JPH05501248A - Pharmaceutically active amino-substituted heteroarylamines - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

Pharmaceutically Active Amino-Substituted Heteroarylamines This invention relates to complex heteroarylamines attached to a simple mo/- or di-substituted amine 7 moiety. These compounds are useful as drugs. 2. Description of Related Art Compounds similar to some of the compounds of the present invention are disclosed in International Application No. Published November 3, 1988 under PCT/US 8 B101212 It is disclosed in International Publication No. WO3B108424. See in particular compounds of formula (II). The known compound of this document has a linking site J[-(CHI), * between the amine site (M) of the molecule and the non-amine site (X,) of the molecule where n is 4 to 14 -]. In the present invention, similar compounds have less than 4 "linking sites". (R,)(R,)N-heteroaryl (1) [wherein R1 is C, -C, alkyl, -0-CH,, -0-CH,CH,, -(t, Ht), , -0-R,-, where n is 2 or 3 and Rl-1 is -H, C, -C, alkyl, -COR1-*, where R+-+ is -H, C, -C, alkyl or -φ, -CH, -CH(OR1-,)-CH,, where R, -, is the same as the above definition, -CH*CH*-(0-CH,CH,),, -0-R1-, where n is 1 or 2, R+-+ is the same as defined above, -(CH,), 1. -Co-R 1-3, where n is 1 to 3 and R, , is 1 0H1 -O-R1-,, where R1- is C, -C, alkyl, or optionally one or more is two -F%CI2. -Br. -No, -OR,-, where C, -C,t or R,- is CI Cs alkyl. -φ, -CH, -CH=CH-Go-R, 1, where R1-5 is the same as the above definition, -(CHI), -N (Rt-sXR+-*) , where R4 is 2 or 3, R+-s and R1-1 are the same or different, -H is also 1 (CH=) -s ORt-3, where n is 2 or 3 and Rt -+ is -H, C2Cs alkyl, Co R-*, here ζ R, - is -H, C, -C, alkyl or is −φ, −CH, −CH(OR,,)−CH,, where R, −, is the same as the above definition. Di, -CH,CH,-(0-CH,CH,). I OR1-1, where n is 1 or Haki 2, Rt-1 is the same as the above definition, (CH,). -CORt-s, this R7 is 1 to 3, and R2-5 is -0-R, , R2-4 is C, -C, alkyl, or optionally 1 or 2 -F, -CQ, -Br . -NOl, C, -C, or Rt-s may be substituted with -OR*-s where C1-Cs alkyl, -φ, or R3 and R2 together with the bonding nitrogen atom may be substituted with pyrrolidine , piperidine, morpholine, piperazine, and the 4-position is -(C1-1t), @-0-R,-, where n is 2 or 3 and R s- is -H,C, -C, alkyl, -Go-Rs-t, where R3-, is -1 (, C, -C, alkyl or -φ, -(CH,),, -Co-R3-1, where n, is 1 to 3 and R32 is -OH.-O-Rs-a, where Rj- is C, -C, alkyl or -CH, -φ, optionally 1 or 2 -F , Cg, ~Br. -No, , C, -C, or -Rs-t may be substituted with 0Rs-a which is C, -C, alkyl -φ, -CH,CH, -(0 -CH,CH,),, -0-R,, where nl. is 1 or 2, R3-1 is the same as the above definition, -CH,CH=CH-Co-R3-2, Here Rss is the same as defined above, or S Ot R3-s, where R3-1 is a pipette substituted with C, -C, alkyl. forming a heterocycle selected from the group consisting of radines; Heteroaryl means that one or two R4-I and R4-1 are the same or different. Nari, -H. from pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl and 4 (C1Cs alkyl)-piperazinyl-NH-OH; -N (R,,XR4-,), -NH-0-CH,~φ, R4- forms a heterocycle selected from the group consisting of -H or CI -0-R,,, -N (CH, CH, -0-R,,) in which R41 is the same as the above definition. pyridin-2-13- and 4-yl, pyrimidin-2- and 4-yl, substituted with pyridin-2-13- and 4-yl, or a pharmaceutically acceptable salt thereof. do. DETAILED DESCRIPTION OF THE INVENTION The amino-substituted heteroarylamines (1) of the present invention can be prepared by known methods. prepared from more known compounds. The present invention includes novel pharmaceutical compounds; the process chemistry used to prepare these novel amino-substituted heteroarylamines (1) is well known to those skilled in the art. There are three general methods for producing the amino-substituted heteroarylamines (1). The method of 710 substituted (preferably chloro)pyrimidines, halo(preferably chloro)pyrimidines, alkylated with primary or secondary amines. zine, halo(preferably chloro)pyrazine, or halo(preferably chloro)to Depart with Riazin. The reaction continues with pyrimidine, pyridazine, and pyrimidine until starting material is consumed. By heating a mixture of pyrazine, pyrazine or triazine and excess liquid amine, Therefore, do it. Temperatures range from about 20-25° to the boiling point of the amine, including about 1 Reaction times of about 24 hours are typical. Preferably halo pyrimidine, pyrimidine Equivalents of dazine, pyrazine or triazine and the amine are reacted in a solvent such as acetonitrile and THF containing an acid scavenger such as potassium carbonate or an acid base such as pyridine or diisopropylethylamine. Excess pyridine can be used both as a solvent and as a base. Reaction time from 1 hour to several days at a temperature of about 20-25' to the boiling point of the solvent Intervals are possible. The processes of Examples 1 to 6 are carried out by this method. In a second method, substituted piperazinopyrimidines, piperazinopyrimidines, by reaction of the appropriate alkyl halide/mesylate/tosylate or functionalized alkyl halide/mesylate/tosylate with a piperazino (secondary amine) intermediate. Prepare pyridine or piperazinotriazine. Although not required, catalytic amounts of iodide can be included in the reaction mixture. Generally, oxidation in the presence of a base such as potassium carbonate, pyridine or diisopropylethylamine The use of polar, non-hydroxyl solvents such as setonitrile is preferred. The processes of Example 8, IO~12.14.20.21.24-26 and 28-30 are carried out by this method. Other substituted 2,3-diaminopyridines can be prepared in several steps by reaction of 2-chloro-3-nitropyridine with a suitable primary or secondary amine. Generally, the use of solvents such as THF or acetonitrile in the presence of excess base is preferred. The 3-ditropyridine intermediate is conveniently prepared by catalytic hydrogenation to the corresponding primary atom. Return to Min. The secondary amine is reductively alkylated to form the corresponding mono- or gives the dialkylamine product. Similarly, 2,5-diaminopyridines are prepared from 2-chloro-5-nitropyridine, and 2,3,6-triaminopyridine is prepared starting from 2,6-dichloro-3-nitropyridine. do. The processes of Examples 15-18 were carried out by this method. The reaction mixture described above is purified by standard methods. Briefly, volatile solvents and reagents are removed by distillation under reduced pressure. The residue is partitioned between a temporary solvent such as ethyl acetate, methylene chloride, ether, etc. and water and/or aqueous bicarbonate. The organic phase is separated, dried and concentrated to give a residue which is chromatographed. Refined by water. Appropriate fractions are pooled and concentrated to a residue. If necessary, the residue is crystallized. Said compounds can be converted to other amino-substituted heteroarylamines (1) by methods known to those skilled in the art (etherification, acylation, hydrolysis, hydrogenolysis, etc.). The compounds can be converted into pharmaceutically acceptable salts by known methods. free carbo Compounds containing xyl groups can be converted into pharmaceutically acceptable base salts by known methods. For example, these include sodium, potassium, aluminum, calcium, and ammonia. and trometamino (THAM) salts. R1 and Rt are separate or R8 and R9 together with the bonding nitrogen atom are pyrrolidine, piperidine, morpholine, piperazine and or form a heterocycle selected from the group consisting of substituted piperazine. When R5 and R, do not together form a cyclic group, R, is C, -C, alkyl Kill, -0-CH,, -(CH,) ,,, -0-R,-,, -(CH,) ,,, -Co-RI-, or -CH, -CH=CH-C0-R+ -i is preferred. When R3 and R9 together form a cyclic group, R, is preferably -H1C+ If a cyclic group is formed, it is preferably morpholine, 4-substituted piperazine, pyrrolidine or piperidine; R1 and R, together form 4-substituted piperazine. Gayo More preferable. Preferably heteroaryl is pyrimidin-4-yl or pyridin-2-yl. Delicious. When heteroaryl is pyrimidin-4-yl, it is 2. - Preferably substituted with 6-di-l-pyrrolidinyl or morpholino, more preferably substituted with Preferably, it is substituted with 2,6-di-1-pyrrolidinyl. Heteroa When ryl is pyridin-2-yl, it is preferably substituted with 3-ethylamino. The amino-substituted heteroarylamine (r) is selected from the compounds of Examples 1-38. Preferably. Since the amino-substituted heteroarylamines (1) of the present invention are amines, They readily form salts when reacted with acids strong enough to form the corresponding salts. to be accomplished. Pharmaceutically acceptable salts include both inorganic and organic acid salts. Preferred pharmaceutically acceptable salt anions include acetate, benzoate, bromide, chloride, citrate, fumarate, mesylate, maleate, phosphate, nitrate. succinate, sulfate and tartrate. In humans, amino-substituted heteroarylamines (1) have been shown to be associated with M-injury, mild and/or moderate to severe head injury, subarachnoid hemorrhage and subsequent cerebral vasospasm, ischemic (thrombotic) embolism) attack, excessive mucus secretion, asthma, muscular dystrophy Adriamycin-induced precardiac, Parkinson's syndrome, Alzheimer's disease, other degenerative neurological disorders, multiple sclerosis, organ damage during post-transplant perfusion, skin graft rejection, hemorrhagic, traumatic and septic shock, and severe diseases such as burn injuries, ARDS (Adult Respiratory Distress Syndrome), inflammatory diseases such as bone or rheumatoid arthritis, nephrotic syndrome (immune), systemic lupus erythmatous disease, allergic reactions, atheroma [11] complications from inflammation (e.g. skin, inflammatory and xerotic diseases), emphysema, stress-induced ulcers, cluster headaches, brain tumors (e.g. periLumora+ water 1! i) , radiation damage (e.g. radiation Accidental exposure to radiation during radiation therapy! ! (from dew), prenatal infant asphyxia and infant hypoxia syndrome, uveitis and optic neuritis, photoretinopathy, age-related plaque degeneration. It is useful in treating eye diseases such as glaucoma, cataracts, and glaucoma. In humans, amino-substituted heteroarylamines (1) are useful in preventing damage from cardiopulmonary resuscitation, neurological or cardiovascular surgery, and myocardial infarction. Amino-substituted heteroarylamines (1) are useful in irrigation solutions used in ophthalmic surgery. Each amino-substituted heteroaryl amine (1) has a different role in treating each of the above-mentioned diseases. It is useful to the extent that However, as known to those skilled in the art, some of the amino-substituted teroarylamines () are good for treating some diseases, while others are good for treating other diseases. It is. Determining which compounds are better than others for individual diseases requires routine rather than experimental testing. Well-known tests are available that can be easily analyzed. For example, the mouse head negative of Hall (all), Journal of Neurosurgery (J, Neurosurge, ) + 62 + 882 (1980). Wound assays will allow one skilled in the art to readily determine which particular amino-substituted heteroarylamines (1) are useful in the acute treatment of M-injuries or mild and/or moderate to severe head injuries. Discloses the decisions that can be made. In addition, Ho The cat 48-hour motor neurodegeneration model of Hall et al., Exp, Neurol., 79.488 (1983) - Useful in treating chronic degenerative neurological disorders such as Kinson syndrome, Alzheimer's disease, etc. Int, Arch, Allergy Appl. lsmunol, 70.169 (1983) A Searis suum sensitized rhesus macaque assay is described. Furthermore, the arachidonic acid 1.D*o test of Kohler, Thrombosis Research, 9.9.67 (1976) inhibits lipid peroxidation and/or prostaglandin cascade. Identification of compounds that inhibit neurotransmitters may be useful in treating spinal cord injuries, mild and/or moderate to severe head injuries, degenerative neurological disorders, etc. any particular compound It is useful to determine which substances inhibit lipid peroxidation and are therefore useful in treating spinal cord injuries, mild and/or moderate to severe head injuries, degenerative neurological disorders, etc. One method is as described by Proyor in Mason's O. Methods or Enzymology, 10 5.293 (1984). Standard conditions for treatment are about 0.05 to about 10 mg/kg/day of amino-substituted heteroarylamines (1) intravenously or about 50 to about 50 mg/kg/day, 1 to 4 times daily. Oral or parenteral administration, such as intravenous (ie, injection, infusion or continuous infusion) or intramuscular administration, at standard oral doses. spinal cord injury, mild and moderate to severe head injury, cardiopulmonary resuscitation injury, myocardial infarction, organ damage during post-transplant perfusion, hemorrhagic, traumatic and septic shock, severe The standard conditions are used to treat inflammatory burns, ARDS, and nephrotic syndrome, and to prevent skin graft rejection. Typical treatment depends on the patient's individual conditions and and depending on the particular compound used, an initial loading dose, eg, 0.01 mg to 2 mg/kg intravenously, followed by a maintenance dose, eg, intravenous infusion for one day to one week. This can be supplemented with intramuscular administration for days, weeks or months to prevent delayed neurodegeneration in nerve applications (eg spinal cord injury, head injury). In treating subarachnoid hemorrhage and subsequent cerebrovascular spasm or ischemic (thromboembolic) stroke, the standard conditions are used and at-risk patients are pretreated orally. Amino-substituted heteroaryls in treating hypermucus secretion and asthma The drugs ([) are administered orally, intravenously, or by inhalation at standard doses. In treating excessive mucus secretion, amino-substituted heteroaryl amines (

The oral dose of [) is about 0.5 to about 50 mg/kg/day. The frequency of administration is 1 to 4 times daily. Suspicious individuals were present several hours before the expected problem. Can be treated in advance. The intravenous dose is about 0.05 to about 20 mg/kg/day. The aerosol formulation contains about 0.05 to about 1.0% amino-substituted heteroaryl. The drug contains amines (1) and is administered or used about 4 times daily as necessary. In treating muscular dystrophy, Parkinson's syndrome, Alzheimer's disease and other neurodegenerative disorders (amyotrophic lateral sclerosis: multiple sclerosis) Amino-substituted heteroarylacenes () are administered orally using a dose of about 50 mg/kg/day, administered or used 1 to 4 times per day. The treatment may continue for several years. In treating adriamycin-induced procardiacity, amino-substituted heteroarylamines ( 1) is administered orally or intravenously. Amino/-substituted heteroarylamines (1) are preferably used for intravenous administration of adriamycin. or pre-treat the individual with amino-substituted heteroarylamines ([)]. To prevent or prevent injury after neurological or cardiovascular surgery, Mino-substituted heteroarylamines (I) are used according to the standard conditions. disease Patients can be pre-treated with a single intravenous or intramuscular dose just prior to surgery and/or administered orally after surgery. In treating osteolytic arthritis and other inflammatory diseases, amino- for about 0.5 to about 50 mg/kg/day of converted heteroarylamines (I) The dose is administered orally or intramuscularly from 1 to 4 times daily. For oral administration, the drug may be administered alone or with other steroidal or non-steroidal anti-inflammatory drugs. Ru. The initial dose in some severe rheumatism patients can be administered intravenously, followed by intravenous infusion for up to 24 hours or longer. Additionally, intra-articular administration can be used. In treating drug allergic reactions, amino-substituted heteroarylamines (1) are administered at doses of about 0.5 to 50 mg/kg/day, administered orally and intravenously 1 to 4 times daily. do. Typical treatment would be an initial intravenous dose followed by oral administration for several days or more. In the treatment of atherosclerosis and emphysema, amino-ffill K heteroarylamines (1) are administered orally 1 to 4 times daily at doses of about 0.5 to 50 mg/kg/day. do. To treat inflammatory skin diseases including burns and dryness, amino-substituted heteroaryl amines (1) orally at a dose of about 0.5 to about 50 mg/kg/day, 1 to 4 times daily, or as needed, at a concentration of about 0.5 to about 5%. Apply topically as a cream, ointment or lotion or equivalent dosage form. In treating these diseases, amino-substituted heteroarylamides (1) can be used with steroid drugs. For use in ophthalmic surgery, from about 0.001 to about 1% of the amino/-substituted heteroaryl An isotonic solution containing Ruamine(r) is used. In treating eye disorders, amino-substituted heteroarylamines (1) are administered orally at a dose of about 0.5 to about 50 mg/kg/day, 1 to 4 times daily, or as needed. As long as about 0. Creams, ointments, or ointments with a concentration of about 1% or topically as a lotion or equivalent dosage form. Amino-substituted heteroarylamines (1) are used in the prevention and treatment of stress ulcers and by drugs such as nonsteroidal anti-inflammatory compounds (NO3AC). Useful in the prevention and treatment of induced gastric intolerance. Stress ulcers are ulcers that develop after exposure to a serious illness such as an injury, burn, major surgery, acute illness, etc. Patients in intensive care units are particularly susceptible to stress ulcers. Also, Ulcers include trauma that can lead to upper gastrointestinal bleeding; such bleeding This appears to be prevented by compounds. N03AC is commonly administered for analgesia. gastrointestinal intolerance characterized by pain and trauma that can lead to bleeding. Often associated with ibuprofen, aspirin, indomethacin, naproxen, pyrro Contains drugs such as oxicam. The amino-substituted heteroarylamines (1) are administered either as tablets, capsules or liquids in doses ranging from about 5 to about 500 mg, two to four times per day, preferably by the oral route. The treatment is preventive, i.e., prevents ulcers from forming in patients at risk of developing trauma, etc. or therapeutically, i.e. once the ulcer has formed. In patients who are unable to administer oral dosage forms due to their clinical condition, amyl/-substituted heteroarylamines (1) may be administered via a nasogastric tube or parenterally, i.e., intravenously or intramuscularly. . Parenteral doses will range from about 1 to about 50 mg/kg, administered 1 to 4 times per day. In chairs, the ami-7-substituted heteroarylamines (I) are useful in treating injuries, intervertebral disease (slipped discs), traumatic cysts, flea bites, and pond allergies. In horses, amino-substituted heteroarylamines ff1(1) are useful in the treatment of colic (endotoxin or septicemia), preoperative pre-treatment for colic, and the treatment of laminitis. In the run, ami/-substituted heteroarylamines (1) are Acute allergic reactions for supplying vaccinations for adenitis, bovine mastitis, oral... and in the treatment of shipping fever. In pigs, amino-substituted heteroarylamines (1) are useful in treating pig stress syndrome and heat stress syndrome. Amino-substituted heteroarylamines (1), as known to those skilled in the art, are It can be used in conjunction with other drugs in the treatment of disease. The exact dose and frequency of administration will depend on the particular amino-substituted heteroarylamine used, the particular disease to be treated, and the severity of the disease to be treated, as is well known to those skilled in the art. , depending on the individual patient's age, weight, general physical condition, and other medications the individual is receiving, the amyl-7-substituted heteroaryl group in the patient's blood may vary. Blood levels or concentrations of miners (1) and/or the individual disease to be treated This can be determined more precisely by measuring the patient's response to the condition. Definitions and Commitments The following definitions and explanations are for terms used throughout this application, including the specification and claims. 1. Formula Promises and Variable Definitions Chemical formulas representing various compounds and molecular fragments in the specification and claims may contain various variables in addition to explicitly defined structural features. . These variable substituents are defined by a letter or a letter followed by a numeric index, e.g. The identity is confirmed. These variable substituents are either monovalent or divalent, i.e. they represent groups linked in a chain by - or two chemical bonds. vinegar. For example, the group zl represents a divalent variable if it is bonded to 2CH, -C(=Z,)H. The groups R, Oyo and RJ are bonded to the formula CH3cHt c (R1)(RJ)H, represents a -valent variable substituent. As mentioned above, when a chemical formula is expressed in a straight line, the variable substituent enclosed in parentheses is bonded to the atom immediately to the left of the variable substituent enclosed in parentheses. When two or more consecutive variable substituents are enclosed in parentheses, the consecutive variable substituents are included in the immediately preceding preceding atom that is not enclosed in parentheses. (Thus, in the above formula, R4 and RJ are bonded to the preceding carbon atom. Also, according to the established system of carbon atom numbering such as steroids, For any atoms on the stem, these carbon atoms are designated C□, where "i" is an integer corresponding to the carbon atomic number. For example, C6 is a stereo Steroids, as traditionally represented by those skilled in the art of steroid chemistry, Represents the 6th position or the carbon atom number of 6 in the carbon nucleus. Similarly, the term "R1" represents a variable substituent (either -valent or divalent) at the C1 position. A chemical formula or portion thereof drawn in a straight line represents a linear group of atoms. The symbol "-" generally represents a bond between two atoms in the chain. Thus, CH , -0-CH, -CH(R1)-CH, is a 2-substituted -l-methoxypropane compound represent something. Similarly, the symbol "==" represents a double bond, e.g. CH, =C(RJ-0-CH, and the symbol r=J represents a triple bond, e.g. HCmiC-CH(R,)-CH, -CH,.The carbonyl group can be expressed in two ways: CO- or =C(=C). Although either one of these will be expressed, the former is preferred over simplicity. When a variable substituent is divalent, in the definition of the variable, the bonds are or both. For example, the variable R6 attached to a carbon atom, such as -C(=R,), is divalent and oxo or keto (thus carbon). (to form a carbonyl group (-Co-)) or as two separately attached monovalent variable substituents α-R, -4 and β-RI-. bivalent strange When the number substituent R, is defined as consisting of two monovalent variable substituents, the divalent variable The conventions used to define the number substituents are of the form "α-RJ:β-R1-k" or some variation thereof. In such a case, both α-R1-J and β-R1- are bonded to the carbon atom to give 10(α-R1-J)(β-R,-,). For example, if the divalent variables R1,C(=RJ- are defined as consisting of two monovalent variable substituents) , the two monovalent variable substituents are α-R@-1:β-R8-1+ ... α-R1,:β-R,-1°, etc., and -C( α−R,−,)(β−R, −,)−+ ・・・・・・−C(α−R1−0)(β−R1−1゜)− etc. are given. Ru. Similarly, for the two-valued variable R8, -C (=R1,), two single-valued variables The substituents are α-R,,,:β-R11-2. Separate α and β configurations (e.g. ring substituents (e.g., due to carbon double bonds in the ring) and ring positions. For substituents attached to non-substituted carbon atoms, the conventions above are still used, but the designations α and β are omitted. Just as a bivalent variable can be defined as two separate monovalent variable substituents, two separate monovalent variable substituents can be defined together to form a bivalent variable. example For example, in the formula -C8(R1)HCt (RJ)H- (C, and CI can be arbitrarily defined as first and second, respectively), R1 and R, together, represent (1)C , and C! can be defined as forming a second bond between (2) oxa (-0-), and thus Describe the code. When R4 and R4 are taken together to form a more complex group such as the group -X-Y-, the configuration of the group is such that CI in the above formula is bonded to X and C2 is bonded to Y. It's like being there. Thus, by convention, the expression "...R1 and R, together form -CH, -CHt-0-CO-..." It means a lactone in which the bonusyl is attached to C1. However, the expression "...RJ and R, together form =Co-0-CH, -CH," When shown, it means a lactone in which the carbonyl is bonded to CI. The carbon atom content of variable substituents is expressed in one of two ways. the first one The method uses subscripts to the overall name of the variable, such as rC, -C, and J, where "1" and "4" are both integers representing the maximum and minimum number of carbon atoms in the variable. Separate line characters from variables with spaces. For example, "rc, -c4 alkyl" represents alkyl of 1 to 4 carbon atoms (including its isomeric forms, unless otherwise indicated). vinegar. If this single index is given, it is the total carbon source of the variable to be defined. Indicates child content. Thus, C,-C,alkylcarbonyl describes =CH,-(CH,)n-0-Go-, where n is 0.1 or 2. According to the second method, the carbon atom content of only each part of the definition is indicated by enclosing the designation "CI-CJ" in parentheses and Indicate this by placing it immediately before (without spaces) the part to be defined. By this arbitrary convention, (C,-C,)alkoxycarbonyl is defined as C,-C4alkoxycarbonyl. It has the same meaning as cycarbonyl group. This is because “C1-C5” is Alcoqui This is because only the carbon atom content of the group is mentioned. Similarly, C,-C,alkoxycarbonyl and (C,-C,)alkoxy(C1-C,)alkyl define alkoxy groups containing 2 to 3 carbon atoms, but the definitions of 2 are different. Toi The reason for this is that the former definition allows the alkoxy or alkyl moiety alone to contain 4 or 5 carbon atoms, whereas the latter definition refers to any of these groups containing 3 carbon atoms. This is because it is limited to children. J-Yono All temperatures are in degrees Celsius. TLC refers to thin layer chromatography. T) (F refers to tetrahydrofuran; saline refers to aqueous saturated sodium chloride solution; NMR refers to nuclear (proton) magnetic resonance spectroscopy; CMR refers to C-13 magnetic resonance spectroscopy, and chemical shifts are measured in chloroform-d (CDC9,). Low figures from tilsilane are reported in ppm (δ) and measured in chloroform-d CCD CQ,). φ refers to phenyl (C, H,). Ether refers to diethyl ether. Pharmaceutically acceptable means acceptable to patients from a pharmacological/toxicological standpoint, and physical/chemical properties with respect to composition, stability, patient tolerability, and bioavailability. Characteristics and/or substances that are acceptable to pharmaceutical scientists from a scientific point of view. Treating or treating refers both to treating the disease as it exists and to preventing the same disease from occurring under circumstances where this is possible, as is well known to those skilled in the art. For example, amino-substituted heteroarylamines ([) are used to treat existing asthma and to prevent it from occurring in the future. For example, amino/-substituted heteroarylamines (1) treat spinal cord injury and prevent rejection of skin grafts. When using a solvent pair, the ratio of the solvents used is volume/9 (V/V). EXAMPLE A person skilled in the art will be able to fully utilize the present invention using the foregoing description and without further elaboration. I believe that it can be implemented to the fullest extent possible. The detailed examples below illustrate the preparation of various compounds and The following description describes how to carry out the various processes of the invention and is merely illustrative and should not be construed in any way as limiting the previous disclosure. Those skilled in the art will be familiar with both the reactants and reaction conditions and techniques. One will readily recognize suitable variations from the law. Practical example 1 4-(1-(hydroxyethyl)methylamino/)-2,6-di-1-pyrrolidinylpyrimidine (1) 4-chloro-2,6-di-1-pyrrolidinylpyrimidine A solution of 15.5 g of Limidine and 30 mQ of 2-(methylamino)ethanol is heated under reflux for about 20 hours. The mixture is cooled and diluted with 150 m of ethyl acetate (!) and 75 m of cassium hydrogen carbonate (IN). The organic extract is washed with water (5 x 50 m ff), saline (lXroomρ), and 100 m of ethyl acetate backwash. Clean, then dry (magnesium sulfate) and concentrate. The residue is crystallized from methanol/water (815,130 mC) to give the title compound. Melting point 108-110'; A solution of 2.53 g of 4-chloro-2,6-di-1-pyrrolidinylpyrimidine and 5 mσ of morpholine is heated under reflux for about 16 hours. The reaction mixture is worked up as in the example (the product is dissolved in ethyl acetate). hard to burn). Two recrystallizations from methanol give the title compound. Melting point 1 803~180.6°, CMRI64°21.162.33, 160.0.7 2.20.66°70, 46°05.45.92, 44.83, 25.45 and 25.196 l-pyrrolidinylpyrimidine (1) A solution of 3.4 g of 4-chloro-2,6-di-1-pyrrolidinylpyrimidine and 50 ml of di(2-methoxyethyl)amine was heated under reflux for about 43 hours. do. Excess amine is distilled under reduced pressure to give a residue, which is partitioned between ethyl acetate/water (both phases are dark in color and separate volumes). The organic extract is dried and concentrated to obtain a gum. The gum was chromatographed on silica gel eluting with ethyl acetate/hexane (50150), appropriate fractions were pooled and concentrated to give the title compound. Ru. CMR162, 29, 162, 1,160, 0°71.25, 70.66.5B, 71.4B, 35.46.01.45°9+, 25.45 and 25.2 06 Example 3A 4-di (2-methoxyethyl)amino-2,6-di-1-virolidi Nylhysorimidine hydrochloride (1) 4-di(2-methoxyethyl)amino-2,6-diO1-pyrrolidinylpyrimidine (Example 3.2.5 g) was dissolved in dilute hydrochloric acid (0.1, N, 1.0 and lyophilize the solution to obtain the title compound. Example 4 A mixture of 5 g of 4-methoxyamino-2,6-di-1-pyrrolidinylmethoxylamine hydrochloride and 3.3 7 g of 4-chloro-2,6-di-1-pyrrolidinylpyrimidine in lOmQ of pyridine was placed in a pressure vessel. and heated on a steam bath for 2 days. Heat (two liquid phases are present). Cool the mixture and carefully add ethyl acetate and aqueous sodium carbonate (20%, 25g+12). Filter the mixture through diatomaceous earth (Celite). The organic phase is washed with water and saline and concentrated to give an oil which is chromatographed on silica gel. Column Elute with ethanol/methylene chloride (10/90), pool appropriate fractions and concentrate. Condensation and rechromatography eluting with ethyl acetate/hexane (50%) gives the title compound, which is crystallized from hexane. Melting point 96,5-98°; CMR166,33,162,2,160,2,73,60,63°47, 46.13.45.97.25.40 and 25.17δ Example 4A 4-Methoxyamino -2,6-di-1-pyrrolidinylpyrimidine hydrochloride (1) General procedure of Example 3A except starting with 4-methoxyami7-2,6-di-1-pyrrolidinylpyrimidine (Example 4) With minor modifications, the designated compound is obtained. Example 54-(di(2-hydroxyethyl)amino)-2,6-di-1-pyro Lysinylpyrimidine (1) 4-chloro-2,6-di-1-pyrrolidinylpyrimidine A solution of 5.2 g of alcohol and 50 ml of citanolamine was heated under reflux for 20 hours. Ru. The mixture was cooled and worked up as in Example 1 to obtain an oil, which Chromate on silica gel eluting with methanol/methylene chloride (10/90). Submit to matography. Appropriate fractions were pooled, concentrated, and the residue was dissolved in aqueous acetone. The title compound is obtained by crystallization. Melting point 119-150°; CMR163,03, 161,63°158.89, 71.89, 61.49, 52.35, 46.27°46.04, 25.34 and 25.146 Pyrimidine (1) Steel In the container, 4-chloro-2,6-di-1-pyrrolidinylvirmidine7. 5g of pifu 100. Methylamine is introduced into the solution over a period of 20 minutes, then the vessel is sealed and heated on a steam bath for about 90 hours. The mixture is then cooled and concentrated under reduced pressure to give an oil, which is mixed with hydrochloric acid (IN, 50 me) and 100 mQ of ether. water The phase is washed with ether and then made basic with potassium hydroxide (45%). workman Extraction with ether gives a solid which is chromatographed on silica gel, eluting with a methanol/methylene chloride mixture. Methanol/methylene chloride A second chromatography, eluting with 5/95 m.p. (5/95) yields the title compound. Melting point 93-94.5'; NMR 4.69.3, 53, 3.44, 2.83 and 1.906 Example 7 4-(2-(2-mer Toxyethoxy)ethylmethylamino)-2,6-pyrrolidinylpyrimidine Hydrogenation of a solution of 4-(2-(hydroxyethyl)methylamino)-2,8-di-1-pyrrolidinylpyrimidine (Example L 1.16 g) in 12 ml of THF) IJium (50% mineral oil dispersion, 240 mg) in THF5mI2. The mixture was stirred for 1 hour, then 1-methquine-2-mesyloxane A solution of 0.9258 siethane in 2 ml J of THF is added. The mixture was stirred under reflux for 2 days, then partitioned between ethyl acetate and water, the phases were separated and the organic phase was concentrated. Shrink to obtain oil. Chromatography on silica gel, eluting with methanol/methylene chloride (5/95) gives the title compound. CMR163,1,162,3,160,0,71,89,71,2B,70.17.69.22,58.94.48.74,46.01,45.8B. 36.4+, 25.46 and 25.216 Harmful noodles Example 7A l-(2-(2-meth) xyethquin)ethylmethylamino)-2,6-pyrrolidinylpyrimidine salt Acid # get something Melting point: 120.5-126° Example 8 4-(3-(ethylamino)-2-pyridinyl)-1-piperazinepropafur (1) 4-(3-(ethylamino)-2-pyridinyl)piperazine 0. 58g, 3-bu A mixture of 0.39 g lomopropatol, 0.195 g potassium carbonate and traces of sodium iodide in 40 mf2 acetonitrile was heated under reflux for 18 hours and then and concentrate under reduced pressure. The residue was partitioned between methylene chloride and a quantity of water, the phases were separated and the organic phase was concentrated to give a solid which was chromatographed on silica gel eluting with methanol/methylene chloride (20/80) 't'. . Pour the appropriate fraction. and concentrate to give the title compound. Crystallize the sample from acetone. Melting point 1 36.5-137°, CMRl 50.23, 137° 27.135.06, 11.9.81, 115.86, 64.22, 61° 59.53.61, 48. 56,37.97.27.03 and 14゜ethylaminopyridine (1) methanesulfonyl chloride 0.4 mQ to 1-(3-ethylami/)=2-pyridine Lupiperazine! , 11g of pyridine 5m+! Add slowly to the medium solution. Mixed The mixture is heated to 20-25° for 7JQC and then left overnight mixed with water. mixture The mixture is diluted with ethyl acetate, the phases are separated, the organic phase is washed with water and saline, and then concentrated to give a yellow oil. Elute with ethyl acetate/hexane (50150) Chromatography on silica gel gives the title compound. Melting point 108-109°, CMR 149,55,137,14,13520,120,33,1+6.37,48.27,45.89,37°95.34.78 and 14. 666 Harumen, f@110 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-methyl piperazineethanoate (1) 4-(2,8-di-l-pyrrolidinyl-4-pyrimidinyl) piperazine 1.513S potassium carbonate 0.345g and 0.76 g of methyl lomoacetate in 100 m of acetonyl (!) The warm mixture is heated under reflux for about 4 hours and then concentrated. The residue is partitioned between methylene chloride and aqueous potassium bicarbonate and the phases are separated. The organic phase is concentrated to give a ura. The oil is eluted with methanol/methylene chloride (5%)/chromatographed on lica gel. Appropriate fractions are pooled and concentrated to give the title compound. CMR1 70,57,1,63,8,162,2°160.0.72.26,59.4B,52.76.51.6+,46°07.45.94.44.11,245.4 4 and 25.18δ Example 10A 4-(2,6-di-l-pyrrolidinyl-4-pyrimidinyl)-1-piperazineethanoate methyl dihydrochloride (1) The if1-isolated diamine solution containing hydrochloric acid (2 equivalents) Lyophilize to obtain the title compound. Example 11 4-(3-(ethylamino)-2-pyridinyl)-1-piperazine Methyl Tanate (1) The general procedure of Example 10 was followed with minor modifications, except that 1.03 g of 4-(3-(ethylamino)-2-pyridinyl)piperazine was reacted with methyl bromoacetate. The title compound is obtained. CMR170°65,150.5,137.17,1 35.0B, 119,57°115.76.59.2B, 53.10,51.5 2.48.4B. 37.99 and 14.64δ Example 12 Benzyl 4-(3-(ethylamino)-2-pyridinyl)piperazine ethanoate (1) 0.84 g of 4-(3-(ethylamino)-2-pyridinyl)piperazine Following the general procedure of Example 1O with minor modifications, except for reaction with 1.14 g of benzyl bromoacetate, the crude title compound is obtained. Methanol/methylene chloride (6 Chromatography on silica gel, eluting with /95) gives the title compound. Melting point 54°, NMR7,7,7,47,6,9,6,8,5,19°4.1.3.3B, 3.15,2.8 and 1.296 Example 134-(3- (ethylamino)-2-pyridinyl)-pyrazineethanoate hydrochloride (1) 4-(3-(ethylamino)-2-pyridinyl)-piperazineethanoic acid benzene (Example 12.1.01 lmol) and hydrochloric acid (2N. A solution of 0.5 methanol in 50 ml of methanol is hydrogenated (50 pgi) in the presence of palladium/carbon (5%, 1 g) for about 4 hours. The mixture is filtered, concentrated, and the residue is dissolved in chloroform/methanol/ Silica eluted with water (65/35/2) Chromatography on gel gives the title compound. Melting point 180-188° Example 14 4-(2,8-di-1-pyrrolidinyl-4-pyrimidinyl)-1-pyrrolidinyl Methyl perazinepropanoate (1) 4-(2,6-di-1-pyrrolidinyl-4-pyrrolidinyl) rimidinyl)-piperazine 1.51 g, potassium carbonate 0.35 g, sodium iodide 0.15 g of aluminum and 0.84 g of methyl 3-bromopropionate in acetonitrile The mixture in a 100 ml bottle is heated under reflux for about 18 hours and then concentrated under reduced pressure. The residue was worked up as in Example 17 to give an oil, which was acetylated. Chromatography on silica gel, eluting with a methylene chloride/methylene chloride mixture, gives a solid which is crystallized from acetone to give the title compound. Melting point 12 0.5-121'; CMR173,0,163,88,162,33,160 ゜0, 72.23.53.54.52.62.51.53.46.0 4゜45.90, 44.22.31.90, 24.45 and 25.19δ actual m Example 15 2-morpholino -3-ethylaminopyridine (1) 2-chloro-3-di 3.17 g of tropyridine, 2 g of potassium carbonate, 5 m12 of morpholine and acetate The mixture of 50 mt of nitrile is stirred for 2.5 hours and then left overnight. The mixture was concentrated under reduced pressure, the residue was partitioned between ethyl acetate and water, the phases were separated, the organic extract was washed with water and saline, dried, and concentrated to give 2-morpholino-3-nitrate. Lopyridine is obtained as a solid. of 2-morpholino-3-nitropyridine in a Parr apparatus (451b, 2 hours). The solution in 150 ml of ethanol is hydrogenated in the presence of palladium/carbon (5%, Ig). The mixture is filtered and the filtrate containing 2-morpholino-3-aminopyridine is concentrated to 50 ml of water bath. 4 mQ of acetaldehyde followed by 1.4 g of sodium cyanoborohydride are added in portions. The mixture is continuously cooled. Stir for 1 hour while cooling, stand at 20-25° overnight, then concentrate under reduced pressure. The residue was partitioned between ethyl acetate and aqueous potassium bicarbonate, the phases were separated and extracted with an organic extract. Concentrate the extract to make oil. Elute the oil with ethyl acetate/hexane (50150) Chromatography on silica gel gives the title compound. Melting point 69.9 to 71.0': CMR150, 20, 137, 33, 135, 13, 119, 95° 116.02.67.24, 49.29, 37.97.14.65δ Example 15A 2 -Morpholino-3-ethylaminopyridine hydrochloride (I) A solution of 2-morpholino-3-dithylaminopyridine (Example 15.0.207 g) in 20 r12 of water containing hydrochloric acid (1 eq.) is filtered through solidified filter paper. do. filter Lyophilize the solution to obtain the title compound. Melting point 205-209° Example 162-((2-acetyloxyethyl)ethylamino)=3-ethyl a Minopyridine (1-1) and 2-((2-hydroxyethyl)ethylamino)-3-ethylamino-pyridine (1-2) 2-chloro-3-nitropyridine3. 17 g, potassium carbonate 2 g and acetonate of 2-(ethylamino)ethanol Lil 5omQ/f1. The compound is reacted as in Example 15 and yields 2-((2-hydroxyethyl)ethylami/)-3-nitroviridine as an oil. A solution of the compound in 10 rJ of acetic anhydride is left at 20-25°. The mixture was then treated with 100 g of water and made slightly basic with potassium hydroxide (45%). and extract with ethyl acetate. The extract is washed with water and Seraino and concentrated to give 1-((2-acetylox/ethyl)ethylamino)-3-nitropyridino. 2-((2-acetylox/ethyl)ethyl) substantially as described in Example 15. By monomerization of thylamino)-3-nitroviridine, 2-((2-acetoxy/)ethyl thylamino)-3-aminopyridine is obtained as ura. The methanolic solution of this solution was reacted with acetaldehyde and Noah/polyhydride as described in Example 15 to give an oil, which was eluted with a mixture of gotyl acetate and hexane. chromatography on silica gel. Appropriate fractions were condensed with 7'-yl to give 2-((2-acetyloxyethyl)ethylamino)-3-ethylamine. Lysine (I-IL CMR171,1,148°9.139.93,134.2 8,120.70,116.40,62°54.49.41,46.32,37.80,20.80, 14.57 and 1275δ, as an oil, and 2-((2-hydroxyethyl)ethylamino-3-ethylaminopyridine ([-2)ll!, points 68-69°, as a solid. Corridor ff 16 (2) UA2-((2-hydroxyethyl)ethylamino)-3-ethylamide/bilinone hydrochloride 2-((2-hydroxyethyl)ethylamino)-3-ethylaminopyridine [Example 16 (2) ] Following the general procedure of Example 3A, but with minor modifications, the title compound is obtained, melting point 3-ethyl Ruaminopyridine (1) A solution of 317 g of 2-chloro-3-nitroviridine in 10 mQ of 2-(methylamino)ethanol is heated under reflux for 2 hours. The mixture was then diluted with methylene chloride. Wash with aqueous carbonate and water. The phases were separated and the organic extract was concentrated to a solid solution. The oil was mixed with methanol/methylene chloride. Chromatography on lilac gel eluting with (5/95). Appropriate amounts were pooled and concentrated to yield 1((2-hydroxyethyl)methylamino)-3-nitropyridine. Acetylation of the cono intermediate as described in Example 16 to obtain 2-((2-acetyloxyethyl)methylamine)-3-nitropyridine as an oil. This nitro compound was hydrogenated and the resulting primary amine was prepared using acetaldehyde/cyanoborohydride trifluoride substantially as described in Example 15. An oil was obtained by treatment with acetone/methylene chloride (10/90). The sample is then subjected to chromatography on licage gel. Pool the appropriate aliquots and concentrate to obtain the title compound. NMR7,7,6,9,6,8,4,,42,4,23,3,27°3.13.2.76,2.06 and 1.316 -methoxyethyl)ami/-3-ethylaminopyridine (1-1) and 2-di(2-methoxyethyl)ami/-3-diethylaminopyridine (t-2) 3.17 g of 2-chloro-3-nitropyridine, carbonic power υ ram 2. Og and 6.67 g of di(2-methoxyethyl)amine in acetonitrile 50r+l! The medium mixture is stirred at 20-25° for 25 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, the phases were separated, and the organic phase was concentrated to give 2-di(2-methoxyethyl ) Amino-3-nitropyridine with Ura and 1. get it. 2.6 g of 2-di(2-methoxyethyl)amino-3-nitropyridine was hydrogenated as described in Example 15 to give 2-di(2-methoxyethyl)amino-3-a Obtain minopyridine. A methanolic solution of this amine 25rr++;! aceto Treat with 2 mQ aldehyde (exothermic). The mixture was cooled to 100 and further acetic acid was added. Add 2 ml of toaldehyde (no heat generation), followed by 0.7 g of sodium cyanoborohydride. The mixture is cooled for 1 hour, stirred at 20-25° overnight, then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous potassium bicarbonate. Separate the phases and concentrate the organic phase to give an oil. The oil was chromatographed on silica gel eluting with ethyl acetate/hexane (50150), the appropriate fractions were pooled and concentrated to give 2-di(2-methoxyethyl ether). Amino-3-ethylaminobinodine (1-1), CMR149,06,1 38,96,133,73,119°86.115.29,70.81.5B, 63,51.23,37° 72 and 14.19, and 2-di(2-methoxyethyl)amino-3-diethylaminopyridine (1-2), CMR154,23 ゜140.10, 136.16.128.17, 115.51, 71゜10.5 7.47, 49.17, 43.30 and 11.19δ,? ask Example 18 (1) A and 1 B (2) A2-di(2-methoxyethyl)a Mino-3-ethylaminopyridine hydrochloride (1-1) and 2-di(2-methoxyethyl)amino-3-diethylaminopyridine hydrochloride (1-2) 2-di(2-methoxyethyl)amino-3- General of Example 3A except starting with ethylaminopyridine [Example 1B (+-1)] and 2-di(2-methoxyethyl)amino-3-diethylaminopyridine [Example 18(1-2)] according to the law After some minor modifications, the title compound is obtained. Practical example 194-di(2-acetyloxytyl)amino-2,6-di-1-pyrrolidinylpyrimidine4-di(2-hydrobowdiethyl)amino-2,6-di-1-pyrroli A mixture of loridinylpyrimidine (Example 5.0.94 g) and 2 ml of acetic anhydride in 10 mQ of ethyl acetate is left at 20-25° overnight. Add 25g of water and mix. The mixture was stirred, warmed, and then diluted with ethyl acetate and aqueous potassium bicarbonate. Ru. The organic phase is separated and concentrated to an oil, which is chromatographed on silica gel. - Attach to Elution with acetone/methylene chloride (7/93) gave the title compound. Ru. Melting point 90-92°, CMR170,91,182,12,159,89° 71.34.62.33.47.55.46.00.45.91.2 5°44.25.21 and 20.866 Example 19A 4-di(2-acetyloxyethyl)amino-2,6-di-1-pyrrolidinylpyrimidine hydrochloride 4-di(2-acetyloxyethyl)amino in hydrochloric acid (0.05N, 20ml) -2,6-di-1-pyrrolidinylpyrimidine (Example 19.1.0 mmol) is lyophilized to give the title compound. Melting point 113-124° Example 20 2-(4-(2-methoxyethyl)-1-piperazinyl)-3-ditylaminopyridine (I) 4-(3-ethylamino)-2-pyridinyl-pipe 1.05 g of Radin was reacted with 1.54 g of 1-methoxy-2-mesyloxyethane. The title compound was obtained by the general method of Example 8, with minor modifications, except that Ru. CMR150, 56, 137, 20, 135, 08° 119.47.11 5.69.70.21.5B, 80.57.94° 53.95.48.4 8, 38.03 and 14.66δ implementation Example 20A 2-(4-(2-methoxyethyl)-1-piperazinyl)-3-ethylaminopyridine hydrochloride (1) 2-(4-(2-methoxyethyl)-1 containing hydrochloric acid (1 equivalent) -Piperazinyl)-3-ethylaminopyridine (Example 20) is lyophilized. Crystallization of the residue from methanol/ethyl acetate gives the title compound. Melting point: 191-191.8゜fruit Example 21 2-(4-(2-acetyloxyethyl)-1-piperazinyl)-3-ethylaminopyridine (1) 4-(3-(ethylamino)-2-pyridinyl)piperazine 1.54g1 diisopropylamine 2mQ and 2-bromoe acetate Stir a medium temperature mixture of 40 g of acetonitrile in 1.1 m12 at 20-25° for 2 days. Stir and then concentrate. The residue is partitioned between ethyl acetate and aqueous potassium bicarbonate, the phases are separated and the organic phase is concentrated. The residue is chromatographed on silica gel, eluting with methanol/methylene chloride (5/95) to give the title compound. CMRl 70.92゜IF) 0.50, 137.25, 135.06, 1+, 9.60, 115゜74.61.68.56.57.48.60.3B, 00, 20.92 and 114 .656 Piperazinyl)-3-ethylamine/pyridine hydrochloride (1) 2-(4-(2-acetylox/ethyl)-1-piperazinyl)-3-ethylamine Following the general procedure of Example 3A except starting with minopyridine (Example 21). Minor modifications are made to obtain the title compound. Example 22 4-((3-ethylamino)-2-pyridinyl)-1-piperazine ethanol (1) 2-(4-(2-acetyloxyethyl)-1-piperazinyl)-3-ethyl a A mixture of minopyridine (Example 21.0.8 g) and aqueous potassium carbonate (10%, 2 mQ) in 20 mQ of methanol is stirred at 20-25° for 1 h, then treated with 0.2 m (l) of acetic acid and concentrated. The residue was dissolved in ethyl acetate and aqueous potassium bicarbonate. distributed among the groups. Concentration of the organic phase gives the title compound. CMR150,44°1. 37.32, 135.06.119.75.115.81, 59°30.57. 60,53.22,48.76.37.98 and I465δ Example 22A 4-((3-ethylamino)-2-pyridinyl)-1-piperazi ethanol hydrochloride (1) Following the general procedure of Example 3A with minor modifications, except starting with 4-((3-ethylamino)-2-pyridinyl)-1-piperazineethanol (Example 22). The title compound is obtained. Example 22B 4-((3-ethylamino)-2-pyridinyl)=1-piperazine fumarate of ethanol ([) 4-((3-ethylamino)-2-pyridinyl)-1-piperazineethanol (1 , Example 22.0.41 g) and fumaric acid 0.19 g in methanol. Concentrate the solution to obtain the title compound. Melting point 3-ethylaminopyridine (1) Hydrolysis of 2-((2-acetoquine ethyl)methylamine)-3-ethylaminopyridine (Example 17) following the general procedure of Example 22 with minor modifications. do. Chroma on silica gel eluting with acetone/methylene chloride (25/75) The title compound is obtained by tography. CMR150,14,137,78,1 33,62°119.74,116.10.5B, 56,55.37,37.9 6°36.65 and 14.466 PI23A 2-((2-hydroxy ethyl) methylamino/)-3-ethyl amine Minopyridine Hydrochloride (1) Following the general procedure of Example 3A, with minor modifications, except starting with 2-((2-hydroxyethyl)methylamino)-3-ethylaminopyridine (Example 23). The title compound is obtained. 1.51 g of diisopropylamine 2rn12 and 1-methquin-2-methyl A mixture of 0.97 g of acetonitrile in 50 mf f is stirred at 20-25° for 4 days and then concentrated. The residue is partitioned between ethyl acetate and aqueous potassium bicarbonate. The organic phase is concentrated and the residue is chromatographed on silica gel, eluting with methanol/methylene chloride (5/9 E+). Appropriate fractions are pooled and concentrated to give the title compound as a solid. CMR 163, 89, 162, 33° 160.0B, 72.21, 69.96.5B, 80.5B, 00° 53.29, 46.04, 45.91.44.12, 25.46 and 25 .196 perazinyl)-2,6-pyrrolidinylpyrimidine (1) Since 1-methoxy-2-mesyloxyethane is replaced with 2-bromoethyl acetate. Otherwise following the general procedure of Example 24 with minor modifications, the title compound is obtained. CMR170, 88, 163, 80° 162.23.72.24.61.70, 56.67.53.11° 48.0B, 45.94, 44.23, 25.44, 25.19 and 20. 936 Example 25A 4-(4-(2-acetyloxyethyl)-1-biperazinyl)-2,6-di-1-pyrrolidinylpyrimidine hydrochloride (1) in 30 mQ of water containing hydrochloric acid (2 equivalents). 4- (4-(2-acetyloxye A solution of methyl)-1-piperazinyl)-2,6-di-1-pyrrolidinylpyrimidine (Example 25.0.30 g) is lyophilized to give the title compound as a solid. Melting point 97-104° Example 264-(2,6-di-1-pyrrolidinyl-4-pyrimidine) Nyl)-1-piperazinepropanol (+)1-methoxy-2-mesyloxye The general method of Example 24 was followed except that Tan was replaced with 3-bromo-1-propatool. Therefore, minor modifications are made to obtain the crude title compound. Methanol/chloride Chromatography on silica gel eluting with tyrene (20/80) followed by raw Crystallization of the component fractions from acetone gives the title compound. Melting point 129-130°; CMR163,79,162,29°160.01,72.33,84. 33.5B, 79, 52.9B. 46.06.45.93.44.24.28.45 and 25.196 Example 2 6A 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-pipera Dinepropanol fumarate (1) 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazine Lopanol (Example 26) was mixed with an equimolar amount of fumaric acid and the crystals were extracted from methanol. Crystallization gives the title compound. Melting point 199.9-205' Example 27 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-pyrrolidinyl Perazine ethanol (1) Following the general procedure of Example 22 with minor modifications, 4-(4-(2-7cetyloxyethyl)-1-piperazinyl)-2,6-di -1-Pyrrolidinylpyrimidine (Example 25) is hydrolyzed to obtain the crude title compound. The filter on silica gel was eluted with methanol/methylene chloride (15/85). The title compound is obtained as a solid by chromatography. CMR163, 86, 1 62, 32, 160, 05°72.29, 59.35, 57.59, 52.59, 48.07, 45°93.44.33, 25.45 and 25.19δ Examples 27A 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-pipe Radineethanol dihydrochloride 4-(2,6-di-1-pyrrolidinyl-4-pyrimidine) Lyophilization of a warm solution of dilute hydrochloric acid (2 equivalents) of ethanol)-1-piperazine (Example 27) gives the title compound. Melting point 238° Decomposition Example 28 Methyl 4-(3-(ethylamino)-2-pyridinyl)-1-piperazinepropanoate (1) 1.04 g of 4-(3-ethylamino)-2-pyridinyl-piperazine was dissolved in 3 Following the general procedure of Example 14 with minor modifications, except for reaction with 0.84 g of methyl -bromo propionate, the title compound is obtained. CMR173, 0, 150, 6, 137, 25, 135, 07° 119.59, 115.72.53.53.53. 24.51.52°48.65.3B, 00.32.06 and 14.656 Example 294-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-pyrrolidinyl Ethyl perazinebutanoate (1) 4-(2,6-di-1-pyrrolidinyl-4-pyri A mixture of 1.51 g of (midinyl)-piperazine, 2 mQ of diisopropylamine and ethyl 4-bromobutyrate in 50 m2 of acetonitrile was stirred at 20-25' for 3 days. Stir and then concentrate. Partition the residue between ethyl acetate and aqueous potassium bicarbonate. Separate the organic phase and concentrate to an oil. Chromatograph on silica gel eluting with methanol/methylene chloride (10/90) The title compound is obtained by roughy. CMR173, 4°164.0, 160.0, 72.23, 60.15, 57.22, 52°85.46.04, 45.90. 44.29, 32.21, 25.45° 25.19, 33.01 and 14. l 2δ Example 30 4-(3-(ethylamino)-2-pyridinyl)-1-piperazineethyl butanoate ([) 1.04 g of 4-(3-ethylamino)-2-pyridinyl)piperazine was dissolved in 4-bromo The general method of Example 14 was followed except for the reaction with 0.98 g of ethyl mobutyrate. No modification is made to obtain the crude title compound. Methanol/methylene chloride (5/ Chromatography on a non-iron gel eluting with 95) gives the title compound. CMR173゜6.150.7,137.5,135.06.119.52,1 15゜67.60.15,60.53,57.60,53.44,48.68゜38.01,32 .09, 21.99, 14.65 and 14.13δ Example 3 14-(3-(ethylamino)-2-pyridinyl)=1-piperazinebutanoic acid (1) 4-(3-(ethylamino)- 2-pyridinyl)-1-piperazinebutanoate (Example 30.0.70 g) and aqueous lithium hydroxide (IN, 2.6 m) in methanol are stirred for about 1 hour under reflux. The mixture is then cooled and diluted with hydrochloric acid (IN). , 2.6 m12) and concentrated. - line 50 ml and then continuously extracted with ether overnight. The extract is concentrated and the residue is crystallized from acetone to give the title compound. Melting point 127-128° 4-chloro-2,6-di-1-morpholinopyrimidine [Rocz, chel I, 41.1047-52 (1967), CA68:1 14539s, 2.84 g] and A mixture of pyrrolidine 25me was heated under reflux for 3 hours. Heat for a while and concentrate. Partition the residue between ethyl acetate and aqueous potassium bicarbonate. Ru. The organic phase is separated, concentrated and the residue is crystallized from methylene chloride/ethyl acetate to give the title compound. Melting point 210-210.8°, CMR 164, 12,162, 17,73° 22.66.96, 66.62, 46.00, 44.77.44. 35 and 25.166 4-chloro0-2.6-di]-morpholinopyrimidine was reacted with piperidine, following the general procedure of Example 32 with minor modifications to give the title compound. Ru. Melting point 217-21B', CMR164,83,164,24,161,3, 73,03,66,93°66.61,45.31,44.76.44.36, 25.39 and di-1) -Piperazine butanoic acid (1) 4-(2,6-di-1-pyrrolidinyl-4-pyrimidine containing lithium hydroxide (IN, 4rnQ) ethyl)-1-piperazinebutanoate (Example 29.1.5 g) and methano Rule 4. Heat the OmQ mixture under reflux overnight, then concentrate. Partition the residue between ethyl acetate and water. The aqueous phase is mixed with hydrochloric acid (IN, 4 mC) and the precipitate is collected and dried to give the title compound. Melting point 186-188° Example 35 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazineethanoic acid (1) 4-(2,6-no-1-pyrrolidinyl-4-pyrimidinyl)-1 -Viperaji Following the general procedure of Example 34, with minor modifications, except starting with methyl ethanate (Example 10), the title compound is obtained. Melting point 226-229° decomposition Example 364-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-pyrimidinyl Perazinepropanoic acid (1) 4-(2,6-di-l-pyrrolidinyl-4-pyrimidine) methyl)-1-piperazinepropanoate (Example 14). Following the general procedure of Example 34 with minor modifications, the title compound is obtained. Real mN37 4-(3-ethylamino-2-pyridinyl)-piperazinepropanoate benzyl ([) 4-(3-ethylamino-2-pyridinyl)-piperazine is converted to 3-bromoprop The title compound is obtained by following the general method of Example 12, except for the reaction with phosphoric acid, and making unnecessary modifications. Example 38 4-(3-ethylamino-2-pyridinyl)-1-piperazinepro Panic acid m salt (1) 4-(3-ethylamino-2-pyridinyl)-t-piperazinepropanoic acid benzene Follow the general procedure of Example 13, except starting with the sample code (Example 37), with minor changes. The title compound is obtained. mA#” PCT/us90105645 International Search Report US 9005645

Claims (16)

[Claims] 1. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1 is C1-C3 alkyl, -O-CH3, -O-CH2CH3, -(CH2)n1-O-R1-1, where n1 is 2 or 3 and R1-1 is -H, C1-C3 alkyl, -CO-R1-2, where R1-2 is -H, C1- C3 alkyl or -φ, -CH2-CH(OR1-1)-CH3, where R1 -1 is the same as the above definition, -CH2CH2-(O-CH2CH2)n2-O-R1-1, where n2 is 1 or or 2, and R1-1 is the same as the above definition, -(CH2)n3-CO-R1-3 , where n3 is 1 to 3 and R1-3 is -OH, -O-R1-4, where R1-4 is C1-C4 alkyl or -CH2-φ, C1-C3 alkyl, Optionally one or two -F, Cl, -Br, -NO2, C1-C3 or R1-7 is C1-C3 alkyl, optionally substituted with -OR1-7 -φ , -CH2-CH=CH-CO-R1-3, where R1-3 is the same as defined above, -(CH2)n4-N(R1-5)(R1-6), where n4 is 2 or 3. R1-5 and R1-6 are the same or different, -H or C1-C3 alkyl le, R2 is -H, C1-C3 alkyl, -(CH2)n5-O-R2-1, where n5 is 2 or 3 and R2-1 is -H, C1-C3 alkyl, -CO-R2-2, where R2-2 is -H, C1- C3 alkyl or -φ, -CH2-CH(OR2-1)-CH3, where R2 -1 is the same as the above definition, -CH2CH2-(O-CH2CH2)n6-O-R2-1, where n6 is 1 or or 2, and R2-1 is the same as the above definition, -(CH2)n7-CO-R2-3 , where n7 is 1 to 3 and R2-3 is -OH, -O-R2-4, R2-4 is C1-C4 alkyl or CH2-φ; C1-C3 alkyl, Optionally one or two -F, -Cl, -Br, -NO2, C1-C3 or may be substituted with -OR2-5 in which R2-5 is C1-C3 alkyl- φ, or R1 and R2, together with the bonded nitrogen atom, represent pyrrolidine, pyrrolidine, Peridine, morpholine, piperazine, and the 4-position is -(CH2)n8-O- R3-1, where n8 is 2 or 3 and R3-1 is -H, C1-C3 alkyl -CO-R3-2, where R3-2 is -H, C1-C3 alkyl or -φ , -(CH2)n9-CO-R3-3, where n9 is 1 to 3 and R3- 3 is -OH, -O-R3-4, where R3-4 is C1-C4 alkyl or -CH2-φ, Optionally one or two -F, Cl, -Br, -NO2, C1-C3 or -R3-6 is C1-C3 alkyl, optionally substituted with -OR3-6- φ, -CH2CH2-(O-CH2CH2)n10-O-R3-1, where n1 0 is 1 or 2, R3-1 is the same as the above definition, -CH2CH=CH-C O-R3-3, where R3-3 is the same as defined above, or -SO2R3-8, where R3-8 is C1-C3 alkyl, a pipera substituted with forming a heterocycle selected from the group consisting of; Heteroaryl means that one or two R4-1 and R4-2 are the same or different. or -H, C1-C3 alkyl, or R4-1 and R4-2 are Together with a bonded nitrogen atom, pyrrolidinyl, piperidinyl, morpholinyl, perazinyl, azetidinyl and 4-(C1-C3 alkyl)-piperazinyl- -N(R4-1)(R4 -2), -NH-O-CH2-φ, -NH-CH2CH2-O-R where R4-3 is -H or C1-C3 alkyl 4-3, R4-3 is the same as the above definition -N(CH2CH2-O-R4-3) 2 replaced with, pyridin-2-, 3- and 4-yl, pyrimidin-2- and 4-yl, pyrazin-2-yl, 1,3,5-triazin-2-yl, pyridazin-2-yl ] An amino-substituted heteroarylamine or a pharmaceutically acceptable salt thereof. 2. R1 is C1-C3 alkyl, -O-CH3, -(CH2)n1-O-R1- 1, -(CH2)n3-CO-R1-3 and -CH2-CH=CH-CO-R 1-3. Rylamine (I). 3. R2 is -H, C1-C3 alkyl and -(CH2)n-O-R2-1, Amino-substituted heteroaryl group according to claim 1 selected from the group consisting of Min (I). 4.4-(2-(hydroxyethyl)methylamino)-2,6-di-1-pyrroli Dinylpyrimidine, 4-di(2-methoxyethyl)amino-2,6-di-1-pyrrolidinylpyrimidine hmm, 4-methoxyamino-2,6-di-1-pyrrolidinylpyrimidine, 4-(di-( 2-hydroxyethyl)amino)-2,6-di-1-pyrrolidinylpyrimidine, 4-Methylamino-2,6-di-1-pyrrolidinylpyrimidine, 4-(2-(2 -methoxyethoxy)ethylmethylamino)-2,6-di-pyrrolidinylpyrimi gin, 2-((2-acetyloxyethyl)ethylamino)-3-ethylaminopyrimi gin, 2-((2-hydroxyethyl)ethylamino)-3-ethylamino-pyridine , 2-((2-acetyloxyethyl)methylamino)-3-ethylaminopyridi hmm, 2-di(2-methoxyethyl)amino-3-ethylaminopyridine, 2-di(2-methoxyethyl)amino-3-diethylaminopyridine, 4-di(2-acetyloxyethyl)amino-2,6-di-1-pyrrolidinylpi Limidine, or 2-((2-hydroxyethyl)methylamino)-3-ethylaminopyridine Amino-substituted heteroarylamine (I) according to claim 1. 5. R1 and R2 together with the bonding nitrogen atom form a heterocycle which is morpholine. Amino-substituted heteroarylamine (I) according to claim 1, comprising: 6.4-morpholino-2,6-di-1-pyrrolidinylpyrimidine, or The amine according to claim 5, which is 2-morpholino-3-ethylaminopyridine. Non-substituted heteroaryl-helamine (I). 7. Piperazie in which R1 and R2 together with the bonding nitrogen atom are substituted at the 4-position the amino-substituted heteroarylamine (I) according to claim 1 which forms a . 8.4-(3-(ethylamino)-2-pyridinyl)-1-piperazinepropano rule, 2-(4-mesyloxy-1-piperazinyl)-3-ethylaminopyridine, 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazine methyl tanate, 4-(3-(ethylamino)-2-pyridinyl)piperazine ethanoate, methyl Benzyl 4-(3-(ethylamino)-2-pyridinyl)piperazineethanoate, 4-(3-(ethylamino)-2-pyridinyl)-piperazineethanoic acid, 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazip methyl lopanoate, 2-(4-(2-methoxyethyl)-1-piperazinyl)-3-ethylaminopi lysine, 2-(4-(2-acetyloxyethyl)-1-piperazinyl)-3-ethyl a minopyridine, 4-((3-ethylamino)-2-pyridinyl)-1-piperazineethanol, 4-(4-(2-methoxyethyl)-1-piperazinyl)-2,6-di-1-pi Loridinylpyrimidine, 4-(4-(2-acetyloxyethyl)-1-pipera) di(dinyl)-2,6-di-pyrrolidinylpyrimidine, 4-(2,6-di-1-pyro lysinyl-4-pyrimidinyl)-1-piperazinepropanol, 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazine Tanol, 4-(3-(ethylamino)-2-pyridinyl)-1-piperazinepropanoate Chill, 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazine ethyl tanate, Ethyl 4-(3-(ethylamino)-2-pyridinyl)-1-piperazinebutanoate le, 4-(3-(ethylamino)-2-pyridinyl)-1-piperazinebutanoic acid, 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazine Tanic acid, 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazine Tanic acid, 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazip lopanoic acid, 4-(3-ethylamino-2-pyridinyl)-1-piperazine benzylpropanoate or 4-(3-ethylamino-2-pyridinyl)-1-piperazinepropanoic acid Amino-substituted heteroarylamine (I) according to claim 7. 9. R1 and R2 together with the bonding nitrogen atom form a ring that is pyrrolidine. Amino-substituted heteroarylamine (I) according to claim 1. 10. The claimed compound is 4-pyrrolidinyl-2,6-di-1-morpholinopyrimidine. Amino-substituted heteroarylamine (I) according to scope item 9. 11. a heterocycle in which R1 and R2 together with the bonding nitrogen atom are piperidine; Amino-substituted heteroarylamines (I) according to claim 1 which form. 12. The claimed compound is 4-piperidinyl-2,6-di-1-morpholinopyrimidine. Amino-substituted heteroarylamine (I) according to scope 1. 13. The amino acid according to claim 1, wherein heteroaryl is pyrimidin-4yl. Non-substituted heteroarylamines (I). 14.4-(2-(hydroxyethyl)methylamino)-2,6-di-1-pyro lysinylpyrimidine, 4-morpholino-2,6-di-1-pyrrolidinylpyrimidine, 4-di(2-meth xyethyl)amino-2,6-di-1-pyrrolidinylpyrimidine, 4-methoxyamino-2,6-di-1-pyrrolidinylpyrimidine, 4-(di-( 2-hydroxyethyl)amino)-2,6-di-1-pyrrolidinylpyrimidine, 4-Methylamino-2,6-di-1-pyrrolidinylpyrimidine, 4-(2-(2 -methoxyethoxy)ethylmethylamino)-2,6-di-pyrrolidinylpyrimi gin, 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazine methyl tanate, 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazip methyl lopanoate, 2-morpholino-3-ethylaminopyridine, 4-di(2-acetyloxyethyl ) amino-2,6-di-1-pyrrolidinylpyrimidine, 4-(4-(2-methoxyethyl)-1-piperazinyl)-2,6-di-1-pi Loridinylpyrimidine, 4-(4-(2-acetyloxyethyl)-1-pipera) di(dinyl)-2,6-di-pyrrolidinylpyrimidine, 4-(2,6-di-1-pyro lysinyl-4-pyrimidinyl)-1-piperazinepropanol, 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazine Tanol, 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazine ethyl tanate, 4-pyrrolidinyl-2,6-di-1-morpholinopyrimidine, 4-piperidinyl -2,6-di-1-morpholinopyrimidine, 4-(2,6-di-1-pyrrolidini) -4-pyrimidinyl)-1-piperazinebutanoic acid, 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazine tannic acid, or 4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazip Lopanoic acid Amino-substituted heteroarylamine (I) according to claim 13. 15. The amino acid according to claim 1, wherein heteroaryl is pyridin-2-yl. Non-substituted heteroarylamines (I). 16.4-(3-(ethylamino)-2-pyridinyl)-1-piperazinepropa Knoll, 2-(4-mesyloxy-1-piperazinyl)-3-ethylaminopyridine, Methyl 4-(3-(ethylamino)-2-pyridinyl)-1-piperazineethanoate le, 4-(3-(ethylamino)-2-pyridinyl)piperazine benzyl ethanoate, 4-(3-(ethylamino)-2-pyridinyl)-piperazineethanoic acid, 2-((2-acetyloxyethyl)ethylamino)-3-ethylaminopyridi hmm, 2-((2-hydroxyethyl)ethylamino)-3-ethylaminopyridine, 2-((2-acetyloxyethyl)methylamino)-3-ethylaminopyridi hmm, 2-di(2-methoxyethyl)amino-3-ethylaminopyridine, 2-di(2-methoxyethyl)amino-3-diethylaminopyridine, 2-(4-(2-methoxyethyl)-1-piperazinyl)-3-ethylaminopi lysine, 2-(4-(2-acetyloxyethyl)-1-piperazinyl)-3-ethyl a minopyridine, 4-((3-ethylamino)-2-pyridinyl)-1-piperazineethanol, 2-((2-hydroxyethyl)methylamino)-3-ethylaminopyridine, 4-(3-(ethylamino)-2-pyridinyl)-1-piperazinepropanoate Chill, Ethyl 4-(3-(ethylamino)-2-pyridinyl)-1-piperazinebutanoate le, 4-(3-(ethylamino-2-pyridinyl)-1-piperazinebutanoic acid, 4-(3-ethylamino-2-pyridinyl)-1-piperazine benzylpropanoate or 4-(3-ethylamino-2-pyridinyl)-1-piperazinepropanoic acid Amino-substituted heteroaryhelamine (I) according to claim 15.