MXPA97004201A - Xantina compounds that have alquinol lateral chains aminated terminalme - Google Patents

Abstract

The compounds of the formula I: in which at least one of the radicals R1 and R3 represent an alkynol radical of the formula IaoIb are suitable for the preparation of medicaments with a neuroprotect effect

Description

Xanthine Compounds having terminally aminated alkynol side chains The invention relates to new xanthine derivatives having at least one alkynol side chain in position 1 or 7 of the xanthine framework, to processes for its preparation and to its use as active substances in medicaments, especially for the treatment and / or the prophylaxis of cerebrovascular diseases, which are characterized by injury due to ischemic causes and by a subsequent necrotic decay of nerve cells (neurons). Post-ischemic neuronal cell death and fatal functional failures due to it, with correspondingly severe neurological and / or psychic symptoms, constitute the common clinical pathological picture of a large number of cerebrovascular diseases. Among them, for example, apoplexy; transient ischemic attacks (TIA); dementia due to multiple infarctions; dementia of the mixed type with vascular and degenerative components (Alzheimer's); spinal cord injuries; brain trauma as a result of head injuries; and neuronal injuries after a heart stop, asphyxia (neonatal) and resuscitation as well as vascular surgical interventions (for example bypass operations) in the area of the main arteries supplying the brain. In clinical practice, apoplexy dominates, also known as attack or stroke, Apoplexia, Apoplexia cerebri or aplopetic insult. This constitutes the foundation of approximately 15% of all cases of deaths (Pschyre bel, Klinisches Wórterbuch (Clinical Dictionary), ed. Torial Wal ter de Gruy ter -Verlag, 255"edi tion, 1986, page 105) and therefore is presented in third place in the statistics of causes of mortality, after heart disease and cancer (Pharmazeutische Zei tung 1994, 139/31: 2.482 - 2.483). Women and men are affected in the same way, A drastic increase in morbidity can be seen from the 6th decade. The incidence rate is currently around the world at around 0.8% of the population with a continuously growing prevalence, especially in industrialized countries, since life expectancy is constantly increasing.

If a stroke is survived, it usually leaves behind permanent injuries, for example paralysis, speech disorders and / or spasmodic and convulsive attacks, which require permanent intensive care of patients with enormous pressure of suffering. also for the relatives and an immense pressure of expenses on the public health. Thus, the disbursement for the treatment and subsequent care of stroke patients, only in the United States of America, is currently estimated at approximately 20 billion US dollars. In addition, approximately 10% of all survivors of stroke suffer a stroke in the course of the first subsequent year with a prognosis of life (Prognosis vi tam) considerably worsened. Sometimes, the development and clinical consecration of an effective drug therapy, which reduces both the acute mortality as well as the magnitude of the neurological deficits and the recurrence rate, and that consequently clearly improves the quality of life after having overcome a stroke, constitute a considerable challenge of social medicinal scope for pharmaceutical research.

The cause of a stroke is always a circulatory disorder linked with oxygen deficiency in the area of a localized brain region. The clinical symptomatology is determined by disorders of consciousness until reaching a coma, often to a spastic hemiplegia, the most different symptoms and motor deficiency, sensory and sensory central deficits and focal or generalized convulsive attacks. A distinction must be made between cerebral hemorrhage or encephalorrhagia associated with a high lethality (primary hemorrhagic insult; in 15% of cases; frequently as massive hemorrhage) after a rupture of vessels, predominantly of the striolenticular arteries, as a consequence of hypertonia, arteriosclerosis or intracranial aneurysm as fundamental ailments; and cerebral infarction or encephalopathy (primary non-hemorrhagic insult, approximately in 85% of cases) with formation of a focus of ischemic softening (necrosis), caused or due to functional ischemia, among other causes due to a crisis due to a decrease in blood pressure, most of the time due to cardiac causes or predominantly due to progressive or persistent ischemia due to stenotic or obliterating vascular processes of arteriosclerotic, thrombotic and embolic genesis in the area of the extracranial and / or intracranial arteries , with preferred location in the internal carotid, middle cerebral and vertebral arteries. The rare symptomatology of an encephalomalacia, which develops slowly, is often referred to as "progressive fulminating attack". As precursor symptoms of a threatening and imminent cerebral infarction, transient ischemic attacks (TIA) that are frequently repeated are considered, which last from 2 to 15 minutes with symptoms of neurological failures that appear transiently, on which a disorder is based. circulatory localization, transient, due to stenosis or caused by microembolisms, and that occur again in the course of a few minutes until at the latest 24 hours, with full restitution. Therefore, an effective treatment of these ischemic attacks would be of great importance for the prophylaxis of stroke. Epidemiologically confirmed risk factors that favor the appearance of cerebral ischemia are, for example, arterial hypertension, hyperlipidemia, hyperuricemia, diabetes mellitus, rheological disorders of the blood, heart failure and the ingestion of contraceptives. hormones (Pschyre bel, Klinisches W? Rterbuch, ed. Torial Wal ter de Gruy te -Verlag, 255th edition, 1986, page 1. 840). The therapy practiced today on cerebrovascular diseases is limited to measures that have no direct influence on cerebral ischemia (Schweiz, Med.Wochenschr., 1994, 124/45: 2. 005-2.012). The therapeutic goal is only the maintenance of a sufficient perfusion in the peripheral sector, still intact, of the focus of ischemia, to confine the progressive infarction of brain tissue in the best of cases. A predominant role is played in the case of presenting the indication of vascular surgical measures, such as intramural de-occlusion or franking of vascular stenoses by extra-intracranial shunt, which, however, are associated with a relatively high surgical risk. Especially the currently available medication measures do not allow any causal treatment, but are aimed exclusively at the ry of clinical symptoms. These include, first, the assurance of a sufficient cardiac function by administration of digital glycosides and antiarrhythmic agents, the regulation of blood pressure, the elimination of metabolic disorders predominantly in the electrolyte and glucose balance, and the avoidance of other foci of thrombosis by means of an antithrombotic therapy with acetylsalicylic acid or heparin, while anticoagulants of the type of vitamin K antagonists (coumarins) are contraindicated because of an increased risk of haemorrhage. Along with this, therapeutic importance is also attributed to the exclusion of the afortioned risk factors. Acute drug treatment of cerebral ischemia is therefore a clinical problem not yet solved (Ann Radiol 1994, 37/1 -2: 132-135). To this result also comes a critical analysis, published recently, of all the major clinical therapeutic studies conducted up to the present time (Lancet 1992, 339/8. 792: 537-53), highlighting once again that the decrease in mortality and the delimitation of lesions due to neurological sequelae in the survivors are evaluation criteria of equal rank for the success of the treatments. On the part of the clinical professionals therefore new therapeutic concepts more oriented to the causes are requested. Promising points of success for this are offered by the complex pathophysiological processes in the vascular and cellular planes, which are presented as a merger, in the form of vicious circles, of the progressive evolution of acute cerebral ischemia. According to the current state of knowledge, the pathogenetic path between cellular ischemia and cell death is characterized by a cascade of physiological and biochemical processes with the participation of a large number of mediator systems, which starts with a deficit supply, consumption of energy-rich compounds and collapse of energy metabolism, and through excessive segregation of excitatory neurotransmitters, such as glutamate and aspartate, in the case of limited or absent replacement leads to the pathological increase in intracellular calcium concentration as a carrier principal of cytotoxicity. Running parallel with the fatal disturbance of calcium homeostasis, other suppressive processes (deleters) contribute to the loss of cellular integrity. These include, among other processes, the activation of phospholipases located in the membranes and the metabolism of arachidonic acid through the formation of free fatty acids and the degradation of these through the pathway of cyclooxygenase and lipoxygenase reactions to form prostaglandins or leukotrienes. as mediators of inflammations, the production of aggressive oxygen radicals with the pronounced damaging potential of cell membranes, the drastic increase in the permeability of membranes, the formation of vasonogenic and cytotoxic brain edemas and the proteolysis of proteins' own structures of the cells, which is triggered by calcium ions. Since all these mechanisms are dependent on time, between the onset of ischemia and cell decay there is a latency period of about 6, up to a maximum of 12 hours, and only within this window of time may drug interventions have any probability of success (Rev. Med. Interne 1994, 15/5: 350 -356). New therapeutic attempts are finally focused on interrupting as early as possible, through deliberate interventions in the cascade of pathogenetic reactions, the progressive evolution of acute cerebral ischemia, and thereby persistently restricting post-ischemic neuronal cell loss. At present, two strategies are essentially followed (Stroke 1990, 21/8, supplement I: 1-130 - 1-131); on the one hand, the thrombolysis of thromboembolic and atherothrombotic occlusions with fibrinolytic agents, such as streptokinase, urokinase and the recombinant tissue plasminogen activator r-tPA, in order to effect an early recanalization of the arterial bloodstream, and on the other hand, cytoprotection, which aims at the survival of neurons under ischemic conditions. The neuroprotective therapeutic principles, which are investigated intensively, especially in the pharmacological sector, but also in the clinical sector, belong to p. ex. the repression of calcium influx in neurons with calcium antagonists (eg nimodipine, nicardipine, flunarizine and mildmopamil), EAA antagonists (excitatory amino acids) (eg competitive and non-competitive NMDA antagonists) (N-methyl-D-aspartate), as well as non-NMDA antagonists) or gangliosides (eg GM-1) blockade of the arachidonic acid cascade as well as the exclusion of its harmful metabolic products with phospholipase inhibitors , cyclooxygenases and lipoxygenases, or antagonists of PAF (platelet activating factor), thrombo-xanos and leukotrienes; the inhibition of lipid peroxidation, which damages cell membranes, with oxygen radical scavengers (eg superoxide dismutase, catalase, alpha-tocopherol, ascorbic acid, Ginkgo-Foli um, allopurinol, tirilazad and melatonin) or heavy metal chelating agents (eg deferoxamine); the confinement of the spread of edema with antiedematous active substances (eg corticosteroids); the decrease in the tendency to thrombosis with anticoagulants (eg heparin) and thrombocyte aggregation inhibitors (eg ASS, ticlopidine, prostacyclin and its more stable synthetic derivatives); and the promotion of endogenous protective factors with serotonin-1A agonists (eg, urapidil and ipsapiron), adenosine modulators (eg propentofylline and vinpocetine) or neurotrophic growth factors (eg, growth factor) transformer TGF- / 31 and the neurotrophic factor derived from the brain) and its release activators (Prog. Neuro-Psychopharmacol., Biol. Psychiatry 1993, 17/1: 21-70; Clin. Neurophar acol. 1990, 13th supplement 3 : page 9-page 25). The highest probabilities of success are naturally recognized as a multifactorial intervention in the pathogenetic cascade of reactions with its complex network of mediating systems that mutually amplify each other (Drugs 1988, 35/4: 468 476) either by combining different drugs with selective action or, more advantageously, by a monopharmaceutical having as broad a spectrum of pharmacological effects as possible. Together with propentofylline (3-methyl-1- (5-oxo-hexyl) -7-propyl-xanthine), already mentioned, pharmacologically and for the most part also clinically, other pharmacologically investigated xanthines such as methylxanthines, widely propagated in nature, theophylline (1,3-dimethyl-xanthine), theobromine (3,7-dimethyl-xanthine) and caffeine (1,3,7-trimethyl-xanthine), as well as synthetic derivatives i, 3, 7-trialkyl, pentoxifylline (3,7-dimethyl-1- (5-oxo-hexyl) -xanthine; Drugs &Aging 1995, 7/6: 480 - 503) and denbuphylline (1, 3 -dibutyl -7- (2-oxo-propyl) -xanthine), but until now it has not been possible to prove any usefulness therapeutic approach in the prophylaxis and treatment of acute ischemic stroke. In contrast, natural methylxanthines can even lead to a worsening of the clinical situation (Schweiz, Rundsch, Med. Prax, 1989, 78/23: 663-666) and should therefore be contraindicated. Only propentofylline seems to occupy a certain exceptional position because of its exclusive profile of pharmacological effects (Gen. Pharmac., 1994, 25/6: 1, 053-1, 058, Drug Rev. Res., 1993, 28/3: 438). 444); however, more controlled clinical studies with a large enough number of patients are necessary in order to be able to evaluate the therapeutic validity of the preparation (J. Cereb. Blood, Flow Metab, 1993, 13/3: 526-530). Surprisingly, it was finally found that the introduction of side chains of alkynols with a terminal amino function at positions 1 and / or 7 of the xanthine framework leads to compounds that are clearly superior to propentofyllin in clinically relevant experimental models. , and therefore have a greater therapeutic potential for the prophylaxis and treatment of cerebrovascular diseases. The invention therefore concerns new xanthine compounds of the formula I representing in it 1) R1 and R3 an alkynol radical of the formula Ia or Ib, R2 a) linear or branched alkyl (C ^^), b) (C3-C6) cycloalkyl or c) cycloalkyl (C4-C8) alkyl, R4 a hydrogen atom or (C1-C3) alkyl, R5, R6 and R7 , independently from each other, a) a hydrogen atom, b) alkyl (C ^ Cg), c) cycloalkyl (C3-C6), d) cycloalkyl-C4-C8 alkyl, e) ar-alkyl (C1-6) C2) of) tri-alkyl (C-, -C4) -silyl, or by forming R5 and R6 in common with the nitrogen atom, to which they are attached, a saturated ring of 4 to 7 members, which is unsubstituted or substituted one to four times with (C1-C4) alkyl, or by forming R5 and R6 in common with the nitrogen atom, to which they are attached, a saturated ring of 4 to 7 members, wherein a -CH2- group of the ring is replaced by a radical taken from the group consisting of O, S, SO, S02 and .13 represents a hydrogen atom, (C1-C3) alkylcarbonyl or (C1-C4) alkyl, and the ring is unsubstituted or substituted by four times with (C1-C4) alkyl, representing alkylene (C1-C6) ) without branching or branching, and representing Z "the anion of an inorganic or organic acid, physiologically compatible, or representing in it 2) R1 or R3 an alkynol radical of the formula Ia or Ib and the other radical R3 or R1 a) a hydrogen atom or b) R8, wherein R8 signifies linear or branched (Cx-C6) alkyl, (C3-C6) cycloalkyl or (C4-C6) alkyl-cycloalkyl, and R2, R4, R5, R6, R7, A and Z being defined as in 1) The compounds of the formula I are preferred, in which only one of the two radicals R1 or R3 represents an alkynol radical of the formula Ib, and the other radical means a hydrogen atom or R8. The formula I, in which R1 represents an alkynol radical of the formula Ia or Ib and R3 represents a hydrogen atom or R.sub.8, Still more preferred are the compounds of the formula I, in which R.sub.1 represents an alkynol radical of the formula la or Ib, R2 represents linear (C1-C4) alkyl, cyclopropyl or cyclopropylmethi lo, R3 represents a) a hydrogen atom or b) R8, wherein R8 signifies linear or branched (Cx-C6) alkyl, cyclopropyl or cyclopropylmethyl, R4 represents a hydrogen atom, methyl or ethyl, R5, R6 and R7, independently they represent a hydrogen atom, (C1-C4) alkyl, cyclopropyl, cyclopropylmethyl or benzyl, or R5 and R6 in common with the nitrogen atom, to which they are attached, they form a saturated ring of 5 up to 6 links taken from the group consisting of morpholine, 4-alkyl (C1-C3) -carbonyl-piperazine, 4-alkyl (C1-C2) -piperazine, piperazine, piperidine, pyrrolidine and thiomorpholine, A represents alkylene (C ^ Cg) without branching and Z ~ represents the anion of an inorganic or organic acid, physiologically compatible. Especially preferred are compounds of the formula I, in which R1 represents an alkynol radical of the formula Ia or Ib, R2 represents (Cx-C4) alkyl, R3 represents linear (C2-C4) alkyl or cyclopropyl, R4 represents a hydrogen atom or methyl, R5, R6 and R7, independently of each other, represent a hydrogen atom, alkyl (Cx-C4) or benzyl, or R5 and R6 in common with the nitrogen atom, to which they are attached, form the ring of morpholine, pyrrolidine, piperidine, 4-methyl-piperazine or 4-acetyl-piperazine, A represents unbranched (C2-C4) alkylene and Z "represents the anion of an inorganic or organic acid, physiologically compatible. the compounds 1- (8-diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-, 1- (5-hydroxy-5-methyl-8-pyrrolidino-oct-6-ynyl) -3-methyl-, 3-butyl-1- (5-hydroxy-5-methyl-8-piperidino-oct-6-ynyl) -, 1- (5-diethylamino-2-hydroxy-2-methyl-pent-3-ynyl) -3-propyl-, 1- (6-dimethylamino-3-hydroxy-3-methyl-hex-4-ynyl) -3 -ethyl-, 1- (7-diethylamino-4-hydroxy-4-methyl-hept-5-ynyl) -3-ethyl-, 1- [8- (4-acetyl-piperazino) -5-hydroxy-5- methyl-oct-6-ynyl] -3-methyl-7-propyl-xanthines as well as their salts by addition of physiologically compatible acids and N, N-diethyl-N- [[4-hydroxy-4-methyl-8-iodide] - (3-methyl-7-propyl-xanthin-1-yl) -oct-2-ynyl] -N-methyl-ammonium. The term "cycloalkyl (C4-C8) alkyl", defines alkyl radicals that are substituted with a (C3-C6) cycloalkyl, the sum of all C atoms being less than or equal to 8. They belong, for example, to the cyclopropyl-methyl radicals up to -pentyl, cyclobutyl-methyl to -butyl, cyclopentyl-methyl to -propyl, as well as cyclohexyl-methyl- and -ethyl. "Ar or ar" designates radicals that are derived from benzene or naphthalene. Appropriate saturated rings of 4 to 7 links for the structural element -NR5R6 they are, for example, 4-alkyl (C1-C4) -piperazine, azetidine, 2,5-dimethyl-pyrrolidine, 2,6-dimethyl-piperidine, morpholine, perhydroazepine (azepane), piperazine, piperidine, pyrrolidine, 2, 2, 6, 6-tetramethyl-piperidine, thiomorpholine and its sulfoxide or sulphone. For the formation of salts by the addition of physiologically compatible acids and quaternary ammonium salts according to formula I with the structural element of formula Ib, halogenated hydrazides such as hydroiodic, hydrobromic and hydroiodic acids are suitable, inter alia. co, the sulfuric, phosphoric, acetic, lactic, maleic, fumaric, oxalic, tartaric, citric, D-gluconic, 4-toluenesulfonic, methanesulfonic, benzenesulfonic and cyclohexylsulfamidic acids or their respective anion Z. The compounds of the formula I according to invention have, by virtue of the secondary or tertiary alcohol structure in the alkynol radical of the formula Ia or Ib, always a center of chirality and therefore exist in enantiomeric forms, In addition, in the case of an asymmetrically branched at the positions of R2 and / or R5 to R8 and / or in the case of an asymmetrically branched alkylene A group, other C asymmetric atoms, such that compounds I now appear in diastereomeric forms. The invention therefore includes both the totality of the pure compounds as regards the stereoisomers and also their mixtures. The invention also concerns a process for the preparation of the compounds of the formula I.

According to variant A of the process, a 3-alkyl-xanthine of the formula II is reacted, wherein R2 is defined as in formula I, without any condensing agent or in the presence of a basic condensation agent, or conversely a salt of the compound of formula II, with a compound of formula III, wherein X represents a halogen atom, preferably chlorine, bromine or iodine, or a sulphonic acid ester radical or phosphoric acid ester, and A, R4, R5 and R6 are defined as in formula I, to form a composed of the formula ic, with an alkynol radical of the formula present by R3 and a hydrogen atom present by R1 according to formula I, and then the compound of formula I is alkylated without any condensing agent or in the presence of a basic condensation agent, or on the other hand a salt of the compound of the formula le, or again with a compound of the formula III to form a compound of the formula Id with two alkinol radicals, the same or different, of the formula present by R1 and R3 according to formula I, or with a compound of formula IV, R8-X (I) wherein R8 is defined as in formula I and X is defined as in formula III, to form a compound of the formula I with the radical R8 present by R1 and the alkynol radical of the formula present by R3 according to formula I, or a 1,3-dialkylxanthine of the formula V is reacted, wherein R2 and R8 are defined as in formula I, without any condensing agent or in the presence of a basic condensation agent, or conversely a salt of the compound of formula V, with a compound of formula III for forming a compound of the formula I, or a 3,7-dialkyl-xanthine of the formula VI is reacted, wherein R2 and R8 are defined as in formula I, without any condensing agent or in the presence of a basic condensation agent, or conversely a salt of the compound of formula VI, with a compound of formula III for form a compound of the formula If with an alkynol radical of the formula present by R1 and the radical R8 present by R3 according to formula I.

According to variant B of the process, a compound of formula II, V or VI, analogously to variant A of the process, is alkylated with a compound of formula VIII, wherein A and R4 are defined as in formula I and X is defined as in formula III, to form a compound of formula IX wherein either R9 and R10 represent two radicals, the same or different, of the formula IXa or on the contrary only R9 or R10 means a radical of the formula IXa and the other radical R10 or R9 represents a hydrogen atom or R8, where R2, A, R4 and R8 are defined as in the formula I, and then the compound of the formula IX is aminomethylated under the conditions of the Mannich reaction (RÓMPP Chemie Lexikon, 9"ed., volume 4, (1991), page 2. 632) with formaldehyde and an amine of the formula X, R3 / H- • N (X) \ R ° where R5 and R6 are defined as in formula I, in the (or in the) terminal ethynyl group (s) to form a compound of the formula le, Id, le or If. According to variant C of the process, a disubstituted xanthine is reacted in 1,3 or 3,7 or trisubstituted in 1,3,7 of the formula XI, wherein either R11 and R12 represent two radicals, the same or different, of the formula Xla, or on the contrary only R11 or L¿ means one radical of the formula Xla and the other radical R12 or R11 represents a hydrogen atom or R8, where R2, A, R4 and R8 are defined as in formula I, with an organometallic compound of the formula XII, wherein R5 and R6 are defined as in formula I and M means an alkali metal, such as sodium, potassium or especially lithium; an alkaline earth metal, such as calcium or especially magnesium, for example in the form of a Grignard compound (-Mg-halide); or a heavy metal, such as cerium, copper or silver; alkylating alkylation at reducing conditions of the carbonyl group (s) to form a compound of the formula le, Id, le, If or Ig with an alkynol radical of the formula present by R1 and a hydrogen atom present by R3 according to formula I. According to variant D of the process, a xanthine of the formula XI is reacted, in which R11 and / or R12 represent the radical of the formula Xla, by way of the Nef reaction (RÓMPP Chemie Lexikon, 9th edition, volume 4 (1991), page 2. 954), or with an acetylide of the formula XIII, HC = C-M (XIII) in which M is defined as in formula XII, or also with an acetylide protected in extreme position, of the formula XIV, Ra-C = CM (XIV) in which M is defined as in formula XII and Ra represents a leaving group easily removable later, for example the trimethylsilyl group (TMS) separable by catalysis with a fluoride, mediating ethinylation of the carbonyl group (s) to form a compound of the formula IX, in which R9 and / or R10 represent the radical of the formula iXa, and then the compound IX obtained is aminomethylated by a Mannich reaction with formaldehyde and an amine of formula X, analogously to variant B of the process, to form a compound of the formula le, Id, le, If or Ig. According to the process variant E, a compound of the formula le, Id, le or If, prepared according to process variants A to D, or a compound of the formula Ig, prepared according to process variants C or D, in the that R5 and / or R6 represent in each case a hydrogen atom, is alkylated under reductive conditions once or twice with an oxo-derivative (aldehyde or ketone) of alkanes (C1-C6), cycloalkanes (C3-C6), cycloalkyl -alkanes (C4-C8) or ar-alkanes (C1-C2). According to the variant F of the process, a compound prepared according to variants A to E of the process is transformed, with a physiologically compatible inorganic or organic acid HZ, into a salt by the addition of acid of the formula I, representing R1 and / or R3 the alkynol radical of the formula Ib, in which R7 represents a hydrogen atom, and Ra is defined as in the formula I. According to the variant G of the process, a compound prepared according to the variants A to E of the process, is transformed with an alkylating agent of the formula VII, wherein R7 is defined as in formula I, with the exception of hydrogen, and Z is defined as in formula III for X, in a quaternary ammonium salt of formula I, with R1 and / or R3 representing the alkynol radical of the formula Ib and R2 being defined as in the formula I. According to variant H of the process, a compound prepared according to variants A to G of the process is separated by chromatography or by fractional crystallization in the pure stereoisomers. The xanthines of the formulas II, V, VI or XI which are used as starting substances in the A to D variants of the process; the alkylating agents of formulas III, IV, VII or VIII; the organometallic compounds of the formulas XII, XIII or XIV; and the amines of the formula X are known or can be prepared according to known methods.

Thus, the alkynols of the formula III, substituted with basic radicals, can be obtained, for example, by an organometallic synthesis, by reacting the halogen-aldehyde compounds or sterically hindered ketones of the formula Hal-A-CO-R4, in a formation or accumulation reaction mediating alkynylation under reducing conditions of the carbonyl function with the propylamine compounds and metals of the formula XII (R5R6N-CH2-C = CM), preferably in the form of the lithium or halogen-magnesium compounds (Grignard ), under standard conditions (as described in more detail below in the case of variants C and D of the procedure). A reaction of the same type of the halogen-aldehydes and the halogen ketones with acetylides of the formula XIII (HCsC-M) or XIV (Ra-CsC-M) leads - after having separated the protective group Ra in the case of being used those of formula XIV - to the alkynols of formula VIII. The 2-propynyl -amines (R5R6N-CH2-CsCH), which form the basis of the organometallic compounds of the formula XII, can be formed or accumulated without problems from the 2-propynyl bromide and the amines of the formula X by direct exchange between halogen and amine, or by rodeo which passes through the metal idides produced in an intermediate manner, in the following reaction of a single container (without isolation of intermediate products) that is known from the literature (Tetrahedron 1992, 48/30: 6,231 -6,244): in THF Formula X C4H9Ü R5R6NL¡ C4H10 78 ° C + H20 (THF = tetrahydrofuran) (phosphate buffer) The reaction of the mono- and di-substituted xanthine derivatives II or le, Ig, V, VI and IX with the corresponding and relevant reagents of the formulas III, IV or VIII is usually carried out in a distribution agent or solvent that is inert in front of the participants in the reactions. Particularly suitable such agents are aprotic, dipolar solvents, for example dimethyl amide, dimethylacetamide, N-methyl-pyrrolidone, tetramethyl urea, hexamethyltriamide of phosphoric acid or dimethylsulfoxide; however, formamide, acetonitrile, acetone, butanone, or alcohols, such as methanol, ethylene glycol, and their mono- or di-alkyl (C -CJ-ethers, ethanol, propanol, isopropanol, and the various butanols; hydrocarbons; such as benzene, toluene or xylenes, halogenated hydrocarbons, such as dichloromethane or chloroform; pyridine, as well as mixtures of said solvents or their mixtures with water. The reaction is conveniently carried out in the presence of an agent of a basic condensation agent. Suitable for this are, for example, hydroxides, carbonates, hydrides or alcoholates of alkali or alkaline earth metals, and organic bases, such as trialkylamines, for example triethylamine or tributylamine, quaternary ammonium or phosphonium hydroxides and crosslinked resins with fixed ammonium or phosphonium groups, eventually replaced. The xanthine derivatives can, however, also be used directly in the form of their salts prepared separately, for example the alkali metal, alkaline earth metal salts or optionally substituted ammonium or phosphonium salts. In addition, the xanthine compounds can be alkylated without problems both in the presence of the aforementioned inorganic condensation agents and also in the form of their alkali metal or alkaline earth metal salts with the cooperation of phase transfer catalysts, e.g. ex. tertiary amines, quaternary ammonium or phosphonium salts or also crown ethers, preferably in a two-phase system under the conditions of a phase transfer catalysis. Suitable phase transfer catalysts, most of which are commercially available, are, among others, the salts of tetra-alkyl (Cx-C4) - and of methyl-trioctyl-ammonium and -phosphonium, those of methyl-, myristyl -, phenyl- and benzyl-tri-alkyl (Cx-C4) - and those of cetyl-trimethyl-ammonium or (C1-C12) alkyl- and benzyl-triphenyl-phosphonium, the compounds which have the largest cation and constituted more symmetrically. In this case, the reaction temperatures are generally between 0 ° C and the boiling point of the reaction medium used in each case, preferably between 20 ° C and 130 ° C, optionally at elevated or reduced pressure. , but usually at atmospheric pressure, the reaction time can be from less than one hour up to several hours. The optional alkylation under reducing conditions of compounds of the formulas up to Ig with a primary amino group (R5 and R6 = H) or secondary (R5 or R6 = H) terminal on the side chain of alkynol to form secondary or tertiary amines, is it effects by reaction with one of the oxo-derivatives (aldehydes or ketones), perfectly known from the literature, of alkanes (C1-C6), cycloalkanes (C3-C6), cycloalkyl-alkanes (C4-C8) or ar-alkanes ( C1-C2) in the presence of an appropriate reducing agent. The reduction of the azomethins formed in an intermediate manner from the oxo-compound and the amine is carried out, for example, with formic acid and its derivatives; however, hydrogenation with complex metal hydrides such as lithium alanate (aluminum hydride), lithium or sodium borohydride (boro-hydride) and especially sodium cyanoboranate is preferred. In this case, it is conveniently worked in a delivery agent or solvent inert to the reactants, for example of an ether such as diethyl ether, dioxane or tetrahydrofuran; or of a lower alcohol, preferably methanol or ethanol; of water or their mixtures with each other, at temperatures between 20 ° C and the boiling point of the reaction mixture.

The conversion of the xanthines to Ig with the HZ acids in the salts by the addition of physiologically compatible acids belongs to the state of the art. For the preparation of the physiologically compatible quaternary ammonium salts, from the xanthines to Ig, by alkylation with the reactants of the formula VII, preferably in the form of alkyl halides (R7Hal), especially the iodides R7I, or dialkyl sulfates (R72S04), it is conveniently worked in distribution agents or inert solvents, such as di-C1-C4 alkyl-ethers, cyclic ethers, aromatic or halogenated hydrocarbons or ketones (eg acetone), or also in mixtures based on these solvents or with the addition of dipolar aprotic solvents (eg dimethylformamide) at temperatures of from 20 ° C up to the boiling point of the relevant reaction medium, often needing several hours until the full reaction is reached. The quaternary salts in this case usually result in crystalline form. If desired, your anion Z ~ can be modified later to desire with the help of anion exchangers. The three-component condensation according to Mannich for aminomethylation (Weygand / Hilgetag: Organisch-che ische Experi entierkunst, 4th edition, 1970, pages 990-993) of compound IX in the terminal acetylene group, CH-acid, can be carried in principle with ammonia, with primary or preferably secondary amines of the formula X in the presence of formaldehyde as the carbonyl component (used either in aqueous solution or more advantageously in solid form as paraformaldehyde) under the catalytic influence of both bases and acids. However, the acid-catalyzed process is preferred, in which the amines X are reacted in the form of their salts, for example the hydrochlorides or acetates. The addition of catalytic amounts of metal salts, such as, for example, zinc (II), iron (III) or especially copper (I) chlorides (J ". Med. Chem. 1990, 33: 3) is often proven. 182 - 3, 189) As a reaction medium, lower alcohols, di (C 1 -C 4) alkyl ethers or preferably cyclic ethers, in particular dioxane, are generally used.The reaction temperature is usually between 20 ° C and 20 ° C. the boiling point of the reaction mixture, preferably between 30 ° C and 70 ° C, the rule constituting reaction periods of up to several hours The mono- or di-oxo-alkyl-xanthines of the formula XI alkylated in position 3, which are used in organometallic reactions according to process variant C as starting substances, are for the most part, among other documents, known from German patent applications DE-OS 2330742 and DE-OS 2402908 , or can be prepared easily from the mono- or di-alkyl-xanthines of the formulas II and respectively V or VI and the halogen-aldehyde compounds or -ketones having the formula Hal-A-CO-R4, optionally also in the form of their open-chain or ring-shaped acetals or ketals, under the alkylation conditions set forth in detail above. In this case, the compounds XI, which in the position of R12 carry a hydrogen atom and in the position of R11 carry an oxo-alkyl radical of the formula Xla, can be obtained without difficulty by the detour passing through the l- oxoalkyl-3,7-dialkylxanthines, in which the alkyl radical in the 7-position represents a readily removable labile group, for example in the form of the benzyl group removable by reduction or of the methoxymethyl, ethoxymethyl, propoxymethyl or butoxymethyl radical which can be separated by hydrolysis , according to the methodology described in detail in the PCT patent document WO 87/00523. Within the compounds of formulas XII, XIII or XIV, suitable for the alkynylation of the carbonyl groups, they occupy a preferential position, because of its easy accessibility and handling, the lithium and halogen-magnesium derivatives (Grig-nard). Thus, the 2-propynyl -amines described above of the formula R5R6N-CH2-CH = CH and the acetylenes protected by only one side of the formula RaC = CH, preferably ethynyltrimethylsilane, can be metalated quantitatively with alkyl (C ^ C ^ -lithium compounds, preferably butyl lithium, in one of the solvents listed below, predominantly anhydrous tetrahydrofuran, at low temperatures between -50 ° C and -80 ° C, or with halogenides of (C 1 -C 4) -magnesium alkyl, for example methylmagnesium or ethylmagnesium chloride or bromide, in a low-boiling ether, usually diethyl ether, at the boiling point, to form Compounds of the formula XII or XIV, which are reacted without intermediate isolation with the carbonyl compounds XI, can be used advantageously as the reagent of the formula XIII, commercially available lithium acetylide in the form of the stable complex with ethylenediam ina, recommending to increase the reactivity the addition of chloride cerium (III) dried in an at least stoichiometric amount (Tetrahedron Letters 1984, 25/38: 4, 233-4.236). The strongly nucleophilic organometallic compounds are very sensitive to hydrolysis and oxidation; its safe handling therefore requires the consequent exclusion of moisture and eventually work under a protective gas atmosphere. The usual solvents or distribution agents for the alkynylation reaction are predominantly those which are also suitable for the preparation of the organometallic compounds. As such, especially ethers with one or several ether oxygen atoms, for example diethyl-, dipropyl-, diisopropyl- or dibutyl-ether, 1,2-dimethoxy-ethane, tetrahydrofuran, dioxane, tetrahydropyran, furan and anisole, are involved. and aliphatic or aromatic hydrocarbons, such as petroleum ether, cyclohexane, benzene, toluene, xylenes, diethylbenzenes and tetrahydronaphthalene; however, tertiary amines, such as triethylamine, or dipolar aprotic solvents can also be used, for example dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone, hexamethyltriamide of phosphoric acid and dimethylsulfoxide, as well as mixtures of the solvents mentioned. The alkynylation reaction is generally carried out at temperatures between -40 ° C and + 100 ° C, preferably between -20 ° C and + 70 ° C or at room temperature, without external cooling, the respective compound usually being used organometallic in a slight excess. Reaction time periods extend in such cases usually from a few minutes to several hours. The decomposition of the alcoholates formed is preferably carried out with water, with an aqueous solution of ammonium chloride or with dilute hydrochloric or acetic acid. The desilylation of both the protected alkynols in ethynyl, obtained from the carbonyl compounds XI by reaction with lithium trimethylsilyl-acetylide (XIV) to form the intermediates of the formula IX, as well as the compounds of the formula I according to invention having N-trialkylsilylated alkynyl side chains can be advantageously carried out by methanolysis in the presence of catalytic amounts of potassium fluoride, which proceeds quantitatively at temperatures ranging from 20 ° C to the boiling point of methanol in the course of a few hours. For the preparation of the compounds I according to the invention in a pure form with respect to the stereoisomers, it is possible to start from either uniformly sterile starting materials of the formulas III or VIII (optionally also II, IV, V, VI, VII, X and / or XI) and of intermediate compounds of the formula IX or, in the case of the C and D variants of the process, the formation of an alkynol from the prochiral carbonyl compounds XI with the organometallic compounds XII, XIII or XIV it can be performed enantioselectively by asymmetric induction in the presence of chiral coadjuvant substances. However, the subsequent separation of the stereoisomeric forms is preferred using methods known per se. Since the diastereoisomers, in contrast to the enantiomers, have different physical and chemical properties, the separation of their mixtures, for example by fractional crystallization or chromatography methods, does not generally pose any difficulties. In contrast to this, the physical splitting of racemates into the enantiomeric (antipodal) forms requires additional precautions; thus, fractional crystallization is achieved only after the formation of diastereomeric salts with an optically active acid HZ, and the separation by chromatography is achieved only in the case of using chiral stationary phases, which have a different spatial affinity with respect to to the enantiomers. The alkynols of the formula IX are not only valuable intermediates for the formation of the compounds of the formula I according to the invention, but also allow the same sense of pharmacological effect to be recognized as that of the final products of the invention. formula I, even when they have a lower solubility in water. Compounds I, because of their valuable pharmacological properties, are outstandingly suitable for use as active substances in medicaments, especially in those which allow an effective curative and prophylactic treatment of cerebrovascular diseases due to ischemias, such as apoplexy, - transient ischemic attacks (TIA); dementia due to multiple infarctions; Dementia of the mixed type with a vascular and degenerative component (Alzheimer's); spinal cord injuries; brain traumas as a result of head injuries; and neuronal injuries after a heart stop, asphyxia (neonatal) and resuscitation as well as vascular surgical procedures (eg, bypass operations) in the area of the main arteries supplying the brain. In such cases, the compounds of the formula I can be administered either alone, for example in the form of microcapsules, in mixtures with each other or in combination with suitable carrier materials. The invention therefore also concerns medicaments, which contain at least one compound of the formula I as active substance. In addition, the present invention concerns on the one hand the use of the medicaments according to the invention within the framework of all forms of therapies currently practiced in the case of cerebrovascular diseases (Schweiz, Med. Wochenschr., 1994, 124/45: 2, 005). - 2. 012), such as primary prevention for the control of threatening and imminent ischemia attacks, acute treatment for the confinement of tissue infarction after the initiation of ischemia, and secondary prophylaxis for the reduction of the rate of recurrence after having undergone an ischemic episode, and on the other hand the application of drugs in the form of pharmaceutical preparations, especially for parenteral and oral administration, but possibly also rectally or transdermally. The appropriate forms of solid galenic preparations or liquids are for example those of granules, powders, tablets, dragees, (micro) capsules, syrups, emulsions, suspensions, gels, preparations with prolonged release of the active substances, suppositories, plasters that yield active substances, aerosols, drops and on all injectable solutions in the form of ampoules or injection bottles for permanent infusion, in the preparation of which adjuvants, such as vehicle materials, disintegrating agents, binders, coating agents, swelling agents, glidants or lubricants, are commonly used. flavors, sweetening agents or solubilizers. As adjuvants frequently used, p. ex. magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talcum, milk albumin, gelatin, starch, vitamins and their derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as, for example, sterile water, a physiological solution of sodium chloride, alcohols, glycerol and other polyvalent alcohols (polyols). Preferably, the pharmaceutical preparations are produced and administered in dosage units, each unit containing as an active component a certain dose of a compound according to formula I. In the case of solid dosage units, such as tablets, capsules and suppositories, this dose it can be up to 1,000 mg, but preferably from 100 to 600 mg, and in the case of injectable solutions in the form of ampoules it can be up to 300 mg, but preferably from 20 to 200 mg. For the treatment of an adult patient - depending on the activity of the compounds according to formula I in humans and the degree of severity of the life threatening disease - daily doses of 100 to 5,000 mg of active substance are indicated, preferably from 300 to 3,000 mg, in the case of oral administration, and from 30 to 3,000 mg, preferably from 50 to 2,000 mg, in the case of intravenous administration. The administration of the daily dose can be done either by taking a single dose in the form of a single dosage unit, or also of several smaller dosage units, as well as by multiple administration of subdivided doses at certain time intervals. In the case of permanent intravenous infusion, the daily dose is from 100 to 5,000 mg, preferably from 500 to 2,000 mg, corresponding to an infusion rate of 0.1 to 3 mg per kg of body weight and hour (h). ), preferably from 0.3 to 1 mg / kg / h. In all forms of application, however, in some cases, higher or lower daily doses may also be appropriate. The compounds of the formula I can also be administered in common with other appropriate active substances, especially those also involved in regulating the cascade of pathogenetic reactions of acute cerebral ischemia, - p. ex. with fibrinolytic agents, calcium antagonists, antagonists of EAA (excitatory amino acids), gangliosides, phospholipase inhibitors, cyclooxygenases and lipoxygenases, PAF (platelet activating factor) antagonists, troboxanos and leukotrienes, oxygen radical scavengers, chelators with heavy metals, anti-oedematous active substances, anticoagulants, thrombocyte aggregation inhibitors, serotonin-1A agonists, adenosine modulators or neurotrophic growth factors and their release activators; or they can be formulated in common when carrying out the production of galenic forms of preparation. Then, with the help of representative examples of preparation, the composition of the compounds according to formula I, compiled according to structural points of view in Table 1, will be explained in more detail. Table 2 shows the compounds of formula IX. For all intermediate and final products, produced at the preparation scale, the structure was confirmed by both 1 H-NMR spectroscopy and also by elemental analysis or mass spectrum (MS).

Example 1: 1- (8-Diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propyl-xanthine hydrochloride according to process variants D and F: DI) 1- (5-Hydroxy-5-methyl-hept-6-ynyl) -3-methyl-7-propyl-xanthine To a suspension of 75.5 g (0.82 mol) of lithium acetylide in the form of the complex with ethylene diamine in 500 ml of dioxane, a solution of 153.2 g (0.5 mol) was added dropwise, with the exclusion of humidity and stirring at room temperature. of 3-methyl-1- (5-oxo-hexyl) -7-propyl-xanthine in 750 ml of dioxane. The weakly exothermic reaction, which was initiated in this case, was terminated by stirring for 6 hours and heating to 70 ° C. Then, it was mixed at room temperature with water, the organic solvent was distilled off very extensively under reduced pressure, the aqueous phase was extracted extensively with chloroform, the extract, after drying over sodium sulfate, was concentrated under reduced pressure and the residue was purified by filtration through a column of silica gel in the eluent chloroform, resulting 150.4 g (91% of theory) of an oil product, which gradually solidified and could be recrystallized in ethyl ester of acetic acid mediating the addition of petroleum ether at the boiling temperature. Yield: 136.8 g (82% of theory); melting point 98 ° C C17H24N403 (MW = 332.41 g / mol) Analysis: Calculated: C 61.42% H 7.28% N 16.86% Found: C 61.48% H 7.37% N 16 , 68% D2) 1- (8-Diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propyl-xanthine 16.6 g (50 mmol) of the compound were stirred at reflux for 5 hours. intermediate from stage DI), 1.8 g (60 mmol) of paraformaldehyde, 7.3 g (0.1 mol) of diethylamine and 0.8 g of zinc chloride (II) in 250 ml of dry dioxane.

After that, the solvent was removed by distillation under reduced pressure and the reddish oily residue was purified by filtration through a column of silica gel in the eluting agent mixture of chloroform and methanol (19: 1). Yield: 12.6 g (60% of theory); light yellow oil C22H35N503 (P.M. = 417.56 g / mol) F3) 1- (8-Diethylamino-5-hydroxy-5-methyl-oc -6-ynyl) -3-methyl-7-propyl-xan ina hydrochloride For the formation of salts, 12.6 g (30%) mmol) of the base from step D2) were dissolved in 30 ml of 1N hydrochloric acid, concentrated by evaporation under reduced pressure to dryness, the solid residue was dried overnight in a vacuum of an oil pump, collected with hot ethanol, the solution was decolorized with activated charcoal, filtered hot, mixed at boiling temperature with diisopropyl ether until turbidity and the hydrochloride was allowed to separate by crystallization on cooling. Yield: 11.5 g (84% of theory); mp 132 ° C C22H36C1N503 (MW = 454.03 g / mol) Analysis: Calculated: C 58.20% H 7, 99% Cl 7, 81% N 15.43% Found: C 58.22% H 8 , 24% Cl 7.84% N 15.37% according to process variants C and F: Cl) N, N-diethyl-2-propynylamine A mixture of 100 ml (0.16 mol) of a 1.6 M solution of n-butyllithium in n-hexane and 100 ml of tetrahydrofuran was cooled to -78 ° C under stirring and mixed at this temperature dropwise with 11.7 g (0.16 mol) of diethylamine; it was then allowed to come to room temperature, stirring was continued for one hour, cooled again to -20 ° C and a solution of 9.04 g (76 mmol) of 2-bromide was added dropwise thereto. -propynyl in 50 ml of tetrahydrofu- rano The reaction mixture was allowed to stand overnight at room temperature, then it was incorporated by stirring in a cold aqueous solution of phosphate buffer, it was extracted extensively with chloroform, the extract was dried over sodium carbonate, concentrated and the residue was concentrated. fractionally distilled on a column. Yield: 6.2 g (73% of theory); boiling point: 117 ° C (literature: 119 ° C) C17H13N (P.M. = 111.19 g / mol) C2) 1- (8-Diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propyl-xanthine To 5.8 g (52 mmol) of N, N-diethyl-2 -propinyl-amine dissolved in 40 ml dry tetrahydrofuran, from the Cl stage), were added dropwise, at temperatures between -60 ° C and -65 ° C, in the course of 30 minutes, 32.4 ml ( 52 mmol) of a 1.6 M solution of n-butyllithium in n-hexane. Stirring was continued for one hour at -70 ° C, then warmed to room temperature and mixed for 20 minutes dropwise with a solution of 12.3 g (40 mmol) of 3-methyl-1- (5- oxo-hexyl) -7-propyl-xanthine in 60 ml of tetrahydrofuran, raising the temperature of the reaction mixture to 35 ° C. After stirring for four hours at room temperature, 100 ml of cold 1N hydrochloric acid were added thereto, stirring was carried out several times with dichloromethane, the aqueous phase was made alkaline with sodium carbonate, the reaction product was extracted with dichloromethane, dried over sodium sulfate and concentrated under reduced pressure. The oily residue was purified by filtration through a column of silica gel in the eluting agent mixture of chloroform and methanol (19: 1). Yield: 13.9 g (83% of theory); colorless oil C22H35N503 (P.M. = 417.56 g / mol) F3) 1- (8-Diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propyl-xan ina hydrochloride The transformation of 13.9 g (33.3 mmol) ) of the base from step C2) in the hydrochloride was carried out as described in the case of variant D of the process, although the use of activated carbon can be dispensed with when recrystallizing from a mixture of ethanol and diisopropyl -tether Yield: 13.8 g (91% of theory); melting point: 132 ° C C22H36C1N503 (MW = 454.03 g / mol) Analysis: Calculated: C 58.20% H 7.99% Cl 7.81% N 15.43% Found: C 58.02% H 8.26% Cl 7.94% N 15.27% according to process variants B and F: Bl) 1-Chloro-5-hydroxy-5-methyl-6-heptin 200 g (2.17 mol) of lithium acetylide in the form of the complex were suspended with ethylene diamine in 800 ml of dry dioxane and, with vigorous stirring and ice cooling, were mixed with, 2 g (2.0 mol) of l-chloro-5-hexanone in rapid succession of dropping, raising the temperature to 48 ° C. The exothermic reaction was allowed to stop without further external cooling with subsequent stirring for 3 hours, 500 ml of water was carefully added thereto, filtered, most of the dioxane was distilled off under reduced pressure, the aqueous phase was extensively extracted with The chloroform was dried, the extract was dried over sodium sulfate, the solvent was removed by evaporation under reduced pressure and the residue was subjected to fractional crystallization: Yield: 190.2 g (59% of theory); Boiling point (8 mbar): 87-88 ° C C8H13C10 (P.M. = 160.65 g / mol) B2) 1- (5-Hydroxy-5-methyl-hept-6-ynyl) -3-methyl-7-propyl-xanthine The mixture of 6.25 g (30 mmol) of 3-methyl-7-propyl-xanthine 4.8 g (30 mmol) of the chloroalquinol from the Step Bl) and 4.15 g (30 mmol) of potassium carbonate in 150 ml of dimethylformamide was stirred for 3 hours at 130 ° C, then filtered hot and concentrated under reduced pressure, the residue was taken up in chloroform , it was washed first with 1N sodium hydroxide solution and then with neutral water, dried over sodium sulfate, the solvent was distilled off under reduced pressure and recrystallized from ethyl acetate by addition of petroleum ether at boiling point. . Yield: 3.6 g (36% of theory); melting point 98 ° C ci7H24N4 ° 3 (MW = 332.41 g / mol) Analysis: Calculated: C 61.42% H 7.28% N 16.86% Found: C 61.63% H 7.41% N 16.87% This intermediate compound, identical to the product of Example 1D1) could be transformed into the final product by a Mannich reaction with paraformaldehyde and diethylamine and with salt formation (Examples 1D2) and 1F3)). according to variants A and F of process Al) 1-Chloro-8-diethylamino-5-hydroxy-5-yl-6-octyne To a solution of 2.0 g (18 mmol) of N, N-diethyl-2 -propynyl-amine (Example 1C1)) in 50 ml of tetrahydrofuran was added dropwise slowly at -78 ° C 12.37 ml (19.8 mmol) of a 1.6 M solution of n-butyllithium in n-hexane. After one hour at -78 ° C, it was warmed to room temperature and mixed with 2.42 g (18 mmol) of 1-chloro-5-hexanone. Stirring was continued for one hour at room temperature, adjusted to pH 7 with 2N hydrochloric acid and partitioned between a 5% solution of sodium hydrogencarbonate and dichloromethane. The organic phase was dried over magnesium sulfate and freed from the solvent under reduced pressure. Yield: 4.38 g (99% of theory); oily product C13H24C1N0 (P.M. = 245.83 g / mol); H NMR (DMS0-d6, 200 MHz): fi 0.97 (t, 6 H, N (CH 2 CH 3) 2); 1.33 (S, 3 H, CH 3); 1.40-1.85 (m, 6 H, CH2); 2.45 (q, 4 H, N (CH2CH3) 2); 3.33 (s, 2 H, NCH2C = C); 3.63 (t, 2 H, CH2C1); .12 (S, 1H, OH) The substance could be used without further purification directly in the alkylation reaction of step A2).

A2) 1- (8-Diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propyl-xanthine To a hot solution at 60 ° C of 2.0 g (9.6 mmol) of 3-methyl-7-propyl-xanthine in 60 ml of dimethylformamide was added 2.12 g (15.3 mmol) of potassium carbonate, and stirred for one hour at 60 ° C. Then, 3.07 g (12.5 mmol) of l-chloro-8-diethylamino-5-hydroxy-5-methyl-6-octine from stage Al) were added dropwise thereto and stirred for 12 hours, 5 hours at 80 ° C. It was then allowed to cool to room temperature, water was added and it was extracted three times with tere. -butyl-methyl-ether. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by flash chromatography, in a mixture of dichloromethane and methanol = 19/1. Yield: 2.29 g (57% of theory); yellowish oil C22H35N503 (P.M. = 417.56 g / mol) The substance was identical to the products prepared in Examples 1D2) and 1C2) and could be converted to the hydrochloride analogously to Example 1F3) Example.- Hydrochloride of (+) -1- (8-diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propy1-antine Example lb: (-) - Hydrochloride 1- (8-diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7- ropi1-antine according to the H and F variants of the process: The racemic 1- (8-diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propyl-xanthine hydrochloride prepared in Example 1 according to the variants A, B, C or D and F of the procedure, it was separated in the pure bases as for the enanti by means of high pressure liquid chromatography (HPLC) in a column (250 x 4.6 mm) with a chiral support material (CSP Chiralpak AD) in the eluting agent mixture of n-hexane and 2-propanol (85 + 15) with addition of diethylamine to the 0.1%. C22H35N503 (M.P. = 417.56 g / mol) Enantiomer (+): retention time 11.61 minutes; Optical purity 100% Enantiomer (-): retention time 14.46 minutes; 100% optical purity. The transformation of the enantiomer bases into the hydrochlorides was carried out according to Example 1F3) in the case of variant C of the process. C22H36C1N503 (P.M. = 454.03 g / mol) Enantiomer (+) la: yield 82%; melting point 86 ° C Enantiomer (-) lb: yield 70%; melting point 89 ° C Example 2: N, N-Diethyl-N- [4-hydroxy-methyl-8- (3-methyl-7-propyl-xanthine-1-yl) -oct-2-ynyl) -N-methyl- iodide ammonium (according to the variant G of the procedure) 1 g (2.4 mmol) of l- (8-diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propyl-xanthine prepared according to Examples 1A2) was initially introduced. , 1C2) or 1D2) - in 30 ml of diethyl ether, was mixed with 425 mg (3.0 mmol) of methyl iodide and stirred at room temperature for 20 hours. After this, 212 mg (1.5 mmol) of methyl iodide were again added thereto and stirred under reflux for 2 hours. The resulting crystallized material was filtered off with suction, washed with diethyl ether and dried. Yield: 813 mg (60% of theory); melting point: 160 ° C C23H38IN5 ° 3 (P-M- = 559.51 g / mol); Mass spectrum: 432 (100%, M +) Example 3: 1- (6-Dimethylamino-3-hydroxy-3-methyl-hex-4-ynyl) -3-methyl-7-propyl-xanthine fumarate according to process variants C and F: Cl) 1- (6-Dimethylamino-3-hydroxy-3-methyl-hex-4-ynyl) -3-methyl-7-propyl-xanthine 4.32 g were reacted ( 52 mmol) of N, N-dimethyl-2-propynylamine, 32.4 ml (52 mmol) of n-butyllithium in the form of a 1.6 M solution in n-hexane and 11.1 g (40 mmol). mmol) of 3-methyl-1- (3-oxo-butyl) -7-propyl-xanthine in tetrahydrofuran, analogously to Example 1C2), and were treated, but chloroform was used instead of dichloromethane as the extraction agent. Yield: 13.2 g (91% of theory); oily product C18H27N503 (P M = 361, 45 g / mol) F2) 1- (6-dimethylamino-3-hydroxy-3-methyl-hex-4-ynyl) -3-methyl-7-propyl-xan ina fumarate For the transformation of the base into the fumarate, the 2 g (36.5 mmol) of the oily substance from step Cl) in 50 ml of ethanol were added and mixed with a hot solution of 4.24 g (36.5 mmol) of fumaric acid in 100 ml of ethanol. . It was then concentrated to incipient cloudiness, boiled and the salt was allowed to separate by crystallization. Yield: 14.1 g (81% of theory); melting point: 170 ° C C22H31N507 (P.M. = 477.53 g / mol) according to process variants D and F: DI) 1- (3-Hydroxy-3-methyl-pent-4-ynyl) -3-methyl-7-propyl-xanthine To a suspension of 36.8 g (0.4 mol) of lithium acetylide in complex form with ethylenediamine and 98.6 g (0.4 mol) of anhydrous cerium (III) chloride, in a mixture in each In the case of 500 ml of dry dioxane and toluene, a solution of 55.7 g (0.2 mol) of 3-methyl-1- (3-) was added dropwise in 45 minutes with stirring at 50 ° C. oxo-butyl) -7-propyl-xanthine in a mixture of in each case 200 ml of dioxane and toluene. Then, stirring was continued for 7 hours at 50 ° C, cooled, mixed with cold water, acidified with 2N hydrochloric acid, extracted intensely with chloroform, the extract was washed with water, dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by filtration through a column of silica gel in the eluent mixture of chloroform and methanol (50: 1), obtaining 35.0 g (58% of theoretical yield) of a solid material, which was recrystallized from ethanol with many losses. Yield: 18.0 g (30% of theory); melting point: 149 ° C C15H20N403 (MW = 304.36 g / mol) Analysis: Calculated: C 59.20% H 6.62% N 18.41% Found: C 58.72% H 6.51% N 18.33% This intermediate compound could be reacted by a Mannich reaction with paraformaldehyde and dimethylamine hydrochloride, analogously to Example 1D2), and subsequent formation of the salt, according to Example 3F2), to give the final product.

Example 4: 1- (5-Hydroxy-5-methyl-8-pyrrolidino-oct-6-ynyl) -3-methyl-7-propyl-xanthine fumarate (according to process variants B or D and F).

The mixture of 9.97 g (30 mmol) of intermediate 1- (5-hydroxy-5-methyl-hept-6-ynyl) -3-methyl-7-propyl-xanthine, from Example 1D1) or prepared according to Example 1B2), 1.02 g (34 mmol) of paraformaldehyde, 2.05 g (34 mmol) of glacial acetic acid, 2.42 g (34 mmol) of pyrrolidine and 0.6 g of copper chloride (I ) in 150 ml of dry dioxane was stirred at 45 ° C for 18 hours, then concentrated under reduced pressure, it was taken up in dichloromethane, extracted three times, each time with 70 ml of 1N hydrochloric acid, the acid extract was made alkaline with sodium carbonate and the product was extracted by stirring with dichloromethane. After drying over sodium sulphate and concentrated by evaporation under reduced pressure, the Mannich base (C22H33N503, MW = 415.55 g / mol) resulted in an almost quantitative yield as an oily crude product, which was transformed into the fumarate with 3.5 g (30 mmol) of fumaric acid, analogously to Example 3F2). Yield: 12.4 g (78% of theory); melting point: 151 ° C C26H37N507 (MW = 531.62 g / mol) Analysis: Calculated: C 58.74% H 7.02% N 13.17% Found: C 58.18% H 6.81% N 18.68% Example 5: 1- (9-Diethylamino-6-hydroxy-6-methyl-non-7-ynyl) -3-methyl-7-propyl-xanthine hydrochloride (according to process variants D and F) DI) 1- (6-Hydroxy-6-methyl-oct-7-ynyl) -3-methyl-7-propyl-xanthine Under a nitrogen atmosphere, with the exclusion of moisture and with stirring, 2.55 were mixed g (26 mmol) of ethynyltrimethylsilane in 25 ml of tetrahydrofuran, at -60 ° C to -70 ° C in 45 minutes, dropwise, with 16.2 ml (26 mmol) of a 1.6 solution. M of n-butyl lithium in n-hexane, stirring was continued for one hour at -70 ° C, allowed to come to room temperature and 6.4 g (20 mmol) were added dropwise over the course of 20 minutes. ) of 3-methyl-1- (6-oxo-heptyl) -7-propyl-xanthine in 20 ml of tetrahydrofuran. Then, stirring was continued for 4 hours at room temperature, 50 ml of cold 1N hydrochloric acid was added, it was extracted extensively with chloroform, the organic phase was dried over sodium sulfate, concentrated by evaporation under reduced pressure and the oily residue it was purified by filtration through a column of silica gel in the agent eluent mixture of chloroform and methanol (10: 1), obtaining 6.8 g (81% of the theoretical yield) of the trimethylsilylated alkynol in the ethynyl C21H34N403Si (MW = 418.62 g / mol, melting point: 91 ° C ). For desilylation, a solution of 4.19 g (10 mmol) of this product in 50 ml of methanol was stirred after adding 58.1 mg (1 mmol) of potassium fluoride for 2 hours at reflux. After that, it was concentrated under reduced pressure, taken up in chloroform, washed with water, dried over sodium sulfate and the solvent was removed under reduced pressure. The oily residue crystallized thoroughly after prolonged rest and was extracted with stirring in petroleum ether. Yield: 3.2 g (92% of theory); melting point: 79 ° C C18H26N403 (MW = 346.44 g / mol) Analysis: Calculated: C 62.41% H 7.56% N 16.17% Found: C 62.23% H 7.41% N 16.41% This intermediate compound could also be prepared by reaction of oxoalkyl-xanthine with lithium acetylide, both analogously to Example 1D1) and also by a reaction aided with cerium (III) chloride according to Example 3D1), but yields, with values of 30 to 50%, were clearly lower, since especially in this case the tendency of the acetylene molecule to react on both sides with the ketone, with the formation of the alkynediol C34H5oNs, became noticeable in a particularly disturbing manner. ° 6 (MW = 666.84 g / mol, melting point: 129 ° C) as a by-product, and the pure isolation of the desired monosubstituted product was carried out with extraordinarily large losses.

D2) 1- (9-Diethylamino-6-hydroxy-6-methyl-non-7-ynyl) -3-methyl-7-propyl-xanthine The Mannich reaction was subjected to 10.4 g (30 mmol) of the compound intermediate prepared according to step Di), analogously to Example 4 with use of 2.49 g (34 mmol) of diethylamine instead of pyrrolidine. The oily crude product obtained was purified by filtration through a column of silica gel in the eluting agent mixture of chloroform and methanol (10: 1). Yield: 8.3 g (64% of theory); oil product C33H37N503 (P.M. = 431.59 g / mol) F3) 1- (9-Diethylamino-6-hydroxy-6-methyl-non-7-ynyl) -3-methyl-7-propyl-xanthine hydrochloride The 8.3 g (19.2 mol) of the base of Mannich from step D2) were dissolved in methanol and mixed with a stoichiometric amount of methanolic hydrochloric acid. The solvent was distilled off under reduced pressure, the residue was dried under high vacuum, digested with dry diethyl ether and the solid material was filtered off with suction. Yield: 8.8 g (98% of theory); melting point: approximately 100 ° C (hygroscopic); C23H38C1N503 (P.M. = 468.05 g / mol) Example 6: 1- (6-Dibutylamino-3-hydroxy-3-methyl-hex-4-ynyl) -3-methyl-7-propyl-xanthine hydrochloride (according to process variants C and F) Cl) 1- (6-Dibutylamino-3-hydroxy-3-methyl-hex-4-ynyl) -3-methyl-7-propyl-xanthine To a solution of 2.09 ml (10.77 mmol) of N, N-dibutyl-2-propynyl-amine in 20 ml of tetrahydrofuran was slowly added at -65 ° C to -70 ° C 6.73 ml (10.77 mmol) of a 15% solution of butyl lithium in n. -hexane. It was stirred for one hour at -60 ° C to -65 ° C, warmed to room temperature and a solution of 2.0 g (7.18 mmol) of 3-methyl- (3-oxo-butyl) was added. -7-propyl-xanthine in 30 ml of tetrahydrofuran. After 30 minutes the slightly exothermic reaction was terminated. It was adjusted to pH 5-6 with 1 N hydrochloric acid and partitioned between dichloromethane and water. The organic phase was washed with water, dried with magnesium sulfate and it was concentrated under reduced pressure. The oily crude product was purified by flash chromatography, in a mixture of dichloromethane and methanol = 19 / 0.75. Yield: 2.37 g (74% of theory); melting point: 73 ° C C24H39N503 (P.M. = 445.61 g / mol) F2) 1- (6-Dibutylamino-3-hydroxy-3-methyl-hex-4-ynyl) -3-methyl-7-propyl-xanthine hydrochloride. 597 mg (1.34 mmol) of the xanthine prepared in Step Cl) in 1.34 ml of 1N hydrochloric acid was concentrated under high vacuum, extracted by stirring with diethyl ether for 2 days and filtered. Yield: 591 mg (91% of theory); melting point: 179 ° C C24H4 0C1N503 (P M = 482, 07 g / mol) Mass spectrum: 446.5 (100%, M + H); 428.5 (32%) Example 7: 1- (6-N-Benzyl-N-methylamino-3-hydroxy-3-methyl-hex-4-ynyl) -3-methyl-7-propyl-xanthine fumarate (according to variants C and F of the process) Cl) 1- (6-N-Benzyl-N-methylamino-3-hydroxy-3-methyl-hex-4-ynyl) -3-methyl-7-propyl-xanthine 1- (6-N-benzyl) N-methylamino-3-hydroxy-3-methyl-hex-4-ynyl) -3-methyl-7-propyl-xanthine by using 3-methyl-1- (3-oxo-butyl) -7-propyl-xanthine and N-benzyl-N-methyl-2-propynylamine according to Example 6C1) as an oily substance with a yield of 86%. C24H31N503 (P.M. = 437.55 g / mol) F2) 1- (6-N-benzyl-N-methylamino-3-hydroxy-3-methyl-hex-4-ynyl) -3-methyl-7-propyl-xan ina fumarate 540 mg (1%) was dissolved in ethanol. , 23 mmol) of the xanthine prepared in step Cl), were mixed with a hot solution of 146 mg (1.23 mmol) of fumaric acid in ethanol and stirred at 50 ° C for 30 minutes. It was concentrated under high vacuum, extracted by stirring in diethyl ether and filtered. Yield: 570 mg (83% of theory); melting point: 104 ° C C28H35N507 (M.P. = 553, 62 g / mol) Mass spectrum: 438.4 (100%, M + H); 420.4 (87%) Example 8: 1- (4-Hydroxy-4-methyl-7- [4-methyl-piperazino] -hept-5-ynyl) -3-methyl-7-propyl-xanthine fumarate according to variants C and F of the Cl method) 4-Methyl-1- (2-propynyl) -piperazine To a solution of 22.2 ml (0.20 mol) of N-methyl-piperazine in 100 ml of toluene 11.1 ml (0.10 mol) of an 80% solution of 2-propynyl bromide in toluene were added by ice-cooling. After reflux for 30 minutes, the resulting N-methyl-piperazine hydrobromide was filtered off with suction, washed with toluene, the filtrate was washed in each case twice with 15% sodium hydroxide solution and with a saturated chloride solution. of sodium, concentrated and distilled in vacuo. Yield: 4.19 g (30% of theory); boiling point: 100 ° C / 47 mbar (GC gas chromatography: 98.6%) C8H14N2 (P.M. = 138.21 g / mol) Mass spectrum: 139.2 (100%, M + H); 138.2 (22%); 101.1 (24%); XH-NMR (DMS0-d6, 300 MHz): d 2.10-2.54 (m, 8 H, CH2); 2.13 (s, 3 H, NCH 3); 3.12 (t, 1 H, C = CE); 3.23 (d, 2 H, NCH2C = C) C2) 1- (4-Hydroxy-4-methyl-7- [4-methyl-piperazino] -hept-5-ynyl) -3-yl-7-propyl-xan ina fumarate 1- (4- hydroxy-4-methyl-7- [4-methyl-piperazino] -hept-5-ynyl) -methyl-7-propyl-xanthine using 3-methyl-1- (4-oxo-pentyl) -7-propyl -xanthin and 4-methyl-l- (2- propinyl) -piperazine from the Cl step), according to Example 6C1), in the form of an oily substance in a yield of 82%. Formation of the salt with fumaric acid was achieved according to Example 7F2) in a yield of 55%. Melting point: 168 ° C C26H38N607 (P.M. = 546.63 g / mol), base C22H34N603 (M.M. = 430.56 g / mol) mass spectrum: 431.4 (100%, M + H); 413.4 (7%) according to process variant D: DI) 1- (4-Hydroxy-4-methyl-hex-5-ynyl) -3-methyl-7-propyl-xanthine This intermediate of the formula IX was formed from methyl-1- (4-oxo-pentyl) -7-propyl-xanthine both by ethynylation aided by cerium (II) chloride with lithium acetylide according to Example 3D1) in 67% yield, as well as by reaction with ethynyl lithiated trimethyl silane and subsequent desilylation analogously to Example 5D1) in an overall yield of 69%. C 16 H 22 N 403 (M.P. = 318.38 g / mol); melting point: 108 ° C Analysis: Calculated: C 60.36% H 6.97% N 17.60% Found: C 60.09% H 7.10% N 17.39% The reaction of this product with N -methyl-piperazine and paraformaldehyde according to Mannich under the reaction conditions described in Example 4, also led to the title compound of the present example in the form of the base.

Example 9: 1- (5-Diethylamino-2-hydroxy-2-methyl-pent-3-ynyl) -3-methyl-7-propyl-xanthine fumarate (according to process variants C and F) 1- (5-Diethylamino-2-hydroxy-2-methyl-pent-3-ynyl) -3-methyl-7-propyl-xanthine was prepared using 3-methyl-1- (2-oxo-propyl) - 7-propyl-xanthine and N, N-diethyl-2-propynylamine according to Example 6C1) as an oily substance in a 48% yield. The formation of the salt with fumaric acid is achieved in accordance with Example 7F2) in a yield of 98. . Melting point: 109 ° C C23H33N5 ° 7 (p.- = 491.56 g / mol), base C19H29N503 (MW = 375.48 g / mol) mass spectrum: 376.2 (30%, M + H); 358.2 (66%); 285.1 (100%); 150.2 (48.) Example 10: 1- (7-Dipropylamino-4-hydroxy-4-yl-hept-5-ynyl) -3-ethyl-7-propyl-xanthine hemifumarate (according to process variants C and F) Cl) 1- (7-dipropylamino-4-hydroxy-4-methyl-hept-5-ynyl) -3-ethyl-7-propyl-xanthine To a solution of 1.36 ml (7.8 mmol) of N, N-dipropyl-2-propynylamine in 6 ml of tetrahydrofuran was added dropwise slowly at -78 ° C 5.3 ml (8.45 mmol) of a 15% solution of butyllithium in n-hexane and stirred for one hour at -78 ° C. After heating to room temperature, a solution of 2.0 g (6.5 mmol) of 3-ethyl-1- (4-oxo-pentyl) -7-propyl-xanthine in 8 ml of tetrahydrofuran was added. After 7 hours at room temperature, it was adjusted to pH 6-7 with 4 N hydrochloric acid and partitioned between a 5% solution of sodium hydrogencarbonate and dichloromethane. The organic phase was dried with magnesium sulfate, concentrated under reduced pressure and purified by flash chromatography in a mixture of dichloromethane and methanol = 19/1. Yield: 0.71 g (24% of theory), oily product, C24H39N503 (M.P. = 445.62 g / mol) F2) 1- (7-Dipropylamino-4-hydroxy-4-methyl-hept-5-ynyl) -3-ethyl-7-propyl-xanthine hemifumarate The formation of the salt to give hemifumarate was achieved with 1 equivalent of fumaric acid according to Example 7F2) with a yield of 86%. Melting point: 117 ° C C26H41N505 (M.P. = 503.65 g / mol) Mass spectrum: 446.2 (100%, M + H); 329.2 (50%); 307.1 (56%); 100.1 (83%); XH-NMR (DMS0-d6, 200 MHz): d = 0.79 (t, 6 H, N (CH 2) 2 CH 3) 2); 0.83 (t, 3 H, N7 (CH2) 2-CH3); 1.23 (t, 3 H, N 3 CH 2 CH 3); 1.33 (s, 3 H, CH 3); 1.26-1.89 (m, 10 H, CH2); 2.32 (t, 4 H, N (CH 2 CH 2 CH 3) 2); 3.31 (s, 2 H, NCH2C = C); 3.88 (t, 2 H, N1-CH2); 4.03 (q, 2 H, N3-CH2); 4.20 (t, 2 H, N7-CH2); 5.12 (S, 1 H, OH); 6.61 (s, 1 H, C = CH-COOH); 8.10 (s, 1 H, N = CH) Example 11: 1- (8-dimethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-ethyl-7-propyl-xanthine fumarate (according to process variants C and F) 1- (8-Dimethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-ethyl-7-propyl-xanthine was prepared using 3-ethyl-1- (5-oxo-hexyl) - 7-propyl-xanthine and N, N-dimethyl-2-propynylamine according to Example 6C1) in the form of an oily substance in a yield of 57%. The formation of the salt to give the fumarate was achieved according to Example 7F2) in a yield of 51%. Melting point: 117 ° C C25H37N507 (M.P. = 519.60 g / mol); base C 21 H 33 N 503 (P M = 403.54 g / mol) mass spectrum: 404.2 (100%, M + H); 386.2 (44%); 321.2 (49%) Example 12: 3-ethyl-1- (3-hydroxy-3-methyl-6-pyrrolidino-hex-4-ynyl) -7-propyl-xanthine fumarate (according to process variants C and F) 3-Ethyl-1- (3-hydroxy-3-methyl-6-pyrrolidino-hex-4-ynyl) -7-propyl-xanthine was prepared using 3-ethyl-1- (3-oxo-butyl) - 7-propyl-xanthine and N- (2-propynyl) -pyrrolidine according to Example 6C1) as an oily substance in a 50% yield. The formation of the salt to give the fumarate was carried out as in Example 7F2) in a yield of 90%.

Melting point: 133 ° C C25H3 5N507 (P M = 517, 59 g / mol), base C21H31N503 (P M = 401, 52 g / mol) mass spectrum: 402.2 (100%, M + H); 116.9 (65%) Example 13: 3, 7-Dipropyl-1- (5-hydroxy-5-methyl-8- [4-methyl-piperazino] -oct-6-ynyl) xanthine fumarate (according to process variants C and F) 3,7-Dipropyl-1- (5-hydroxy-5-methyl-8- [4-methyl-piperazino] -oct-6-ynyl) -xanthine was prepared using 3,7-dipropyl-1- (5 -oxo-hexyl) -xanthine and 4-methyl-1- (2-propynyl) -piperazine from Example 8C1), according to Example 6C1), as an oily substance in a 71% yield. The formation of the salt to give the fumarate was achieved according to Example 7F2) in a yield of 95%. Melting point: 98 ° C C29H44N607 (M.M. = 588.71 g / mol), base C25H40N6O3 (P.M. = 472.64 g / mol) mass spectrum: 473.2 (98%, M + H); 335.1 (95%); 138, 9 (100%); 85.1 (67%) Example 14: 3-Butyl-1- (5-hydroxy-5-methyl-8-piperidino-oct-6-ynyl) -7-propyl-xanthine hydrochloride (according to process variants C and F) Cl) 3-Butyl-1- (5-hydroxy-5-methyl-8-piperidino-oct-6-ynyl) -7-propyl-xanthine The compound was prepared using 3-butyl-1- (5-oxo) hexyl) -7-propyl-xanthine and N- (2-propynyl) -piperidine, according to Example 6C1) as an oily substance in a yield of 58%. C26H41N503 (P.M. = 471.65 g / mol) F2) 3-Butyl-1- (5-hydroxy-5-methyl-8-piperidino-oct-6-ynyl) -7-propyl-xanthine hydrochloride 470 mg (1 mmol) of the xanthine prepared in methanol were dissolved in methanol. Step Cl) were mixed with 1 ml of 1N hydrochloric acid, concentrated in high vacuum, extracted by stirring with acetone and filtered. Yield: 450 mg (84% of theory), melting point: 177 ° C. 'C26H42C1N503 (M.P. = 508.11 g / mol) mass spectrum: 472.5 (100%, M + H); 454.4 (12%) Example 15: 3-Butyl-1- (6-dipropylamino-3-hydroxy-3-methyl-hex-4-ynyl) -7-propyl-xanthine (according to variant C of the process) 3-Butyl-1- (6-dipropylamino-3-hydroxy-3-methyl-hex-4-ynyl) -7-propyl-xanthine was prepared using 3-butyl-1- (3-oxo-butyl) - 7-propyl-xanthine and N, N-dipropyl-2-propynylamine according to Example 6C1) in a yield of 28%. Melting point: 101 ° C; C25H4 1N503 (P .M. = 459, 64 g / mol) mass spectrum.- 460.2 (100%; M + H); 442.2 (15%) Example 16: 3-Butyl-1- (5-hydroxy-5-methyl-8-morpholino-oct-6-ynyl) -7-propyl-xanthine hydrochloride (according to process variants C and F) 3-Butyl-1- (5-hydroxy-5-methyl-8-morpholino-oct-6-ynyl) -7-propyl-xanthine was prepared using 3-butyl-1- (5-oxo-hexyl) - 7-propyl-xanthine and N- (2-propynyl) -morpholine, according to Example 6C1), in the form of an oily substance in a yield of 76%. Formation of the salt to give the hydrochloride was achieved according to Example 14F2) in an 86% yield. Melting point: 126 ° C. C25H4 0ClN5O4 (P. M = 510, 08 g / mol), base C2 bH3gN., 04 (P M = 473, 63 g / mol) Mass spectrum: 474.3 (100%, M + H); 456.4 (83%) Example 17: 7- (8-Diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-l-propyl-xanthine hydrochloride according to process variants C and F: 7- (8-diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-1-propyl-xanthine was prepared using 3-methyl-7 - (5-oxo-hexyl) -1-propyl-xanthine and of N, N-diethyl-2-propynylamine, according to Example 6C1), in the form of an oily substance in a yield of 35%. Formation of the salt to give the hydrochloride was achieved according to Example 14F2) in a 64% yield. Melting point: 127 ° C C22H36C1N503 (MW = 454.01 g (mol), base C22H35N503 (MW = 417.55 g / mol) mass spectrum: 418.3 (100%, M + H); 400.3 (35%) according to process variants B and F: Bl) 7- (5-Hydroxy-5-methyl-hept-6-ynyl) -3-methyl-xanthine. 33.2 g (0%) were stirred at 120 ° C for 6 hours. 2 mol) of 3-methyl-xanthine in 350 ml of dimethylformamide with 32.1 g (0.2 mol) of l-chloro-5-hydroxy-5-methyl-6-heptin from Example 1B1) in the presence , 8 g (0.1 mol) of potassium carbonate. Afterwards the hot mixture was filtered, concentrated by evaporation under reduced pressure to dryness, taken up in ethanol, mixed at boiling temperature with diisopropyl ether until cloudy and allowed to separate by crystallization on cooling. Yield: 38.8 g (67% of theory); melting point: 173 ° C C14H18N403 (MW = 290.33 g / mol) Analysis: Calculated: C 57.92% H 6.25% N 19.30% Found: C 57.62% H 6.27% N 19.20% B2) 7- (5-Hydroxy-5-methyl-hept-6-ynyl) -3-methyl-1-propyl-xanthine 19.5 g (67 mmol) of the intermediate from stage Bl was reacted, 9.3 g (67 mmol) of potassium carbonate and 8.24 g (67 mmol) of propyl bromide in 200 ml of dimethylformamide - as described in step Bl) -. Purification of the oily crude product was effected by filtration through a column of silica gel with ethyl acetate as the eluent and subsequent recrystallization of the solid material in diisopropyl ether with the addition of ethyl acetate at the boil until the transparent solution is given. Yield: 15.1 g (68% of theory); melting point: 97 ° C C17H24N403 (P M = 332, 41 g / mol) Analysis: Calculated: C 61.42% H 7.28% N 16.86% Found: C 61.20% H 7, 39% N 16.74% The products of steps Bl) and B2) are obtainable as compounds of formula IX from the Mannich reaction. Thus, the reaction of the alkynol from step B2) with diethylamine and paraformaldehyde, analogously to Example 4, and the formation of the salt according to Example 1F3) also provided the co-taxation of the title of the present Example.

Example 18: 1, 7-Bis- (8-diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-xanthine (according to variant C of the process) The compound was prepared with the use of 1, 7-bis- (5-oxo-hexyl) -3-methyl-xanthine and N, N-diethyl-2-propynylamine according to Example 6C1) as an oily substance in a yield of 30%. C32H52N6 ° 4 (-M- = 584.82 g / mol) XH-NMR (DMS0-d6, 300 MHz) d = 0.93 and 0.94 (2 t, 12 H, N (CH2CH3) 2); 1.20-1.62 and 1.71-1.85 (m, 12 H, CH2); 1.31 (s, 6 H, CH 3); 2.32-2.48 (ra, 8 H, N (CH 2 CH 3) 2); 3.35 (2 s, 4 H, NCH2C = C); 3.42 (s, 3 H, N 3 CH 3); 3.80-3.90 (m, 2 H, N7CH2); 4.24 (t, 2 H, N1CH2); 5.10 and 5.11 (2 s, 2 H, OH); 8.08 (s, 1 H, N = CH) Example 19: 1- (7-Dipropylamino-4-hydroxy-4-methyl-hept-5-ynyl) -3-methyl-xanthine according to variant C of the procedure. The compound was prepared according to Example 6C1) from 3-methyl-1- (4-oxo-pentyl) -xanthine and N, N-dipropyl-2-propynyl-amine in the form of an oily substance, with a yield of 51% C20H31N5O3 (M.P. = 389.51 g / mol) mass spectrum: 390.2 (100%, M + H); 372.2 (47%) XH-NMR (DMSO-dg, 300 MHz): d = 0.80 (t, 6 H, N (CH 2) 2 -CH 3); 1.32-1.88 (m, 8 H, CH2); 1.32 (s, 3 H, C (OH) CH 3); 2.32 (broad m, 4 H, NCH2-C2H5); 3.33 (s, 2 H, NCH2-C = C); 3.45 (s, 3 H, N3-CH3); 3.90 (t, 2 H, N1- ^); 5.12 (s, 1H, OH); 8.04 (s, 1 H, N = CH); 13.53 (broad s, 1 H, N7-H) according to process variant B: Bl) 7-Ethoxymethyl-1- (5-hydroxy-5-methyl-hept-6-ynyl) -3-methyl-xanthine. 44.84 g (0.2 mol) of 7-ethoxymethyl-3-methyl-xanthine, analogously to Example 1B2), with 32.13 g (0.2 mol) of l-chloro-5-hydroxy-5-methyl-6-heptin from Example 1B1), and were treated. Yield: 52.3 g (75% of theory); melting point: 106 ° C C17H24N404 (P M = 348, 41 g / mol) Analysis: Calculated: C 58.61% H 6.94% N 16.08% Found: C 58.41% H 7, 08% N 15,97% B2) 1- (5-Hydroxy-5-methyl-hept-6-ynyl) -3-methyl-xanthine 41.8 g (0.12 mol) of the alkynol from the stage were stirred at 60 ° C for 4 hours. Bl), in each case in 600 ml of 1 N hydrochloric acid and glacial acetic acid. Afterwards, it was concentrated under reduced pressure, neutralized with 1N sodium hydroxide solution, the product was extracted with chloroform, the extract was dried over sodium sulfate, concentrated by evaporation under reduced pressure and the residue, after purification by Flash chromatography with chloroform as the mobile phase was recrystallized from a mixture of ethanol and petroleum ether. Yield: 23.6 g (68% of theory); melting point 172 ° C C14H18N403 (MW = 290.33 g / mol) Analysis: Calculated: C 57.92% H 6.25% N 19.30% Found: C 57.65% H 6.25% N 19 , 33% The Mannich reaction of this intermediate compound with dipropylamine and paraformaldehyde according to Example 4 also led to the title compound of the present Example.

Example 20: 3-Cyclopropyl-1- (8-diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -7-propyl-xanthine hydrochloride (according to process variants C and F) 3-Cyclopropyl-1- (8-diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -7-propyl-xanthine according to Example 6C1) was prepared from 3-cyclopropyl-1- (5- oxo-hexyl) -7-propyl-xanthine and N, N-diethyl-2-propynylamine in the form of an oily substance in a yield of 89%. Formation of the salt to give the hydrochloride was achieved according to Example 6F2) in a yield of 93%. Melting point: 146 ° C C24H38C1N503 (MW = 480.06 g / mol), base: C24H37N503 (MW = 443.60 g / mol) mass spectrum: 444, 3 (100%; M + H), -426 , 3 (41%); 253.1 (21%) Example 21: 1- (8-Diethylamino-5-hydroxy-oct-6-ynyl) -3-methyl-7-propyl-xanthine hydrochloride (according to process variants C and F) Cl) 1- (8-Diethylamino-5-hydroxy-oct-6-ynyl) -3-methyl-7-propyl-xanthine Under argon and with stirring, they were slowly added dropwise at -78 ° C to a solution of 676 μl (4.9 mmol) of N, N-diethyl-2-propynylamine in 4 ml of tetrahydrofuran, 2.93 ml (4.68 mmol) of a 15% solution of butyllithium in n-hexane. It was stirred at this temperature for one hour, warmed to room temperature and a solution of 1.05 g (3.6 mmol) of 3-methyl-1- (5-oxo-pentyl) -7-propyl was added slowly. -xanthine in 5 ml of tetrahydrofuran. After 1.5 hours the reaction was finished. It was neutralized with 4 N hydrochloric acid, the tetrahydrofuran was removed in vacuo, the residue was taken up in dichloromethane, washed with a saturated solution of sodium hydrogencarbonate, dried over magnesium sulfate, the drying agent was removed by filtration and the solvent it was removed under reduced pressure. The crude product was purified by flash chromatography with the mixture of eluting agents dichloromethane, methanol and saturated ammonia solution = 19/1 / 0.05. Yield: 1.1 g (76% of theory); yellowish oil C21H33N503 (P.M. = 403.53 g / mol) F2) 1- (8-Diethylamino-5-hydroxy-oct-6-ynyl) -3-methyl-7-propyl-xanthine hydrochloride 430 mg (1.07 mmol) of the xanthine prepared in step Cl were dissolved) in 1.07 ml of 1 N hydrochloric acid, concentrated in high vacuum, mixed with pentane and stirred for 3 days. After removal of the pentane, it was mixed with diethyl ether and stirring was continued for another four weeks until complete crystallization. The diethyl ether was removed, and the residue was stirred again for 10 minutes with pentane. After having After removing the pentane, the residue was again treated with pentane, which was then completely removed in the rotary evaporator and then in high vacuum. The product remained as a solid white material. Yield: 460 mg (98% of theory); melting point: 65 ° C C21H34C1N503 (P.M. = 439.99 g / mol) mass spectrum: 404.3 (100%, M + H) Example 22: 1- (8-Amino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propyl-xanthine hydrochloride (according to process variants C and F) Cl) N, N'-bis- (trimethylsilyl) -2-propynylamine Under argon and with stirring were added dropwise slowly at -78 ° C, to a solution of 95 ml of diethyl ether and 95 ml (152 ml). mmol) of a 15% solution of butyllithium in n-hexane, 32 ml (154 mmol) of hexamethyldisilazane. The mixture was allowed to come to room temperature, stirred for one hour, cooled to -20 ° C and 8.24 ml (73 mmol) of an 80% solution of 2- bromide were slowly added dropwise. propinyl in toluene. After the addition, the cooling bath was removed and stirred for 5 hours at room temperature. Then, the reaction mixture was poured into 200 ml of a phosphate buffer, which was composed of 7.36 g of potassium dihydrogen phosphate, 5.81 g of disodium hydrogen phosphate and 200 ml of water. The precipitate was filtered with suction, the phases were separated, the organic phase was washed with water and dried over sodium carbonate, the drying agent was filtered off, the solvent was removed in a rotary evaporator and the residue was fractionated by distillation in vacuum made twice. Yield: 9.26 g (63% of theory); boiling point: 50 ° C / 4 mbar C9H21NSi2 (MW = 199.45 g / mol) XH-NMR (DMS0-d6, 250 MHz): d = 0.11 (s, 18 H, C [Si (CH3) 3] _ ); 3.00 (t, 1 H, C = CH); 3.50 (d, 2 H, NCH2C = C) C2) 1- (8-Amino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propyl-xanthine Under argon and with stirring were slowly added dropwise at -40 ° C, to a solution of 9.26 g (46.5 mmol) of N, N-bis- (trimethylsilyl) -2-propynylamine from step Cl) in 50 ml of tetrahydrofuran, 29 ml (46.5 mmol) of a 15% solution of butyl lithium in n-hexane. Then, it was warmed to room temperature, cooled again to -40 ° C and a solution of 14.25 g (46.5 mmol) of 3-methyl-1- (5-oxo-hexyl) was added slowly. -7-propyl-xanthine in 40 ml of tetrahydrofuran. After having removed the cooling bath, it was stirred at room temperature for 6 hours. Then, the reaction mixture was poured into an ammonium chloride solution, saturated and cooled to 0 ° C, the aqueous phase was extracted with ether, the organic phase was dried over sodium sulfate, the drying agent was filtered off and the solvent was removed under reduced pressure. The crude product was chromatographed with rapid resolution first with the mixtures of eluting agents dichloromethane, methanol and a saturated solution of ammonia = 19 / 1.5 / 2.5 and then 9/1 / 2.5. Yield: 9.79 g (58% of theory); yellowish oil C18H27N503 (MW = 361.45 g / mol) The compound can also be obtained by direct reaction with 2-propynylamine: Under argon and with stirring, they were slowly added dropwise at -78 ° C, to a solution of 630 μl (9.1 mmol) of 2-propynylamine in 20 ml of tetrahydrofuran, 5.3 ml (8.49 mmol) of a 15% solution of butyllithium in n-hexane. It was stirred for one hour at this temperature, warmed to room temperature and a solution of 2.0 g (6.53 mmol) of 3-methyl-1- (5-oxo-hexyl) -7-propyl was slowly added. -xanthine in 5 ml of tetrahydrofuran to the suspension, which in the meantime had turned yellow. After 3 hours, the reaction had stopped. It was neutralized with 2N hydrochloric acid and with a 5% solution of sodium hydrogencarbonate, extracted with dichloromethane, dried over magnesium sulfate, the drying agent was filtered off and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography with the mixture of eluting agents dichloromethane, methanol and saturated ammonia solution = 19/1 / 0.02. Since the 1.4 g obtained from the product were still slightly contaminated, they were again purified by flash chromatography (in the mixture of dichloromethane, methanol and saturated ammonia solution = 19 / 1.5 / 0, 02). Yield: 1.01 g (43%), - yellowish oil F3) 1- (8-amino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propyl-xanthine hydrochloride 940 mg (2.6 mmol) of the xanthine prepared in step C2) in 2.6 ml of 1 N hydrochloric acid, concentrated in high vacuum, mixed with pentane and stirred for 3 weeks. The resulting solid material was filtered with suction. The portion which in this case was again deliquesced (hygroscopic) was added back to the flask, dissolved in a little water, dried in vacuo, mixed again with pentane and stirred. After two days, the pentane was removed, and the remaining powdery solid material was separated from the non-crystallized product. Yield: 587 mg (57% of theory) of a white solid material, melting point: 80 ° C, 345 mg (33% of theory) of a non-crystallized product C18H28C1N503 (MW = 397.91 g / mol ), base: C18H27N503 (MW = 361.45 g / mol) mass spectrum: 362.3 (7%, M + H); 344.2 (59%); 209.0 (100%) Example 23: 1- (8-Ethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propyl-xanthine (according to variant C of the process) Cl) N-Ethyl-2-propynylamine At -78 ° C 33 ml (0.5 mol) of ethylamine were condensed in a heated flask and flushed with argon. After heating to 0 ° C, 5.57 ml (50 mmol) of an 80% solution of 2-propynyl bromide in toluene was slowly added dropwise over 45 minutes. In the gas chromatogram a complete reaction was manifested after one hour. The excess ethylamine was expelled with nitrogen after the ice bath had been removed, the residue was taken up with a mixture of diethyl ether and water, the aqueous phase was extracted several times with diethyl ether, the phases in diethyl ether were combined. dried with potassium carbonate, the drying agent was removed by filtration and the filtrate was concentrated in a rotary evaporator. Subsequent fractional crystallization afforded 937 mg (18% of theory) of a mixture of 83% N-ethyl-2-propynylamine and 17% toluene, which was further reacted directly. C 5 H 9 N (M.M. 83, 15 g / mol) 1 H-NMR (CDC 13, 250 MHz): d = 1.12 (t, 3 H, CH 2 CH 3); 1.30 (broad s, NH); 2.20 (t, 1 H, CaCl); 2.74 (q, 2 H, CH2CH3); 3.42 (d, 2 H, NCH2C = C) C2) 1- (8-Ethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propyl-xanthine Under argon and with stirring were slowly added dropwise at -78 ° C, to a solution of 937 mg (9.35 mmol) of N-ethyl-2-propynylamine (83% in toluene from Cl step) in 30 ml of tetrahydrofuran, 5.43 ml (8.69 mmol) of a 15% solution of butyl lithium in n-hexane. It was stirred for one hour at this temperature, warmed to room temperature and a solution of 2.05 g (6.68 mmol) of 3-methyl-1- (5-oxo-hexyl) -7-propyl was added slowly. - xanthine in 12 ml of tetrahydrofuran to the solution which had turned white in the meantime. After one hour it was neutralized with 2N hydrochloric acid and with a 5% solution of sodium hydrogencarbonate, extracted with dichloromethane, dried over magnesium sulfate, the drying agent was removed by filtration and the solvent was removed under reduced pressure. . The crude product was purified by flash chromatography with the mixture of eluting agents dichloromethane, methanol and saturated ammonia solution = 19 / 1.5 / 0.02. Yield: 2.35 g (90%), - oil 1.3 g of the product, still doped with dichloromethane, was dissolved in a mixture of acetone and water and then released again from the solvent in a rotary evaporator and then in high vacuum . 1.3 g of a viscous oil, free of solvent, remained as residue. C20H31N5O3 (M.P. = 389.56 g / mol) XH-NMR (DMS0-d6, 200 MHz): d = 0.85 (t, 3 H, N7 (CH2) 2CH3); 0.98 (t, 3 H, NCH2CH3); 1.30-1.65 (m, 6 H, CH2); 1.30 (s, 3 H, C (OH) CH 3); 1.79 (sex, 2 H, N7CH2CH2CH3); 2.56 (q, 2 H, NCH2CH3); 3.30 (s, 2 H, NCH2C- = C); 3.44 (s, 3 H, N3CH3); 3.77-3.95 (m, 2 H, 1 ^); 4.21 (t, 2 H, N7CH2); 5.07 (S, 1 H, OH); 8.10 (s, 1 H, N = CH) Example 24: 1- (8-Ethyl-propylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propyl-xanthine (according to variant E of the process) 650 mg (1.67 mmol) of 1- (8-ethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-7-propyl-xanthine from Example 23 was dissolved in 30 ml of ethanol. After cooling to -78 ° C, 602 μl (8.34 mmol) of propionaldehyde was added, then warmed to 0 ° C and mixed with 105 mg (1.67 mmol) of sodium cyanoborohydride. In order to complete the reaction, a pinch of sodium cyanoborohydride was added after 2 hours and, after 3 hours, again 602 μl (8.34 mmol) of propionaldehyde and 105 mg (1.67 mmol) of sodium cyanoborohydride. After completion of the reaction, the reaction mixture was concentrated under reduced pressure in a rotary evaporator, the residue was mixed with a saturated solution of sodium hydrogencarbonate, the aqueous phase was extracted with dichloromethane, the combined extracts were dried with sulfate extract of magnesium, the drying agent was removed by filtration and the filtrate was concentrated under reduced pressure in a rotary evaporator. The crude product was purified by flash chromatography with the mixture of eluting agents dichloromethane, methanol and saturated ammonia = 19/1 / 0.02. Yield: 503 mg (70%), -oil C23H37N503 (P.M. = 431.65 g / mol), mass spectrum: 432.4 (100%, M + H); 414.3 (44%); X H-NMR (DMSO-d 6, 200 MHz): d = 0.75-0.88 (2 t, 6 H, NCH 2) 2 CH 3, N 7 (CH 2) 2 CH 3); 0.94 (t, 3 H, NCH 2 CH 3); 1.30-1.68 (m, 8 H, CH2); 1.30 (s, 3 H, C (0) CH3); 1.79 (sex, 2 H, N7CH2-CH2CH3); 2.24-2.45 (m, 4 H, NCH2CH2CH3, NCH2CH3); 3.32 (s, 2 H, NCH2C = C); 3.43 (s, 3 H, N3CH3); 3.76-3.95 (m, 2 H, N1 ^); 4.21 (t, 2 H, N7CH2); 5.06 (s, 1 H, OH); 8.10 (s, 1 H, N = CH).

Table 1 Compounds according to Formula I 9 - Example Ri R ° isolated as P.f. [° C] 57 -. 57 -CH, - (CH) 2-CH3 fumarate 125 58 -. 58 -C2H5 - (CH2) 2-CH3 fumarate 70 59 -. 59 - (CH2) 2-CH (CH2) 2-CH, hydrochloride 153 60 -. 60 -CH- (CH2) 2"H, fumarate 76 61 -. 61 -C2H5 - (CH2) 2-CH hydrochloride 128 62 -. 62-CH, - (CH) 2-CH 3 fumarate 140 Example R¿ isolated as P.f. [° C] 63 -. 63 -C2H5 - (CH2) 2 'H3 base 99 64 -. 64 -CH, - (CH2) 2-CH3 iodide oil 65 -. 65 -C2H5 - (CH2) 2-CH, iodide 145 66 -. 66 -C2H5 - (CH) 2-CH iodide oil 67 -. 67 - (CH) -CH3 - (CH2) 2-CH3 hydrochloride 137 68 -. 68 - (CH) 2-CH3 - (CH2) -CH3 iodide 145 Example R1 R¿R * isolated as P.f. [° C] 81 -. 81 - (CH2) 2-CH3 - (CH2) 2-CH3 fumarate 85 82 -. 82 -CH, - (CH) 2"CH3 iodide oil 83 -. 83 -C2H5 - (CH2) 2-CH3 iodide 100 84 -. 84 -C2H5 - (CH2) 2-CH3 iodide oil 85 -. 85 - (CH2) 2-CH3 -. { CH2) 2-CH iodide 118 Example R 'R isolated as P.f. [° C] 98 (CH2) 3-CH3 (CH2) 2-CH, hydrochloride 97 99 -. 99 -CH, - (CH2) 2"CH iodide 118 100 -. 100 -C2H5 (CH2) 2"H iodide 175 101 -. 101 - (CH2) 2_CH - (CH2) 2"H iodide 148 102 (CH2) 3-CH- - (CH2) 2-CH iodide 130 103 -. 103 -CH, - (CH2) 2"H iodide 193 P.f. represents melting point higr. represents hygroscopic (desc.) represents (with decomposition) Table 2 Compounds of Formula IX: Pharmacological test and results The pronounced neuronal protective effect of the compounds according to formula I could be demonstrated in suitability models relevant to the clinic in animal experiments, including in the investigations the xanthine derivative propentofylline (3-methyl-1- (5) -oxo-hexyl) -7-propyl-xanthine) as a comparative preparation. The results of the tests show that the compounds according to the invention are clearly superior to the comparative preparation and, as a consequence, have a greater therapeutic potential for the curative and prophylactic treatment of cerebrovascular diseases. 1. - Neuroprotective effect in the model of transient global ischemia in a gerbil To carry out the experiments, which were carried out in accordance with the norms of the German Law for the Protection of Animals, 30 male Mongolian gerbils with a body weight between 60 and 70 g were randomly distributed into two groups, each of 15 animals. The animals of the first group received, 30 minutes after the ischemia period, the respective test substance by intraperitoneal injection, while the animals of the second group, which served as an untreated control group, received only the same volume of the relevant vehicle. . For the generation of provisional forebrain ischemia, the animals were fixed in the supine position under halothane narcosis on a hot operating table, both common carotid arteries were carefully exposed and by means of microaneurysm forceps they were closed for three minutes (J. Cereb. Blood Flow Metab. 1987, 7/1: 74/81). At 7 days after the ischemia period of 3 minutes, the animals were decapitated in narcosis with halothane, the brains were extracted quickly and carefully, they were fixed first by immersion in a solution of Carnoy (mixture of ethanol, chloroform and acetic acid = 6: 3: 1) and then imbibed in paraffin, Then coronary sections with a thickness of 4 to 6 μm were prepared through the hippocampus, approximately at the height of the bregma (sinciput), and this was stained with hematoxylin and eosin. Afterwards, in the framework of a blind experiment, the magnitude of the eosinophilic necrosis of the pyramidal cells in the CA 1 region of the hippocampus was determined by means of an optical microscope with the help of a semiquantitative histopathological qualification (0 = no necrosis; = slight necrosis, 2 = intermediate severity necrosis, 3 = severe necrosis and 4 = complete necrosis). The percentage modification of the mean histopathological rating of the group with preparation compared to that of the untreated control group served as the magnitude of assessment for the neuroprotective effect. The results of the experiments are compiled in Table 3.

Table 3: Inhibition of ischemic nerve cell lesions in a Mongolian gerbil The surprisingly good neuroprotective activity of the compounds of the formula I according to the invention could also be convincingly verified in the experimental arrangements described below, which according to the process technique are even more expensive. 2. Inhibitory effect on neurological symptomatology in the model of permanent focal cerebral ischemia in a rat Adult male Sprague-Dawley rats weighing 300 to 400 g were used as experimental animals with a focal cerebral infarction experimentally generated by permanent occlusion of the artery Central Brain (MCA) (J.

Cereb. Blood Flow Metab. 1981, 1: 53-60). Surgical extraction and preparation, which lasted approximately 20 to 30 minutes, was performed under anesthesia with laughing gas (nitrous oxide) containing from 1 to 1.2% halothane, which was added and mixed with breathing air with breathing spontaneous through a mask for gases. After catheterization of the right femoral artery and vein for the measurement of blood pressure, blood extractions and subsequent administration of the test substance occlusion of the left MCA was carried out under a large microscopic increase for operations Surgical procedures through subtemporal access without elimination of the zygomatic arch and the temporo-parietal muscles by electrocoagulation and subsequent cutting of the vessels, monitoring the course of the surgical operation by continuous recording of the mean arterial blood pressure with the help of an electromechanical recorder of pressure (polygraph model 7E Polygraph; Grass, USA).

After the surgery, the animals were allowed to wake up from the narcosis and their body temperature was maintained with a heating mantle.

(Homeothermic Blanket System, Harvard Apparatus, United Kingdom) in the normal range around 37 ° C. At 15 minutes after occlusion of the vessels, the animals of the group with preparation (n = 8) were administered the substance under test in the form of an intraperitoneal injection of a bolus of 10 mg / kg as initiating dose. and treatment was continued by permanent infusion for 24 hours at 0.1 mg / kg / min through the venous catheter with the help of a special, freely rotating system. of the tensile control group (Harvard Apparatus, United Kingdom), while the animals of the untreated control group (n = 7) received by a corresponding route only the vehicle (physiological sodium chloride solution) at 15 minutes before and immediately afterwards. of the occlusion of the vessels as well as shortly after the beginning of the permanent infusion of the preparation under test or of the vehicle, were checked in order to determine the physiological irregularities arterial blood gases and the pH value (analyzer 178 pH / del blood gas, - Corning, USA) as well as the hematocrit and blood glucose level: after that the arterial catheter could be removed, in addition, from the beginning of the surgical operation up to 10 minutes After the beginning of the permanent infusion and a few minutes before the end of the experiment, the temperature of the bilateral temporoparietal musculature was determined rectally (Ther 2250 - 1; Ahlborn Mess - und Regel technik, German Federal Republic) and body temperature. Twenty-four hours after the occlusion of the vessels, permanent infusion was completed and the magnitude of the neurological deficit due to ischemia was determined with the help of the scale of symptoms of four graduation steps according to Bederson et al. (Stroke 1986, 17: 422-476) with the following evaluation criteria: 0 = no phenomenon of neurological failure; i = flexed posture of the forelimbs; 2 = decreased resistance force against lateral thrust without circular movements 3 = same symptomatology as in the case of grade 2, but with circular movements. For the biostatistical analysis of the experiment data, the frequency distribution of the neurological scores of the group with preparation and of the group was compared using the Student t test (level of significance p <0.05). In this case, the compound according to Example 1 produced a significant decrease (p <0.01) in the neurological deficit (1.1 + 0.4, mean value ± SD (standard deviation)) compared with that of the untreated control animals (2.3 ± 0.5, mean value ± SD) corresponding to an improvement in the neurological status of around 52%, without recognizing any type of negative influence on the parameters physiological investigated. 3. Neuroprotective effect in the model of permanent focal cerebral ischemia in a rat The experimental installation corresponded very extensively to the method described in Experiment 2. The groups with preparation and control covered in each case n = 6 animals. The substances tested were, however, administered exclusively intraperitoneally, renouncing the permanent intravenous infusion, which is very complicated in the case of an awake animal, and specifically by administration at three times each time of 10 mg / kg in the intervals of time of 15 minutes, 3 and 6 hours after the surgical occlusion of the MCA. After a duration of the 24-hour experiment, the animals were decapitated under narcosis, the brains were extracted quickly and carefully, they were frozen at -10 ° C for 10 minutes and then the forebrains were cut into cut planes defined in 8 coronary sections. , which were stained using a cresyl staining technique. In the manner of a blind experiment, the infarcted, non-colorable regions of the coronary sections were then measured by planimetric means, after graphical transfer to a diagram, and by integration along all the surface values (Neuroscí Lett. 1992, 147: 41-44) the volume of infarction in the left cerebral hemisphere affected by ischemia was determined. The significance (level <0.05) of the differences between the untreated control group and the groups with preparation was evaluated with the Student t test.

When testing the compounds according to the invention in the direct comparison with propentofylline, for example the preparation based on Preparation Example 1, after intraperitoneal administration of 3 x 10 mg / kg (which corresponds to 3 x 22 μmol / kg) led to a statistically significant reduction (p <0.05) of 56% infarct volume (99 ± 17 μl; mean value ± SD) compared to that of the untreated control group (222 ± 43 μl, mean value + DT), while the comparative propentofylline preparation, also in the dose of 3 x 10 mg / kg (corresponding to 3 x 33 μmol / kg), produced a decrease of 43% (127 ± 28 μl, - mean value ± DT). 4. Neuroprotective effect in the model of permanent focal cerebral ischemia in a mouse In this experimental setup, the effect of the compounds of the formula I on the comparison with propentofylline as a reference substance for the necrotic lesions on the surface of the cortex was investigated Cerebral (cortex) after permanent occlusion of the right MCA, which is a reliable measure of infarct volume (J. Pharmacol, Methods 1992, 27: 27-32). As experimental animals, male Swiss CD1 mice with a body weight comprised between 33 and 40 g were used, whose right MCA had been occluded by surgical intervention, analogously to Experiment 2, mediating narcosis with chloral hydrate (400 mg / kg i.p.). Four mice were subjected to a sham operation, in which the CSF had certainly been released in the same way, but had not been occluded, - these animals constituted the control group, with which it was necessary to quantify an eventual and possible influence of the surgical intervention on nerve cell lesions. Since both anesthesia and ischemia usually induce hypothermia, which can lead to a decrease in the size of an infarct (Brain Res. 1992, 587: 66-72), also in this experimental model the temperature of the temporoparietal muscles during surgical manipulation with a halogen thermal lamp and body temperature were maintained throughout the duration of the experiment, by appropriate adjustment of the temperature of the environment, in the normal range around 37 ° C. At 5 minutes as well as at 3 and 6 hours after the occlusion of the MCA, the animals of the group with preparation (n = 12) were administered the respective substance under test - dissolved in distilled water - by injection via intraperitoneal (ip) in each case of 10 mg / kg, while animals of the placebo group (n = 12) received only the vehicle and animals of the control group (n = 4) received neither the preparation nor the vehicle. Twenty-four hours after vessel occlusion, the animals were decapitated under narcosis with isoflurane, the brains were removed and stained for 30 to 40 minutes in a 2% aqueous solution of 2, 3, 5 chloride. -triphenyl-tetrazolium (TTC), hot at 37 ° C. After that, the cerebral cortex of the right hemisphere was isolated and the surface area with infarction, not colorable with TTC, was measured by image analysis (BIOCOM). The statistical evaluation of the results of the experiment was carried out with the nonparametric tests according to Kruskal-allis and Mann-Whitney. In this case it was revealed that in the sham operated mice of the control group practically no necrosis appeared in the cortex, while the animals treated with vehicle of the placebo group, as a consequence of the focal ischemia, had significant neuronal lesions with a surface area with infarction of 31.3 ± 1.7 mm2 (mean value ± SD, p = 0.0002). This injury could be reduced, for example by the compound of Example 1, significantly by about 38% up to 19.3 ± 1.5 mm2 (mean value ± SD, p = 0.0001), while with propentofylline As a comparative preparation, limitation of the lesion was achieved around only one % up to 25.2 ± 2.1 mm2 (mean value ± SD, p = 0.0153). Since neither the difference between both groups with preparation had statistical significance, with p < 0.05, the compound according to the invention was manifested with respect to the comparative preparation as a neuroprotective active in a significantly more intense manner.

Claims (17)

1.- Compound of formula I in pure form according to the stereoisomers or as a mixture of stereoisomers, in which i) R1 and R3 represent an alkynol radical of the formula Ia or Ib, R ^ a) straight or branched (C1-C5) alkyl, b) C3-C6 cycloalkyl or c) cycloalkyl (C4-C8) alkyl, R4 a hydrogen atom or alkyl (Ci-,), r.5 R6 and R7, independently of one another, a) a hydrogen atom, b) C2-C6 alkyl, c) C3-C3 cycloalkyl, d) C4-C8 cycloalkyl-alkyl, e) ar (C1-C2) alkyl) of tri-alkyl (Cx-C4) -silyl, or forming R5 and R6 in common with the nitrogen atom, to which they are attached, a saturated ring of 4 to 7 members, which is unsubstituted or substituted one to four times with alkyl (C ^ Cj), or forming R5 and R6 in common with the nitrogen atom, to which they are attached, a saturated ring of 4 to 7 members, wherein a -CH2- group of the ring is replaced by a radical taken from the group consisting of O, S, SO, S02 and NR13, R13 represents a hydrogen atom, (C1-C3) alkylcarbonyl or (C1-C4) alkyl, and the ring is unsubstituted or substituted one to four times with alkyl (C- ^^ - ^), representing Unbranched or branched (C1-C6) alkylene, and Z- representing the anion of an inorganic or organic acid, physiologically compatible, or representing therein 2) R1 or R3 an alkynol radical of the formula Ia or Ib and the other radical R3 or R1 a) a hydrogen atom or b) R8, in which R8 signifies linear or branched (C ^ Cg) alkyl, (C3-C6) cycloalkyl or (C4-C8) cycloalkyl-alkyl and R2, R4 are defined, R5, R6, R7, A and Z as in 1).

2. Compound of the formula I according to claim 1, characterized in that only one of the two radicals R1 or R3 represents an alkynol radical of the formula Ia or Ib and the other radical means a hydrogen atom or R8.

3. Compound of the formula I according to claims 1 or 2, characterized in that R1 represents an alkynol radical of the formula Ia or Ib and R3 represents a hydrogen atom or R8.

4. - Compound of formula I according to one or more of claims 1 to 3, wherein R 1 represents an alkynol radical of the formula Ia or Ib, R 2 represents linear (C 1 -C 4) alkyl, cyclopropyl or cyclopropylmethyl, R 3 represents a) a hydrogen atom or b) R 8, wherein R 8 means alkyl (C 4) Cg) linear or branched, cyclopropyl or cyclopropylmethyl, R4 represents a hydrogen atom, methyl or ethyl, R5, R6 and R7, independently of each other, represent a hydrogen atom, (C1-C4) alkyl, cyclopropyl, cyclopropylmethyl or benzyl , or R5 and R6 in common with the nitrogen atom, to which they are attached, form a saturated ring of 5 to 6 links taken from the group consisting of morpholine, 4-alkyl (C1-C3) -carbonyl-piperazine, 4-alkyl (C1-C2) -piperazine, piperazine, piperidine, pyrrolidine and thiomorpholine, A represents un-branched (C1-C5) alkylene and Z "represents the anion of an inorganic or organic, physiologically compatible acid

5.- Compound of the formula I according to claim 4, wherein R1 represents a alkynol dical of the formula Ia or Ib, R2 represents alkyl (C ^ C ^, R3 represents linear (C2-C4) alkyl or cyclopropyl, R4 represents a hydrogen or methyl atom, R5, R6 and R7, independently of each other , represent a hydrogen atom, (C 1 -C 4) alkyl or benzyl, or R 5 and R 6 in common with the nitrogen atom, to which they are attached, form the ring of morpholine, pyrrolidine, piperidine, 4-methyl-piperazine or acetyl-piperazine, A represents (C2-C4) alkylene without branching and Z "represents the anion of an inorganic or organic acid, physiologically compatible.

6. Compound of the formula I according to claim 5, characterized in that it represents 1- (8-diethylamino-5-hydroxy-5-methyl-oct-6-ynyl) -3-methyl-, 1- (5-hydroxy-5-methyl-8-pyrrolidino-oct-6-ynyl) -3-methyl-, 3-butyl-1- (5-hydroxy-5-methyl-8-piperidino-oct-6-) inil) -1- (5-diethylamino-2-hydroxy-2-methyl-pent-3-ynyl) -3-propyl-, 1- (6-dimethylamino-3-hydroxy-3-methyl-hex-4-ynyl) - 3-Ethyl-, 1- (7-diethylamino-4-hydroxy-4-methyl-hept-5-ynyl) -3-ethyl-, 1- [8- (4-acetyl-piperazino) -5-hydroxy-5 -methyl-oct-6-ynyl] -3-methyl-7-propyl-xanthines as well as their salts by the addition of physiologically compatible acids or N, N-diethyl-N- [4-hydroxy-4-methyl-8-iodide] - (3-methyl-7-propyl-xanthin-1-yl) -oct-2-ynyl] -N-methyl-ammonium.

7. Process for the preparation of the compound of the formula I according to one or more of claims 1 to 6, characterized in that, according to the variant A of the process, a 3-alkyl-xanthine of the formula II is reacted, wherein R2 is defined as in formula I, without any condensing agent or in the presence of a basic condensation agent, or conversely a salt of the compound of formula II, with a compound of formula III wherein X represents chloro, bromo, iodo or a sulphonic acid ester radical or phosphoric acid ester, and A, R4, R5 and R6 are defined as in formula I, to form a compound of the formula with an alkynol radical of the formula present by R3 and a hydrogen atom present by R1 according to formula I, and then the compound of the formula is alkylated without any condensing agent or in the presence of a basic condensation agent, or on the other hand a salt of the compound of the formula le or again with a compound of the formula III to form a compound of the formula Id with two alkinol radicals, the same or different, of the formula present by R 1 and R 3 according to formula I, or with a compound of formula IV, (IV) Ra-X wherein R8 is defined as in formula I and X is defined as in formula III, to form a compound of the formula I with the radical R8 present by R1 and the alkynol radical of the formula present by R3 according to formula I, or a 1,3-dialkyl-xanthine of the formula V is reacted, wherein R2 and R8 are defined as in formula I, without any condensing agent or in the presence of a basic condensation agent, or conversely a salt of the compound of formula V, with a compound of formula II for forming a compound of the formula LE, or a 3,7-dialkyl-xanthine of the formula VI is reacted, wherein R2 and R8 are defined as in formula I, without any condensing agent or in the presence of a basic condensation agent, or conversely a salt of the compound of formula VI, with a compound of formula III for give a compound of the formula If with an alkynol radical of the formula present by R1 and the radical R8 present by R3 according to formula I; or according to variant B of the process, a compound of the formula II, V or VI is alkylated, analogously to the variant A of the process, with a compound VIII, wherein A and R4 are defined as in formula I and X is defined as in formula III, to give a compound of formula IX, wherein either R9 and R10 represent two radicals, the same or different, of the formula IXa or on the contrary only R9 or R10 represents a radical of the formula IXa and the other radical R10 or R9 represents a hydrogen atom or R8, R2, A, R4 and R8 being defined as in the formula I, and then the amino is compound of formula IX under the conditions of the Mannich reaction with formaldehyde and with an amine of formula X, R5 / (X) HN R6 wherein R5 and R6 are defined as in formula I, in the terminal ethynyl group (s) to form a compound of the formula If; or according to variant C of the process, a disubstituted xanthine is reacted in 1,3 or 3,7 or trisubstituted in 1,3,7, of the formula XI, wherein either R11 and R12 represent two radicals, the same or different, of the formula Xla or on the contrary only R11 or R12 represents a radical of the formula Xla and the other radical R12 or R11 represents a hydrogen atom or R8, R2, A, R4 and R8 being defined as in the formula I, with an organometallic compound of the formula XII, wherein R5 and R6 are defined as in formula I and M means an alkaline, alkaline earth or heavy metal, mediating reductive alkynylation of the carbonyl group (s) to form a compound of the formula le, , Le, If or Ig with an alkynol radical of the formula present by R1 and a hydrogen atom present by R3 according to formula I; or according to variant D of the process, a xanthine of the formula XI is reacted, in which R11 and / or R12 represent the radical of the formula Xla, by way of the reaction of Nef or with an acetylide of the formula XIII, HC = C-M (XIII) wherein M is defined as in formula XII, or conversely with a terminally protected acetylide of formula XIV, Ra-C = C-M (XIV) wherein M is defined as in formula XII and Ra, represents a leaving group easily removable later, mediating ethynylation of the carbonyl group (s) to form a compound of formula IX, wherein R 9 and / or R 10 represent the radical of the formula IXa, and then the compound IX obtained is aminomethylated by a Mannich reaction with formaldehyde and with an amine of the formula X analogously to the variant B of the process to give a compound of the formula , Id, le, If or Ig; or according to the process variant E, a compound of the formula le, Id, le or If, prepared according to process variants A to D, or a compound of the formula Ig, prepared according to process variants C or D, in wherein R5 and / or R6 represent in each case a hydrogen atom, is alkylated under reductive conditions once or twice with an oxo-derivative (aldehyde or ketone) of alkanes (C ^ Cg), cycloalkanes (C3-) C6), cycloalkyl-alkanes (C4-C8) or ar-alkanes (C1-C2); or according to the variant F of the process, a compound prepared according to variants A to E of the process is converted, with a physiologically compatible organic or inorganic HZ acid, into an acid addition salt of the formula I, representing R1 and / or R3 the alkynol radical of the formula Ib, in which R7 represents a hydrogen atom and R2 is defined as in the formula I; or according to the variant G of the process, a compound prepared according to variants A to E of the process is converted with an alkylating agent of the formula VII wherein R7 is defined as in formula I, with the exception of hydrogen, and Z is defined as in formula III for X, in a quaternary ammonium salt of formula I, with R1 and / or R3 representing the alkynol radical of formula Ib and R2 being defined as in formula I; or according to the variant H of the process, a compound, prepared according to variants A to G of the process, is separated by chromatography or by fractional crystallization in the pure stereoisomers.

8. Medicament, characterized by the content of a therapeutically effective amount of at least one compound of the formula I in a pure form according to the stereoisomers or as a mixture of stereoisomers, according to one or more of claims 1 to 6, or Prepared according to claim 7.

9. The medicament according to claim 8, characterized in that it additionally contains an effective amount of at least one active substance taken from the group consisting of fibrinolytic agents, calcium antagonists, excitatory amino acid antagonists, gangliosides. , inhibitors of phospholipases, cyclooxygenases or lipoxygenases, antagonists of PAF (platelet activating factor), of thromboxanes or leukotrienes, oxygen radical scavengers, chelators with heavy metals, antiedematous active substances, anticoagulants, inhibitors of thrombocyte aggregation, agonists of serotonin A, adenosine modulators and growth factors neurotrophs or their release activators.

10. Use of the compound of formula I according to one or more of claims 1 to 6, or prepared according to claim 7, for the preparation of a medicament intended for the curative or prophylactic treatment of cerebrovascular diseases.

11. Use according to claim 10 for the curative and prophylactic treatment of a disease taken from the group of apoplexy, transient ischemic attacks, dementia due to multiple infarctions, dementia of the mixed type with vascular and degenerative components (Alzheimer's), spinal cord injuries and brain traumas as a consequence of head injuries.

12. Use according to claim 10, for the curative and prophylactic treatment of neuronal injuries after a heart arrest, asphyxia, neonatal asphyxia, resuscitation or vascular surgical interventions in the area of the main arteries supplying the brain.

13. - Use according to one or more of claims 10 to 12 for primary prevention, acute treatment and secondary prophylaxis of cerebrovascular diseases.

14. Use according to one or more of claims 10 to 13 for parenteral, oral, rectal or transdermal application.

15. Process for the preparation of a medicament according to claims 8 or 9, characterized in that at least one compound of the formula I according to one or more of claims 1 to 6 is carried with pharmaceutically acceptable carrier materials and additives and physiologically compatible diluents and / or other active substances and adjuvants, to an appropriate presentation form.

16. - Compound of formula IX in a pure form as regards stereoisomers or as mixtures of stereoisomers wherein R9 and R10 represent two radicals, the same or different, of the formula IXa or only R9 or R10 represent the radical of the formula IXa and the other radical R10 or R9 represents a hydrogen atom or R8, where R2, A, R4 and R8 are defined as in the formula I according to claim 1.

17.- Medications , characterized by the content of a therapeutically effective amount of at least one compound of formula IX according to claim 16.