NEUROLOGICALLY ACTIVE COMPOUNDS

Abstract: This invention provides pharmacologically active compounds having the capability of reestablishing previously destroyed neurological functions in a mammal. These active compounds comprise the reaction product of a guanidino, aminoguanidino, 2-imadazolino, 2-hydrazinoimidazolino or 2-guanidinobenzimidazolino group with a methylated xanthine group. These compounds provide a combination receptor activity designed to stimulate appropriate receptors in the brain and spinal cord and thus tonically stimulate motor neurons.

Description: Title: NEUROLOGICALLY ACTIVE COMPOUNDS This is a continuation in part of Serial No. 150,767, filed February 1, 1988, which is a divisional of Serial No. 691,830, filed January 16, 1985, now Patent No. 4,742,054, issued on May 3, 1988, which was a continuation of Serial No. 443,915, filed November 23, 1982. This invention relates to a group of adrenergically active compounds and more particularly compounds which include a guanidino group. It has previously been recognized that a variety of guanidine derivatives have alpha 2 -adrenergic agonist activity in vivo. A variety of guanidine derivatives have also been used clinically as anti-hypertensive agents, including clonidine, guanabenz, guanacline, guanadrel, guanazodine, guanethidine, guanfacine and guanochlor, guanoxabenz and guanoxan. There has recently been interest in the treatment of severe spinal trauma so as to, at the very least, reduce ensuing spasticity, and in many cases, apparently, result in the regaining of sensory-motor control below the trauma level, even if such trauma had resulted in a complete neurological transection of the spinal cord. Publications by the present inventor and by others, confirming by independent tests the inventor's results with the use of clonidine, a known alpha 2 - adrenoceptor agonist, include, for example: "Functional Restoration of the Traumatically Injured Spinal Cord in Cats by Clonidine", Naftchi, N. E. , SCIENCE 217. pages 1042-1044 (1982); THE FCS NEWSLETTER". May 1986, pages 2 and 3, "Functional Recovery of Rhythmic Motor Patterns in the Spinal Cord Injured via Neurotransmitter Activation", Catholic Medical Center, Hanover, New Hampshire in association with Dartmouth Medical School and Karσlinska Institute; THE PHYSIOLOGIST. Volume 27, page 220, August 1984, "Histochemical Correlates Of Behavioral Effect of Alpha-2 Adrenergic Agonist in Spinal Rats", N " . E. Naftchi, et al, and a more complete text provided in a paper given at the American Congress For Rehabilitation Medicine, 61st Annual Session, October 23, 1984, "Newer Research in Spinal Cord Injury, Mechanism and Prevention of Acute Spinal Cord Injury" by N. Eric Naftchi. Clonidine and guanabenz, two alpha 2 -adrenergic receptor agonists used in the earlier work, had limited usefulness as a result of desensitization of the subject upon long-term treatment, and the sedative, or sleep-inducing effect of these two agents which tended to reduce mobility and the ability to eat. In addition, these compounds also result in drastic undesirable hypotensive effects, and syncopy, and further included constipation and rectal impaction in certain quadraplegic subjects, which can also result, paradoxically, in severe hypertension, a syndrome known as autonomic hyperreflexia. GENERAL DESCRIPTION OF THE INVENTION: It is an object of the present invention to provide novel compounds which have the capability of restoring to a mammal apparently normal central nervous system neural function, resulting in sensory-motor return following damage to the central nervous system caused by trauma or disease. It is a further object of the present invention to provide novel compounds having such capability and which do not have undesirable side effects which would otherwise interfere with the treatment of any mammal having such damaged central nervous system. As a further object of the invention, novel compounds are provided which are effective as anti-spastic, or spasmolytic, agents for the control of spasticity caused as a result of neurological damage. These drugs would also produce little or no sedation and would not lower blood pressure. DETAILED DESCRIPTION OF THE INVENTION; In accordance with the present invention, there are provided pharmacologically active compounds having the capability of reestablishing previously destroyed neurological functions in a traumatized or diseased mammal. These compounds comprise the reaction product of a guanidino, aminoguanidino, 2-imidazolino, 2-hydrazinoimidazolino or 2- guanidinobenzimidazolino group with a methylated xanthine group, which provide a combination of receptor activity designed to stimulate appropriate receptors in the brain and spinal cord and thus tonically stimulate motor neurons, in spite of a severely damaged central nervous system; they are highly lipophilic and thus capable of crossing the blood/CNS barrier. These compounds preferably have the following general formula: Wherein g and r can have a value of 0 or 1, to a total of one, h can be 0 or 1, and n is 0 or an integer of at least 1 and preferably not greater than 2; the R groups can be hydrogen or non-interfering organic groups. R- ^ and R 2 and R 3 preferably include alkyl groups or hydrogen atoms, at least one of R χ and R 2 and/or R 3 most preferably comprising an alkyl group. R-L and/or R 3 can be the bridging group to the guanidino moiety outside of the brackets, and can be an aliphatic group, saturated or unsaturated, preferably including a carboxyl group or a carbonyl group, oxygen, nitrogen, sulfur, connected to a nitrogen atom of the guanidino group by a double bond. Thus and R 3 can preferably include acetyl, acetaldehyde, propionyl, hydroxyalkyl. R 4 and R 5 can each be hydrogen, or any non- interfering organic group, preferably including lower alkyl, alkoxy, thioalkyl, alkenyl, aryl, aralkyl, or alkaryl or nucleoside group, or any such group substituted with NH 2 , OH, OCH 3 , or halogen, sulfur, oxygen, or N0 2 . R 6 , if present, is a bridging group forming a closed heterocyclic ring compound with the two nitrogen atoms on the guanidino group, and can be any non-interfering organic group, which can include additional nitrogen atoms, halogen atoms, oxygen atoms, and can be aliphatic, cycloaliphatic, or aromatic, so as to form groups such as, e.g., imidazole, benzimidazole, triazine, thiopyri idine, triazolethiol, diphenyl-2-imidazole-thiol. The novel compounds of the present invention have an alpha 2 -adrenergic receptor agonist moiety and a beta- adrenoceptor agonist moiety. Preferably, the beta-receptor agonist moiety is derived from a compound that has an indirect beta-adrenergic effect, such as the substituted xanthines, which enhance the metabolic effect of cyclic adenosine 3', 5',- monophosphate (c-AMP) , by blocking c-AMP phosphodiesterase. These xanthines further enhance microcirculation within the muscle mass by increasing local vasodilation. The present invention builds upon the effects noted in the parent application hereto by combining in a single compound or complex the effects of the alpha 2 and beta agonists. As was noted during the earlier work, the previously known alpha 2 -adrenergic receptor agonists ("alpha- 2 agonists") , have other direct physiological effects on the mammal being treated, which often are contraindicated following trauma such as spinal injury, e.g., the hypotensive effect of clonidine and quanabenz. It was recognized that such undesirable side effects can be counteracted by the simultaneous or sequential administration of an antagonist or a pressor agent, such as angiotensin II which could be titrated against the alpha 2 - agonist. Usually, it was extremely difficult to avoid any such hypotensive effect, or some time serious hypertensive effects. The compounds of the present invention which include the guanidino, 2-amino-imidazolino, 2-hydrazino-imidazolino, or 2- guanidinobenz-imidazolino 2,3,5-s-triazine moiety from alpha 2 agonist plus a beta-agonist moiety avoid any hypotensive effect, and result in an improved reactivation and reestablishment of the descending monoaminergic pathways and ascending nociceptive pathways while also improving upon and speeding up the affirmative process of restoring motor and sensory functions to almost one/third ofthe time required by the alpha 2 agonists. The indirect beta-agonists such as substituted xanthines act by inhibiting the enzyme phosphodiesterase, with the effect of increasing the ratio of c-AMP to c-GMP (cyclic guanosine-3,5-monophosphate) . In addition, moieties derived from direct acting beta-agonist, such as 4-hydroxy-3- methoxymandelic acid, 3,4-dihydroxymandelic aldehyde, 3,4- dihydroxyphenyl(beta-hydroxy)-acetaldehyde may be combined through their aldehyde or carboxyl groups with guanidine, aminoguanidine, etc. to yield internally neutralized compounds which have similar effect. Referring to Formula 1, the xanthine group is connected to the guanidino group through one of the guanidino- nitrogen atoms. In addition, it has been found that similar effects can be obtained when in the guanidino moiety, one of the nitrogen atoms in the guanidino group shown in Formula 1 is replaced by a sulphur or an oxygen atom. Typical species of this class of mixed agonist compounds are set out in the working examples below, as well by the following list: 1. Guanidino-7-Acetyltheophylline 2. 2-Guanidinobenzimidazolyl-7-Acetyltheophylline 3. 3,4,5-Trimethoxybenzylidene-2-Hydrazinoimidazole 4. 2-Hydrazinoimidazoyl-7-Acetyltheophylline 5. Theobromine-1-Acetyl Guanidine 6. Theophylline-7-Acetylamidoguanidine 7. Theobromine-1-Acetylamidoguanidine 8. Theophylline-7-Acetyliminoguanidine 9. 2,4,6-Tris(7-Acetamidotheophylline)-1,3,5-s-Triazine 10. 2,4-Bis(2,6-Dicholorbenzylideneimino)-6-(7- Acetamidotheophylline)-1,3,5-s-Triazine 11. 2,4-Bis(1-Naphthylacetamido)-6(7-Acetamidotheophylline)- ,3,5-s-Triazine 12. 2,4-Bis(7-Acetamidotheophylline)-6-(2,6-Dichlorobenzyl- ideneamino)-1,3,5-s-Triazine 13. Theophylline-7-Ethyleneiminoguanidine With mixed agonist or agonist-antagonist properties, the compounds of the present invention can be used as medicaments for mammals in the form of pharmaceutical preparations suitable for administration orally, parenterally, intraperitoneally, intravenously or as nasal spray. These compounds can be administered in a substantially pure form, with other active ingredients which may be desirable, or merely with a suitable pharmaceutical vehicle. The compounds are generally crystalline solids which may be at least partially soluble in commonly used organic salts. They are also generally soluble in liquid pharmaceutical vehicles, including water. Generally, the compounds can be formed as physiologically acceptable salts including the salts of inorganic acids, such as hydrochloric, hydriodic, sulfuric or phosphoric, as well as organic acids including acetic, malic, ethionic, malonic, citric, benzoic and pamoic. Generally, these acid addition salts are more soluble in water than the compounds per se. Formulation in a pharmaceutical vehicle can be carried out in accordance with techniques and in vehicles which are wholly conventional to those skilled in the art for the intended mode of administration. For example, preparations for oral administration can be in either liquid or solid form, including for example syrups, elixirs, powders, capsules or tablets. The materials are preferably prepared for unit dosage form as powders which are preferably pressed into tablets or suitably encapsulated in, for example, conventional gelatine capsules. Any powders or compressed tablets can generally also comprise the usually suitable excipients and/or diluents, such as starch, lactose, stearic acid, magnesium stearate, dextrin or polyvinylpyrrolidone. Other suitable solid carriers include magnesium stearate, sicaryl alcohol, talc, vegetable oils or fats, alcohols such an benzyl alcohols, gums, waxes, alkylene or polyalkylene glycols, such as propylene glycol or polypropylene glycol and any other well known carriers. Suitable sterile solutions or suspensions can be prepared for parenteral or intraperitoneal administration, e.g., intravenous, containing for example water, physiological saline, benzyl alcohol, ethyl oleate, methylcellulose, dimethyl sulfoxide, polyethylene glycol liquid, as well as other liquid excipients well known in the pharmaceutical or veterinary art. Other auxiliary pharmaceutical materials which can be present include preservatives, stabilizers, wetting or emulsifying agents, or osmotic salts or buffering agents, as is well known to the pharmaceutical or veterinary art. As these formulations are generally well known and conventional, more specific instructions need not be presented for purposes of defining this invention. As stated, the mixed alpha/beta receptor active compounds of the present invention are most effective in treating the undesirable after-effects of traumatic spinal injury, including even transection of spinal cord. Restoration of at least some normal sensory and motor control can be obtained as a result of treatment, especially if carried out within a relatively short time after injury to the spinal cord. Because the compounds of the present invention do not have many of the undesirable side effects of utilizing the prior alpha 2 -adrenoreceptor agonists of the parent application, it is not necessary to postpone treatment using these novel compounds until after stabilization of the vital signs and recovery from the initial shock. Indeed, many of these compounds are also effective in treating the initial shock conditions by way of stabilizing or even slightly elevating arterial blood pressure and improving microprofusion pressure in the area of injury. Thus, the compounds of the present invention have positive hemodynamic effect as well as positive neurological effects. In all cases, as explained in the earlier work, it is necessary to insure, by taking active surgical steps, if necessary, to remove any mechanical obstruction and compression pressure as created by crushed bone, growth of scar tissue or connective tissue or any other mechanical cause, especially in chronic spinal cord injured mammals. The mixed agonists of this invention also have been found to interfere with the formation of undesirable scar tissue at the trauma site. It is believed that these mixed agonists interfere with triple helix formation in the synthesis of collagen protein, thus preventing or reducing the formation of hard scar tissue at the trauma site. During treatment using the compounds of the present invention, it is greatly preferred that the plasma level of the compound in the blood stream of the mammal being treated be maintained as constant as feasible. This is especially important with respect to spinal injuries in order to reduce or substantially eliminate autonomic dysreflexia and spasticity during treatment until permanent return of sensory and motor function has been obtained. These compounds generally should be administered in a proportion of at least about 10 mcg/kg of body weight, and preferably in an amount of at least 15 meg and preferably not more than about 100 mcg/kg of body weight, and most preferably not more than about 70 mcg/kg of body weight. However, it has been found that the optimal proportion in the blood is not directly proportional to body weight, but rather to a combination of factors including body weight and body superficial area. It may be preferable to administer these novel pharmacological agents using a sustained release form, for example, the conventionally available sustained release capsules or sustained release transdermal products. Alternatively, if it is not feasible to utilize the sustained release forms, these novel compounds can be administered regularly at relatively short intervals, for example, 2 to 4 times per day. Although not as desirable for chronic long-term treatment, these compounds can, at least initially after the trauma, be administered intraperitoneally or intravenously to maintain a constant, tonic effect by slow administration of medication, or as a single injection, at intervals. An additional effect of the present novel compounds, especially important in the immediate aftermath of traumatic injury and shock, is the immediate stimulation " of spinal cord motor neurons, which keeps the muscle mass from wasting, preventing loss of weight and demineralization of the skeleton, all of which are common occurrences after severe spinal cord trauma. Further, by avoiding constipation, as is often caused by wholly alpha 2 agonists, extreme hypertension and autonomic hyperreflexia are also avoided. Further, since the compounds are relatively internally neutralized with respect to c-AMP and c-GMP, alpha receptor supersensitivity will be greatly minimized. Most of the novel compounds of the present invention in accordance with Formula I above, can be prepared by reacting a first compound ("A") including a guanidino group, which can be present as part of a heterocyclic group, e.g., an amino triazine group, an amino arylimidazole, e.g., an amino benzylimidazole, or an aminoimidazoline group, or an equivalent thio compound where one of the nitrogen atoms forming any of the above groups is replaced by a sulphur atom, with a second compound ("B") comprising a direct or indirect beta-adrenergic receptor. agonist, such as a substituted xanthine or analogs of beta-hydroxy-phenyl acetic acid, aldehyde or a ine. Each of the above A and B compounds preferably include a carboxyl group, an aldehyde (carbonyl) group, a hydroxyl group or an amino (-NH 2 ) , which are mutually reactive. Most preferably, the "A" compound reach through a primary or secondary amino nitrogen atom forming part of the guanidino or aminoguanidino moiety. Suitable group A compounds include guanidine, guanidine hydrochloride, guanidine acetic acid, a inoguanidine (or its acid addition salts) , 2-guanidinobenz imidazole hydrogen bromide acid addition salt, 2-amino-imidazoline, 2- a inodihydrothiazine, 2-hydrazinoimidazoline hydrogen bromide acid addition salt, 2,4,6-triamino-l,3,5-s-triazine, 2,4- diamino-6-phenyl-l,3,5-s-triazine, 2,4-bis(diethylamino)-6- hydrazino-1,3,5-s-triazine, 4-methyl-4H-l,2,4-triazole-3- thiole, 4,5,diphenyl-2-imidazole-thiole, 2-(4-aminophenyl-6- ethyl-benzothiazole and their acid addition salts. Useful B group compounds which are preferably direct or indirect beta-agonists, can be, for example, theophylline, etofylline, theophylline 7-acetic acid, theophylline 7 acetaldehyde, 7-(2,3-dihydroxy)- propyltheophylline, 1- theobromine acetic acid, 1-theobromine acetaldehyde. The following examples provide common procedures for preparing species which are preferred for their activity within the group of compounds constituting the invention. These procedures are similar to methods commonly used in the preparation of complex organic chemicals. These illustrative compounds within the present invention may, of course, also be prepared by other paths. In each example, the final product is designated by a capital letter, to provide a shorthand identification for the compound in subsequent portions of this text. EXAMPLE 1 Preparation of Guanidino-7-Acetyltheophylline(C) 7-Theophyllineacetic acid (THAA) (0.42 moles, 100 grams) is admixed with excess thionyl chloride (S0C1 2 ) and slowly heated to 45°C. and refluxed for 2 hours. When reaction is completed, the excess S0C1 2 is removed under vacuum evaporation at 50°C, in the presence of benzene (80 grams). The vacuum evaporation with benzene is repeated three times to eliminate all residual SOCl 2 . The resultant compound (7- theophyllineacetic acid chloride ("ThAc") is added to a solution of guanidine hydrochloride (0.25 mols, 60 grams) and 5 equivalents of 2 normal sodium hydroxide at 0°C. The resulting mixture is stirred vigorously for thirty (30) minutes until a precipitate is completely formed. The resultant yellow precipitate is filtered out by Whatman No. 1 filter paper; the filtered solid is admixed with water and the pH reduced to 8 by the addition of HC1. The aqueous solution is again vacuum evaporated at 25°C, and the resultant dry yellow solid is dissolved in an alcohol solution of 80% ethanol and water and reσrystalized. The resultant product has a molecular weight of 280.26 and has the formula shown in Table II. EXAMPLE 2 Preparation 2 - Guanidinobenzvimidazolyl-7-Acetyltheophylline f"D ) The acylchloride of THAA is obtained by following the same procedure in EXAMPLE 1 above. The ThAc (100 g.) is then added dropwise to a solution of 2-guanidine-benzimidazσle(GBI) (74 grams) in a mixture of benzene and pyridine (which is active both as a catalyst and to neutralize the by-product hydrogen chloride. The reacting mixture is held overnight at room temperature (21 β C); the benzene layer is then separated by decanting and washed with a 2 Normal aqueous solution of HC1 (to remove any excess pyridine) , subsequently washed with a 2 Normal aqueous solution of sodium hydroxide, and then washed with pure water, until substantially neutral (pH 6.8-7.2). The benzene solution is then dried under vacuum (at 25°C.) and the resultant solid is dissolved and recrystalized from an aqueous solution of 80% ethanol. The product has a molecular weight of 394.4 and has the formula shown in Table II. EXAMPLES 3-14 Additional Preparations Following the same procedures as in Examples 1 and 2, additional compounds can be prepared by reacting the reagents to form the compounds as indicated in Table I. Biological Activity The novel compounds of the present invention have been tested and found to be extremely effective in treating severe neurological disorders of the type resulting from either severe traumatic injury to the spinal cord or from systemic diseases such as multiple sclerosis. These compounds are believed to act upon receptors at several sites. The stimulating of the receptors in the spinal cord, either directly or indirectly, tonically stimulates the motor neurons, thus preserving muscle mass. These drugs generally have long- term ameliorative effects, which apparently bring about a reorganization within the nervous system, providing for regaining of central nervous system control over lost functions in those portions of the body distal to the brain and below the damaged spinal cord site. These compounds reduce and result in control over spasticity in the distal bodily portions, for example, over the urinary tract or the legs; also significantly, the desirable results are obtained without sedating or lowering the blood pressure of the mammal. In the following examples, specific methods of administration are described. However, it is believed, unless otherwise stated, that similar response can be elicited by following other means of administration. A cat was anesthetized using intravenous pentobarbital (30 mg/kg) after which its arterial blood pressure was continuously monitored for at least two hours. After recording stable arterial blood pressure, a dorsal laminectomy was performed in the thoracic region of the cat from T 3 to 5 ; after restoration of blood pressure, the cat was traumatized by means of a twenty gram weight being dropped from a height of twenty-five centimeters (500 g-cm force) on the exposed spinal column dura at the fourth thoracic segment. The cat was not thereafter treated except to surgically clean the trauma region and assist in the healing of the surgery. The cat was regularly observed over a four month period. Somatosensory-evoked potentials (SEPs) were measured and recorded for this cat, " immediately before the spinal trauma, 10, 20 and 30 minutes after the trauma, and two hours after the trauma, and then again 30 days after the trauma. The SEPs were generated by stimulating the sciatic nerve by means of needle electrodes inserted through the posterior thighs. It is known that the recording of SEPs from the so atosensory cortex by stimulating lower extremities requires the presence of intact ascending pathways. The absence of SEPs indicates a complete disruption of the spinal cord tracks.' Beginning 10 minutes after impact, the SEP was substantially completely absent from the thus injured cat. The cat did not regain the use of its lower extremities, nor did it ever regain bladder and bowel control. The animal progressed from acute, flaccid phase to chronic, spastic and autonomically dysreflexic phase of paralysis. Comparative Example B The spinal cord of a group of rats was completely transected. After surgery, the rats were treated with guanabenz (4.0 milligrams per milliliter of dextrose in 5% water solution) was commenced 72 hours after the lesion. The drug (0.4 ml.) was given twice per day intraperitoneally. Following each administration of the guanabenz rats became sedated for at least 2 to 4 hours. Each rat showed a condition of bloody eyes and nose for a period of 5 to 7 days after the transection. The guanabenz was administered at a dosage rate of 5 mg/kg bid intraperitoneally. During the first two-week period there was substantially no restoration of proper plantar placement, weight bearing on the hind legs and/or control walking. However, by the third week of such treatment, proper plantar placement, weight bearing on the hind legs and walking movements coordinated between the front and hind legs were observed in substantially all of the rats to a satisfactory degree. The rats-, however, showed a significant loss of muscle mass in their hind legs, and were weaker than previously. Working Example 1 In a further group of rats the spinal cord was transected in accordance with the above Comparative Examples. After surgery and cleaning and mechanical treatment of the wounds in the same fashion, an intraperitoneal injection of guanidino-7-acetyltheophylline ("C") was administered at a dose of 5.0 mg/kg 24 hours post surgery. Within a 7 to 9 day period, all 6 rats were restored to engaging in coordinated walking movements between the front legs and the hind legs, including proper plantar placement and full weight bearing on the hind legs. Within 36 hours after the spinal transection, i.e., only 12 hours after initial administration of Compound C, the initial bloody eyes and nose condition had substantially disappeared. The muscle mass and apparent strength of the hind legs were substantially not reduced and the animals maintained normal activity during the entire course of treatment without any indication of sedation or lethargy. Further the animals continued to eat in substantially normal quantities. Twenty-four and forty-eight hours post-transection, i.e., immediately after each day's initial intraperitoneal administration of Compound C, reflexes such as the tail-flick and cross-extension had returned ( i.e., within 12 minutes after injection) . This short-term strong response was observed for at least 1-1/2 hours after each injection and gradually diminished until subsequent readministration of Compound C, guanphylline. Within 8 to 11 days the response was clearly permanent, and was accompanied by long-term therapeutic restoration of coordinated movements, plantar placements and weight-bearing by the hind legs. None of these rats treated with Compound C developed any spasticity within six months after the spinal cord transection. Measurement of blood pressure in the cat and sheep shows a slight increase immediately after administration of Compound C, which returns substantially to normal within ten (10) minutes. Three weeks after discontinuance of the treatment with Compound C, the condition of the animal remained extremely stable and the animal clearly had greater control over his movements than those treated with guanabenz, whereas the control rats of Comparative Example A were substantially incapacitated. Working Example 2 It was noted that the untreated rats in Comparative Example A developed severe spasticity within three weeks after transection. Treatment of three of these control rats three weeks after trauma by administration of Compound C intraperitoneally for 7 days, (4..0 mg/kg BID), resulted in a marked decrease in spasticity within 4 days and a complete elimination after 7 days. None of the rats initially treated with the Compound C developed spasticity at any time. Working Example 3 Ten (10) cats were spinally traumatized in accordance with the procedure set forth above in Comparative Example A, for the rats. Five (5) of these spinal cats were treated with Compound C commencing three (3) hours after trauma and five (5) of the cats were treated with guanabenz beginning at the same time. The cats treated with guanabenz (4 mg/kg bid) exhibited tight urinary sphincter and dyssinergia during urodynamic examination four to five weeks after treatment began. Those cats treated with substantially the same quantity of Compound C during the same period had substantially completely recovered urinary bladder function and exhibited little or no dyssinergia after only seven to twnety-one days of treatment. Spinalized cats required eight weeks of treatment with guanabenz before approaching almost normal micturition. Cats treated with Compound C, required only three to five weeks of treatment to achieve the same results. It is clear that the novel compounds of this invention are effective not only for the smaller mammals, but also for larger mammals including primates. When testing the other compounds listed in Table I above, in accordance with the above procedures, substantially the same results are achieved. MOLAR COMPOUND RATIO ABBREV. :B PRODUCT C GUANIDINE. HC1 THEOPHYLLIHE-7-ACETIC ACID 1: GUANIDINO-7-ACETYLTHEOPHYLLINE D 2-GUANIDINOBENZ IMIDAZOLE THEOPHY LIHE-7-ACETIC ACID 1; 2-GUANIDIN0BENZIMIDAZ0LYL-7-ACETYLTHE0PHYLLINE E 2-HYDRAZINOIMIDΛZOLINE,HBR THEOPHYLLINE-7-ACETIC ACID 1; 2-HYDRAZXNOIMIDAZOYL-7-ACETYLTHEOPHYLLINE P GUANIDINE 1-THEOBROMINEACETIC ACID 1: THEOBROMINE-1-ACETYL GUANIDINE C 2 AMINOGUANIDINE THEOPHYLLINE-7-ACETIC ACID 1; THEOPHYLLINE-7-ACETYLAMIDO-GUANIDINE G AMINOGUANIDINE 1-THEOBROMINEACETIC ACID Is THEOBROMINE-1-ACETYLAMIDO-GUANIDINE 7. N AMINOGUANIDINE THEOPHYLLINE-7-ACETALDEHYDE l! THEOPHYLLINE-7-ETHYLENEIMINO-GUANXDINE 8. C GUANIDINE THEOPHYLLINE-7-ACETALDEHYDE 1i1 THEOPHYLLXNE-7-ETHYLENE-GUANIDINE GUANIDINO-ACETIC ACID 7-(2,3-DXHYDROXY)PROPYL 2:1 7-(2,3-DIGUANIDINOACETATE)PROPYLTHEOPHY LINE THEOPHYLLINE 10. H 2,4,6-TRIAMINO-β-TRIAZINE THEOPHYLLINE-7-ACETXC ACID 1:3 2,4,6-TRXS(7-ACETAMXDOTHEOPHYLLXNE) -1,3,4-S-TRIAZINE 11. J 2,4,6-TRIAMINO-β-TRIλZINB 2,6-DXCHLOROBENZALDEHYDE + 1:2:1 2,4-BIS(2,6-DICHLOROBENZYLIDENEIMXNO)-6-(7- THEOPHYLLINE-7-ACETIC ACID ACETAMIDOTHEOPHYLLINE)-1,3,5-a-TRIAZINE 12. K 2,4,6-TRIAMINθ-O-TRϊAZINE 1-NAPHTHYLACETXC ACID + 1:2:1 2,4-BIS(1-NAPHTHYLACETAMIDO)-6-(7-ACETAMIDO- THE0PHYLLINE-7-ACETIC ACID THEOPHYLLXNE)-1,3,4-S-TRIAZINE 13. L 2,4,6-TRIΛMINO-β-TRIAZINE 2,6-DICHLOROBENZALADEHYDE + 1:1:2 2, -BIS(7-ACETAMIDOTHEOPHYLLINE)- THE0PHYLLINE-7-ACETIC ACID 6-(2,6-DXCHLOROBENZYLIDENEAMINO)- 1,3,5-S-TRIAZINE 14. 2,4,6-TRIλMINO-a-TRIλZINE THEOPHYLLXNE-7-ACETIC ACID 18IsI 2-(7-ACETAMIDOTHEOPHYLLINE)-4-(X-ACETAMIDO- 1-THEOBROMINEACETIC ACID THEOBROMINE)-6-AMINO-l,3,4-β-TRIAZINE 15. 4,5-DIPHENYL-2- THEOPHYLLINE-7-ACETXC ACID 1:1 THEOPHYLLINE-7-ACETYL-2-( ,5,-DIPHENYL)-2- IMIDAZOLETHIOLE THIOMIDAZOLE 16. 2-(4-AMINOPHENYL)-6- 1-THEOBROMINEACETIC ACID 1S1 l-THEOBROMINEACETYL-2-(4-AMINOPHENYL)-6- METHYL-BENZOTHIAZOLE METHYLBENZOTHIAZOLE TABLE I

Claims: THE PATENTABLE EMBODIMENTS OF THIS INVENTION WHICH ARE CLAIMED ARE AS FOLLOWS: 1. Pharmacologically active compounds having the capability of reestablishing previously destroyed neurological functions in a traumatized or diseased mammal, these compounds comprising the reaction product of a guanidino, aminoguanidino, 2-imidazolino, 2-hydrazinoimidazolino or 2- guanidinobenzi idazolino group with a methylated xanthine group, which provide a combination of receptor activity designed to stimulate appropriate receptors in the brain and spinal cord and thus tonically stimulate motor neurons, in spite of a severely damaged central nervous system. 2. Pharmacologically active compounds having the capability of reestablishing previously destroyed neurological functions in a traumatized or diseased mammal, these compounds having the general formula: wherein g and r can have a value of 0 or 1, to a total of one, h can be 0 or 1, and n is 0 or an integer of at least 1 and preferably not greater than 2; the R groups comprising hydrogen or non-interfering organic groups. 3. The compounds of Claim 2, wherein R- ^ and R 2 and R 3 preferably include alkyl groups or hydrogen atoms, at least one of R.^ and R 2 and/or R 3 comprising an alkyl group; R^_ and/or R 3 can be the bridging group to the guanidino moiety outside of the brackets, and can be an aliphatic group, saturated or unsaturated, or such group including a carboxyl group or a carbonyl group, oxygen, nitrogen, sulfur, connected to a nitrogen atom of the guanidino group by a double bond; R 4 and 5 can each be hydrogen, or lower alkyl, alkoxy, thioalkyl, alkenyl, aryl, aralkyl, or alkaryl or nucleoside group, or any such group substituted with NH 2 , OH, OCH 3 , or halogen, sulfur, oxygen, or N0 2 ; g can be a bridging organic group forming a closed heterocyclic ring compound with the two nitrogen atoms on the guanidino group, and can include additional nitrogen atoms, halogen atoms, oxygen atoms.

Inventors: NAFTCHI N ERIC, NAFTCHI, N., ERIC
Applicants: NAFTCHI N ERIC, NAFTCHI, N., ERIC
Application year: 1989
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P25, C07D473