer-ized video image analyzer.
The average diameter of each type of muscle fiber is indicated in Table 1.
2~89~9 Table 1 Before inter- Interruption After After ruption of of the 3 hrs 6 hrs the blood blood circulation circulation Muscle Fiber Type 1 Control 34.45 34.07 39.2 38.85 Compound 1 36.50 36.28 39.89~ 43.42 Muscle Fiber Type 2a Control 39.99 37.05 41.91 44.08 Compound 1 45.09 44.75 48.55~ 53.37 Before interruption Interruptlon of After 12 After 18 After 24 of the blood the blood hours hours hours circulation circulatlon Muscle Fiber Type 1 Control 34.45 33.63 37.03' 37.99' 40.26' Compound 1 36.50 33.21 35.79 34.68 33.00 .
: Muscle Fiber Type 2a Control 39.99 45.86 49.98' 51.55- 54.62' Compound 1 45.09 38.69 42.28 41.31 40.24 . ~ ~ _ .. ._.__ ___ _.___ --T . . . , _ .' .
.
-` ~0899S~
The values identified by ~ differ significantly from the values before the interruption of the blood circulation;
p < 0.05.
The values in Table 1 show that the muscle tissues of the animals treated with compound 1 reveal a significantly reduced swelling of the muscle fibers of Type 1 and 2a after 18 - 24 hours restoration of blood flow.
-
Claims (14)
1. The use of at least one xanthine derivative of the formula I
(I) in which at least one of the radicals R1 and R3 is a tertiary hydroxyalkyl group of the formula Ia (Ia) in which R4 is an alkyl group with 1, 2 or 3 carbon atoms and n is an integer of 2 - 5 and - if only one of the radicals R1 or R3 is such a tertiary hydroxyalkyl group of the formula Ia - the other radical is a hydrogen atom or an aliphatic hydrocarbon radical R5 which has 1 to 6 car-bon atoms and whose carbon chain can be interrupted by 1 or 2 oxygen atoms or substituted by an oxo group or by 1 or 2 hydroxyl groups, these oxo and hydroxyl groups being separated by at least 2 carbon atoms from the ring nitrogen, and R2 is an alkyl group with 1 - 4 carbon atoms, for the preparation of pharmaceuticals for the prophylaxis and treatment of muscle damage which may occur after interruption of the blood circulation.
(I) in which at least one of the radicals R1 and R3 is a tertiary hydroxyalkyl group of the formula Ia (Ia) in which R4 is an alkyl group with 1, 2 or 3 carbon atoms and n is an integer of 2 - 5 and - if only one of the radicals R1 or R3 is such a tertiary hydroxyalkyl group of the formula Ia - the other radical is a hydrogen atom or an aliphatic hydrocarbon radical R5 which has 1 to 6 car-bon atoms and whose carbon chain can be interrupted by 1 or 2 oxygen atoms or substituted by an oxo group or by 1 or 2 hydroxyl groups, these oxo and hydroxyl groups being separated by at least 2 carbon atoms from the ring nitrogen, and R2 is an alkyl group with 1 - 4 carbon atoms, for the preparation of pharmaceuticals for the prophylaxis and treatment of muscle damage which may occur after interruption of the blood circulation.
2. The use as claimed in claim 1, wherein at least one xanthine derivative of the formula I in which R2 is methyl or ethyl and/or only one of the two radicals R1 or R3 is the tertiary hydroxyalkyl group of the formula Ia defined in claim 1 is employed.
3. The use as claimed in claim 1 or 2, wherein at least one xanthine derivative of the formula I in which R1 or R3 is [(.omega.-1)-hydroxy-(.omega.-1)-methyl]-pentyl, -hexyl or -heptyl is employed.
4. The use as claimed in one or more of claims 1 - 3, wherein at least one xanthine derivative of the formula I
in which R1 is [(.omega.-1)-hydroxy-(.omega.-1)-methyl]-pentyl, -hexyl or -heptyl, R2 is methyl or ethyl and R3 is hydrogen, alkyl or alkoxyalkyl with, in each case, 1 - 4 carbon atoms or hydroxyalkyl with 2 - 5 carbon atoms is employed.
in which R1 is [(.omega.-1)-hydroxy-(.omega.-1)-methyl]-pentyl, -hexyl or -heptyl, R2 is methyl or ethyl and R3 is hydrogen, alkyl or alkoxyalkyl with, in each case, 1 - 4 carbon atoms or hydroxyalkyl with 2 - 5 carbon atoms is employed.
5. The use of 7-ethoxymethyl-1-(5-hydroxy-5-methylhexyl)-3-methylxanthine for the preparation of pharmaceuticals for the prophylaxis and treatment of muscle damage which may occur after interruption of the blood circulation.
6. The use as claimed in one or more of claims 1 - 5 for the preparation of pharmaceuticals for prolonging the operation time after interruption of the blood circulation.
7. The use as claimed in one or more of claims 1 - 6 for the preparation of pharmaceuticals for the stabilization of the membrane of muscle cells.
8. The use as claimed in one or more of claims 1 - 7 before, after and during an operation in which there is an interruption of the blood circulation.
9. A pharmaceutical for the prophylaxis and treatment of muscle damage which may occur after interruption of the blood circulation, which has an effective content of at least one xanthine derivative of the formula I
(I) in which at least one of the radicals R1 and R3 is a tertiary hydroxyalkyl group of the formula Ia (Ia) in which R4 is an alkyl group with 1, 2 or 3 carbon atoms and n is an integer of 2 - 5 and - if only one of the radicals R1 or R3 is such a tertiary hydroxyalkyl group of the formula Ia - the other radical is a hydrogen atom or an aliphatic hydrocarbon radical R5 which has 1 to 6 car-bon atoms and whose carbon chain can be interrupted by 1 or 2 oxygen atoms or substituted by an oxo group or by 1 or 2 hydroxyl groups, these oxo and hydroxyl groups being separated by at least 2 carbon atoms from the ring nitrogen, and R2 is an alkyl group with 1 - 4 carbon atoms, besides pharmaceutically suitable and physiologic-ally tolerated excipients, diluents and/or other active and ancillary substances.
(I) in which at least one of the radicals R1 and R3 is a tertiary hydroxyalkyl group of the formula Ia (Ia) in which R4 is an alkyl group with 1, 2 or 3 carbon atoms and n is an integer of 2 - 5 and - if only one of the radicals R1 or R3 is such a tertiary hydroxyalkyl group of the formula Ia - the other radical is a hydrogen atom or an aliphatic hydrocarbon radical R5 which has 1 to 6 car-bon atoms and whose carbon chain can be interrupted by 1 or 2 oxygen atoms or substituted by an oxo group or by 1 or 2 hydroxyl groups, these oxo and hydroxyl groups being separated by at least 2 carbon atoms from the ring nitrogen, and R2 is an alkyl group with 1 - 4 carbon atoms, besides pharmaceutically suitable and physiologic-ally tolerated excipients, diluents and/or other active and ancillary substances.
10. A pharmaceutical as claimed in claim 9, which con-tains at least one xanthine derivative of the formula I
in which R2 is methyl or ethyl and/or only one of the two radicals R1 or R3 is the tertiary hydroxyalkyl group of the formula Ia defined in Claim 1.
in which R2 is methyl or ethyl and/or only one of the two radicals R1 or R3 is the tertiary hydroxyalkyl group of the formula Ia defined in Claim 1.
11. A pharmaceutical as claimed in claim 9 or 10, which contains at least one xanthine derivative of the formula I in which R1 or R3 is [(.omega.-1)-hydroxy-(.omega.-1)-methyl]-pentyl, -hexyl or -heptyl.
12. A pharmaceutical as claimed in claim 9 or 10, which contains at least one xanthine derivative of the formula I in which R1 is [(.omega.-1)-hydroxy-(.omega.-1)-methyl]-pentyl, -hexyl or -heptyl, R2 is methyl or ethyl and R3 is hydrogen, alkyl or alkoxyalkyl with, in each case, 1 -4 carbon atoms or hydroxyalkyl with 2 - 5 carbon atoms.
13. A pharmaceutical as claimed in one or more of claims 9 - 12, which contains 7-ethoxymethyl-1-(5-hydroxy-5-methylhexyl)-3-methylxanthine.
14. A process for the preparation of a pharmaceutical as claimed in one or more of claims 9 - 13, which comprises converting at least one xanthine derivative of the formula I with a physiologically acceptable vehicle and other suitable active, additional or ancillary substances into a form suitable for administration.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4205424 | 1992-02-22 | ||
| DEP4205424.9 | 1992-02-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2089959A1 true CA2089959A1 (en) | 1993-08-23 |
Family
ID=6452327
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002089959A Abandoned CA2089959A1 (en) | 1992-02-22 | 1993-02-19 | Use of xanthine derivatives for the treatment of muscle damage after interruption of the blood circulation |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0557876B1 (en) |
| JP (1) | JP3193800B2 (en) |
| KR (1) | KR930017580A (en) |
| AT (1) | ATE146078T1 (en) |
| AU (1) | AU658979B2 (en) |
| CA (1) | CA2089959A1 (en) |
| DE (1) | DE59304710D1 (en) |
| DK (1) | DK0557876T3 (en) |
| ES (1) | ES2096115T3 (en) |
| GR (1) | GR3022183T3 (en) |
| HU (1) | HUT64472A (en) |
| TW (1) | TW288977B (en) |
| ZA (1) | ZA931184B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3792266B2 (en) * | 1994-06-16 | 2006-07-05 | 森精機興産株式会社 | Method and apparatus for correcting thermal displacement of machine tool |
| DE19540798A1 (en) * | 1995-11-02 | 1997-05-07 | Hoechst Ag | Alkylxanthine phosphonates and alkylxanthine phosphine oxides and their use as medicines |
| US5981536A (en) * | 1996-07-31 | 1999-11-09 | Hoechst Aktiengesellschaft | Use of xanthine derivatives for the modulation of apoptosis |
| US5856330A (en) * | 1996-07-31 | 1999-01-05 | Hoechst Aktiengesellschaft | Use of xanthine derivatives for the inhibition of dephosphorylation of cofilin |
| WO2007041506A1 (en) * | 2005-10-03 | 2007-04-12 | Melior Discovery, Inc. | Purine formulations and methods for managing disorders |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH608236A5 (en) * | 1974-01-22 | 1978-12-29 | Wuelfing J A Fa | |
| DE3525801A1 (en) * | 1985-07-19 | 1987-01-22 | Hoechst Ag | TERTIA HYDROXYALKYLXANTHINE, METHOD FOR THE PRODUCTION THEREOF, THE MEDICINAL PRODUCT CONTAINING IT AND THEIR USE |
| GB8621870D0 (en) * | 1986-09-11 | 1986-10-15 | Beecham Group Plc | Active compounds |
| EP0484785B1 (en) * | 1990-11-07 | 1996-05-22 | Hoechst-Roussel Pharmaceuticals Incorporated | Use of xanthines for the preparation of a medicament effective for inhibiting the replication of human retroviruses |
-
1993
- 1993-02-17 AT AT93102450T patent/ATE146078T1/en not_active IP Right Cessation
- 1993-02-17 DK DK93102450.9T patent/DK0557876T3/en active
- 1993-02-17 TW TW082101087A patent/TW288977B/zh active
- 1993-02-17 EP EP93102450A patent/EP0557876B1/en not_active Expired - Lifetime
- 1993-02-17 ES ES93102450T patent/ES2096115T3/en not_active Expired - Lifetime
- 1993-02-17 DE DE59304710T patent/DE59304710D1/en not_active Expired - Lifetime
- 1993-02-19 CA CA002089959A patent/CA2089959A1/en not_active Abandoned
- 1993-02-19 AU AU33761/93A patent/AU658979B2/en not_active Ceased
- 1993-02-19 ZA ZA931184A patent/ZA931184B/en unknown
- 1993-02-19 JP JP02951693A patent/JP3193800B2/en not_active Expired - Lifetime
- 1993-02-22 HU HU9300476A patent/HUT64472A/en unknown
- 1993-02-22 KR KR1019930002426A patent/KR930017580A/en not_active Application Discontinuation
-
1996
- 1996-12-30 GR GR960403651T patent/GR3022183T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA931184B (en) | 1993-09-16 |
| HU9300476D0 (en) | 1993-05-28 |
| ES2096115T3 (en) | 1997-03-01 |
| EP0557876B1 (en) | 1996-12-11 |
| DE59304710D1 (en) | 1997-01-23 |
| ATE146078T1 (en) | 1996-12-15 |
| KR930017580A (en) | 1993-09-20 |
| DK0557876T3 (en) | 1997-05-26 |
| GR3022183T3 (en) | 1997-03-31 |
| JPH069634A (en) | 1994-01-18 |
| AU3376193A (en) | 1993-08-26 |
| HUT64472A (en) | 1994-01-28 |
| AU658979B2 (en) | 1995-05-04 |
| EP0557876A1 (en) | 1993-09-01 |
| TW288977B (en) | 1996-10-21 |
| JP3193800B2 (en) | 2001-07-30 |
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Legal Events
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| FZDE | Discontinued |