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WO1991006542A1 - Amines d'heteroaryle substituees par amino et a activite pharmaceutique - Google Patents

Amines d'heteroaryle substituees par amino et a activite pharmaceutique Download PDF

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Publication number
WO1991006542A1
WO1991006542A1 PCT/US1990/005645 US9005645W WO9106542A1 WO 1991006542 A1 WO1991006542 A1 WO 1991006542A1 US 9005645 W US9005645 W US 9005645W WO 9106542 A1 WO9106542 A1 WO 9106542A1
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Prior art keywords
amino
piperazine
alkyl
ethylamino
pyrrolidinyl
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PCT/US1990/005645
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English (en)
Inventor
Donald E. Ayer
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Pharmacia and Upjohn Co
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Upjohn Co
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Priority to KR1019920700951A priority Critical patent/KR927003545A/ko
Publication of WO1991006542A1 publication Critical patent/WO1991006542A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms

Definitions

  • the invention relates to complex heteroaryl amines attached to a simple mono- or di-substituted amino portion. These compounds are useful as pharmaceuticals.
  • the known compounds of the reference have a "connector portion" [-(CH 2 ) n2 -] between the amine portion (M) and the non-amine portion (X 2 ) of the molecule in which n 2 is 4-14.
  • the "connector portion" of the similar compounds is less than 4.
  • R 1 is C 1 -C 3 aikyl
  • n 1 is 2 or 3 and R 1-1 is -H, C 1 -C 3 alkyl, -CO-R 1-2 where R 1-2 is -H, C 1 -C 3 alkyl or - ⁇ ,
  • n 2 is 1 or 2 and where R 1-1 is as defined above,
  • n 3 is 1 thru 3 and R 1-3 is
  • R 1-4 is C 1 -C 4 alkyl or -CH 2 - ⁇
  • - ⁇ optionally substituted with 1 or 2 -F, -Cl, -Br,
  • -CH 2 -CH CH-CO-R 1-3 where R 1-3 is as defined above, -(CH 2 ) n4 -N(R 1-5 )(R 1-6 ) where n 4 is 2 or 3 and R 1-5 and R 1-6 are the same or different and are -H and C 1 -C 3 alkyl,
  • R 2 is -H
  • n 5 is 2 or 3 and R 2-1 is -H, C 1 -C 3 alkyl, -CO-R 2-2 where R 2-2 is -H, C 1 -C 3 alkyl or - ⁇ ,
  • n 7 is 1 thru 3 and R 2-3 is
  • R 2-4 is C 1 -C 4 alkyl or -CH 2 -ö;
  • - ⁇ optionally substituted with 1 or 2 -F, -Cl, -Br, -NO 2 , C 1 -C 3 or
  • R 2-5 is C 1 -C 3 alkyl, and where R 1 and R 2 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of pyrrolidine, piperidine, morpholine, piperazine and piperazine substituted in the 4- position with
  • n 8 is 2 or 3 and where R 3-1 is -H, C 1 -C 3 alkyl, -CO- R 3-2 where R 3-2 is -H, C 1 -C 3 alkyl or - ⁇ ,
  • n 9 is 1 thru 3 and R 3-3 is
  • R 3-4 is C 1 -C 4 alkyl or -CH 2 - ⁇
  • - ⁇ optionally substituted with 1 or 2 -F, -Cl, -Br, -NO 2 , C 1 -C 3 or - OR 3-6 where R 3-6 is C 1 -C 3 alkyl,
  • n 10 is 1 or 2 and where R 3-1 is as defined above,
  • -CH 2 -CH CH-CO-R 3-3 where R 3-3 is as defined above, -SO 2 R 3-5 where R 3-5 is C 1 -C 3 alkyl;
  • R 4-1 and R 4-2 are the same or different and are -H, C 1 -C 3 alkyl and where R 4-1 and R 4-2 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl and 4-(C 1 -C 3 alkyl)-piperazinyl -NH-OH
  • R 4-3 is -H or C 1 -C 3 alkyl
  • R 4-3 is as defined above, and pharmaceutically acceptable salts thereof.
  • the amino-substituted heteroaryl amines (I) of the present invention are prepared from known compounds by methods well known to those skilled in the art.
  • the present invention involves novel pharmaceutical compounds; the process chemistry used to produce these novel amino-substituted heteroaryl amines (I) is well known to those skilled in the art.
  • One method starts with a substituted halo (preferably chloro) pyrimidine, halo (preferably chloro) pyridazine, halo (preferably chloro)pyrazine or halo (preferably chloro)triazine which is alkylated with a primary or secondary amine.
  • the reaction may be carried out by heating a mixture of the pyrimidine, pyridazine, pyrazine or triazine and excess liquid amine until the starting material is consumed.
  • the temperatures involved range from about 20-25° to the boiling point of the amine, and reaction times of about 1 to about 24 hr are usual.
  • halo pyrimidine, pyridazine, pyrazine or triazine and the amine react in solvents such as acetonitrile and THF containing an acid scavenger such as potassium carbonate or an organic base such as pyridine or diisopropylethylamine.
  • solvents such as acetonitrile and THF containing an acid scavenger such as potassium carbonate or an organic base such as pyridine or diisopropylethylamine.
  • an acid scavenger such as potassium carbonate
  • organic base such as pyridine or diisopropylethylamine
  • piperazinopyridines or piperazinotriazines are prepared by reaction of the appropriate alkyl halide/mesylate/- tosylate or functionalized alkyl halide/mesylate/tosylate with the piperazino (secondary amine) intermediate. While not necessary, a catalytic amount of iodide may be included in the reaction mixture. Generally the use of a polar, nonhydroxylic solvent such as acetonitrile in the presence of a base such as potassium carbonate, pyridine or diisopropylethylamine is preferred. The process of EXAMPLES 8, 10-12, 14, 20, 21, 24-26 and 28-30 are performed by this method.
  • 2,3-diaminopyridines may be prepared in several steps by reaction of 2-chloro-3-nitropyridine with the appropriate primary or secondary amine. Generally use of a solvent such as THF or acetonitrile in the presence of excess base is preferred.
  • the 3-nitropyridine intermediate is conveniently reduced by catalytic hydrogenation, to the corresponding primary amine.
  • the primary amine may be reductively alkylated to give the corresponding mono- and dialkylamine products.
  • 2,5-diaminopyridines are prepared from 2-chloro-5-nitropyridine and 2,3,6-triaminopyridineare prepared from starting with 2,6-dichloro-3-nitropyridine. The process of EXAMPLES 15-18 were performed by this method.
  • reaction mixtures described above are purified by standard methods. Briefly, volatile solvents and reagents are removed by distillation under reduced pressure. The residue is partitioned between an organic solvent such as ethyl acetate, methylene chloride, ether, etc and water and/or aqueous bicarbonate. The organic phase is separated, dried and concentrated to a residue which is purified by chromatography. The appropriate fractions are pooled and concentrated to a residue. The residue is crystallized if necessary.
  • the compounds described above can be transformed to other amino-substituted heteroaryl amines (I) by methods known to those skilled in the art (etherification, acylation, hydrolysis, hydrogenolysis, etc).
  • the compounds may be converted to salts of pharmaceutically acceptable acids by known methods.
  • the compounds containing a free carboxyl group can be converted to salts of pharmaceutically acceptable bases by known methods. These include, for example, sodium, potassium, aluminum, calcium, ammonium and tromethamine (T ⁇ AM) salts.
  • R 1 and R 2 can either be separate or R 1 and R 2 can be taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of pyrrolidine, piperidine, morpholine, piperazine and piperazine substituted in the 4-position.
  • R 1 and R 2 are not taken together to form a cyclic moiety, it is preferred that R 2 is -H, C 1 -C 3 alkyl and -(CH 2 ) n5 -O-R 2-1 .
  • R 1 and R 2 are taken together to form a cyclic moiety it is preferred that it be morpholine, piperazine substituted in the 4-position, pyrrolidine or piperidine; it is more preferred that R 1 and R 2 are taken together to form piperazine substituted in the 4- position.
  • heteroaryl is pyrimidin-4-yl or pyridin-2-yl. It is preferred that when heteroaryl is pyrimidin-4-yl that it is substituted with 2,6-di-1-pyrrolidinyl or morpholino, more preferrably with 2,6-di-1-pyrrolidinyl. It is preferred that when heteroaryl is pyridin-2-yl it is substituted with 3-ethylamino.
  • amino-substituted heteroaryl amine (I) is selected from the compounds of EXAMPLES 1-38.
  • amino-substituted heteroaryl amines (I) of the present invention are amines, they readily form salts when reacted with acids of sufficient strength to produce the corresponding salts.
  • Pharmaceutically acceptable salts include salts of both inorganic and organic acids.
  • the anions of preferred pharmaceutically acceptable salts include acetate, benzoate, bromide, chloride, citrate, fumarate, mesylate, maleate, phosphate, nitrate, succinate, sulfate and tartrate.
  • the amino-substituted heteroaryl amines (I) are useful in treating spinal trauma, mild and/or moderate to severe head injury, subarachnoid hemorrhage and subsequent cerebral vasospasm, ischemic (thromboembolic) stroke, excess mucous secretion, asthma, muscular dystrophy, adriamycin-induced cardiac toxicity, Parkin- sonism, Alzheimer's disease, other degenerative neurological disorders, multiple sclerosis, organ damage during reperfusion after transplant, skin graft rejection, hemorrhagic, traumatic and septic shock, and conditions such as severe burns, ARDS (adult respiratory distress syndrome), inflammatory diseases such as osteo- or rheumatoid arthritis, nephrotic syndrome (immunological), systemic lupus erythematosis, allergic reactions, atherosclerosis, inflammation (for example dermatological, inflammatory and psoriasis conditions), emphysema, stress induced ulcers, cluster headaches
  • peritumoral edema peritumoral edema
  • radiation damage for example during radiation treatment or from accidental exposure to radiation
  • pre-birth infant strangulation and infant hypoxia syndrome such opthalmic disorders as uveitis and optic neuritis, photic retinopathy, age-related macular degeneration, cataracts and glaucoma.
  • the amino-substituted heteroaryl amines (I) are useful in preventing damage following cardiopulmonary resuscitation, neurological or cardiovascular surgery and from cardiac infarction.
  • the amino-substituted heteroaryl amines (I) are useful in irrigation solutions used in eye surgery.
  • each of the amino-substituted heteroaryl amines (I) is useful to a different degree for treating each of the conditions above. However, as is known to those skilled in the art, some of the amino-substituted heteroaryl amines (I) are better for treating some conditions and others are better for treating other conditions.
  • the mouse head injury assay of Hall, J. Neurosurg., 62, 882 (1980) discloses an assay from which one skilled in the art can readily determine which particular amino-substituted heteroaryl amines (I) are useful in the acute treatment of spinal trauma or mild and/or moderate to severe head injury.
  • the cat 48 hr motor nerve degeneration model of Hall et al, Exp. Neurol., 79, 488 (1983) discloses a routine assay from which one skilled in the art can readily determine which particular amino-substituted heteroaryl amines (I) are useful in treating chronic degenerative neurological disorders such as Parkinsonism, Alzheimer's disease, etc. H. Johnson in Int. Arch. Allergy Appl. Immunol., 70, 169 (1983) has described the Ascaris suum sensitized rhesus monkey assay for anti-asthma drugs.
  • Another method useful for determining which particular compounds inhibit lipid peroxidation and which are therefore useful in treating spinal trauma, mild and/or moderate to severe head injury, degenerative neurological disorders, etc is described by Pryor in Methods of Enzymology 105, 293 (1984).
  • the standard conditions for treatment are to give the amino-substituted heteroaryl amines (I) orally or parenterally, e.g. IV (that is by injection, infusion or continuous drip) or IM, with a standard dose of about 0.05 to about 10 mg/kg/day IV or about 0.5 to about 50 mg/kg/day, one to four times daily by mouth.
  • Typical treatment will involve an initial loading dose, e.g. an IV dose of 0.01 mg to 2 mg/kg followed by maintenance dosing e.g. IV infusion for a day to a week depending on the particular condition of the patient and the particular compound used. This may be supplemented with IM or oral dosing for days, weeks or months to prevent delayed neuronal degeneration in neurological applications (eg spinal trauma, head injury).
  • the amino-substituted heteroaryl amines (I) are administered orally, IV and by inhalation in the standard dose.
  • the oral dose of the amino-substituted heteroaryl amines (I) used is from about 0.5 to about 50 mg/kg/day.
  • the frequency of administration is one through 4 times daily.
  • the susceptible individuals can be pre-treated a few hours before an expected problem.
  • the IV dose is about 0.05 to about 20 mg/kg/day.
  • the aerosol formulation contains about 0.05 to about 1.0% of the amino-substituted heteroaryl amines (I) and is administered or used about four times daily as needed.
  • amino-substituted heteroaryl amines (I) are administered orally using a dose of about 0.5 to about 50 mg/kg/day, administered or used one to four times a day. The treatment may go on for years.
  • the amino-substituted heteroaryl amines (I) are administered orally or IV using a dose of about 0.05 to about 50 mg/kg/day, preferrably about 0.5 to about 10 mg/kg/day.
  • the amino-substituted heteroaryl amines (I) are preferably given concomitantly with IV adriamycin or the individual is pre-treated with the amino-substituted heteroaryl amines (I).
  • the amino-substituted heteroaryl amines (I) are used according to the standard conditions.
  • the patient can be pretreated with a single IV or IM dose just prior to surgery and/or orally after surgery.
  • the amino-substituted heteroaryl amines (I) are given orally or IM in doses of about 0.5 to about 50 mg/kg/day, one to four times daily. Orally the drug will be given alone or with other steroidal or nonsteroidal antiinflammatory agents.
  • the initial dose with some severe rheumatoid patients may be given IV and followed with an IV drip for up to 24 hr or more.
  • intra-articular administration may be employed.
  • the amino-substituted heteroaryl amines (I) are given in a dose of about 0.5 to 50 mg/kg/day, administered one to four times daily orally and IV.
  • Typical treatment would be an initial IV loading dose followed by oral dosing for a few days or more.
  • the amino-substituted heteroaryl amines (I) are given orally in a dose of about 0.5 to about 50 mg/kg/day, one to four times daily.
  • the amino-substituted heteroaryl amines (I) are given orally in a dose of about 0.5 to about 50 mg/kg/day, one to four times daily or applied topically as a cream, ointment or lotion or equivalent dosage form in a concentration of about 0.05 to about 5% as long as needed.
  • the amino-substituted heteroaryl amines (I) can be used with steroidal agents.
  • an isoosmolar solution containing about 0.001 to about 1% of the amino-substituted heteroaryl amines (I) is used.
  • the amino-substituted heteroaryl amines (I) are given orally in a dose of about 0.5 to about 50 mg/kg/day, one to four times daily or applied topically as a cream, ointment or lotion or equivalent dosage form in a concentration of about 0.001 to about 1 % as long as needed.
  • the amino-substituted heteroaryl amines (I) are useful in the prevention and treatment of stress ulcers and of gastric intolerance caused by drugs such as nonsteroidal antiinflammatory compounds (NOSAC).
  • Stress ulcers are ulcers that develop after exposure to severe conditions such as trauma, burns, sepsis, extensive surgery, acute illnesses, and the like. Patients in intensive care units are particularly prone to develop stress ulcers. Stress ulcers also include lesions that can lead to upper gastrointestinal bleeding; such bleeding is likely to be prevented by these compounds.
  • NOSAC includes drugs such as ibuprofen, aspirin, indomethacin, naproxen, piroxicam and the like that are usually taken for analgesia, and that are often associated with gastrointestinal intolerance characterized by pain and lesions that may lead to bleeding.
  • the amino-substituted heteroaryl amines (I) will be administered preferentially by the oral route either as tablets, capsules or liquids, in doses ranging from about 5 to about 500 mg, two to four times a day.
  • the treatment would be either preventive, i.e., starting before ulcers have formed in patients at risk of developing such lesions, or therapeutic, i.e., once the ulcers have formed.
  • the amino- substituted heteroaryl amines (I) would be given either through a nasogastric tube, or parenterally, i.e., IV or IM.
  • the parenteral doses would range from about 1 to about 100 mg/kg and be administered one to four times a day.
  • amino-substituted heteroaryl amines (l) are useful in treating trauma, intervertebral diseases (slipped disk), traumatic shock, flea bite and other allergies.
  • amino-substituted heteroaryl amines (I) are useful in treating endotoxic or septic shock which follows colic, pretreatment before surgery for colic and treatment of Founder (laminitis).
  • the amino-substituted heteroaryl amines (I) are useful in treating acute coliform mastitis, bovine mastitis, acute allergic reaction to feed lot vaccination and shipping fever.
  • the amino-substituted heteroaryl amines (I) are useful in treating porcine stress syndrome and thermal stress syndrome.
  • amino-substituted heteroaryl amines (I) can be used with other pharmaceutical agents in treatment of the conditions listed above as is known to those skilled in the art.
  • the exact dosage and frequency of administration depends on the particular amino-substituted heteroaryl amines (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the amino-substituted heteroaryl amines (I) in the patient's blood and/or the patients response to the particular condition being treated.
  • R i and R j would represent monovalent variable substituents if attached to the formula CH 3 -CH 2 -C(R i )(R j )H 2 .
  • variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis.
  • each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses.
  • both R i and R j are bonded to the preceding carbon atom.
  • C i represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry.
  • R 6 represents a variable substituent (either monovalent or bivalent) at the C 6 position.
  • variable R i attachee to a carbon atom as
  • R i When a bivalent variable, R i , is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form " ⁇ -R i-j : ⁇ - R i-k " or some variant thereof. In such a case both ⁇ -R i-j and ⁇ -R i-k are attached to the carbon atom to give -C( ⁇ -R i-j )( ⁇ -R i-k )-.
  • the two monovalent variable substituents are ⁇ -R 6-1 : ⁇ -R 6-2 , .... ⁇ -R 6-9 : ⁇ -R 6-10 , etc, giving -C( ⁇ -R 6 _ 1 )(B-R 6-2 )-, .... -C( ⁇ -R 6-9 )( ⁇ -R 6-10 )-, etc.
  • bivalent variable may be defined as two separate monovalent variable substituents
  • two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable.
  • R i and R j may be defined to be taken together to form (1) a second bond between C 1 and C 2 or (2) a bivalent group such as oxa (-O-) and the formula thereby describes an epoxide.
  • the carbon atom content of variable substituents is indicated in one of two ways.
  • the first method uses a prefix to the entire name of the variable such as " C 1 -C 4 ", where both " 1 " and “4" are integers representing the minimum and maximum number of carbon atoms in the variable.
  • the prefix is separated from the variable by a space.
  • “ C 1 -C 4 alkyl” represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined.
  • C 2 -C 4 alkoxycarbonyl describes a group CH 3 -(CH 2 ) n -O-CO- where n is zero, one or two.
  • the carbon atom content of only each portion of the definition is indicated separately by enclosing the " C i -C j " designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined.
  • C 1 -C 3 )alkoxycarbonyl has the same meaning as C 2 -C 4 alkoxycarbonyl because the " C 1 -C 3 " refers only to the carbon atom content of the alkoxy group.
  • C 2 -C 6 alkoxyalkyl and (C 1 - C 3 )alkoxy(C 1 -C 3 )alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms
  • the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
  • TLC refers to thin-layer chromatography
  • THF refers to tetrahydrofuran
  • Saline refers to an aqueous saturated sodium chloride solution.
  • NMR nuclear (proton) magnetic resonance spectroscopy
  • chemical shifts are reported in ppm ( ⁇ ) downfield from tetramethylsilane and are measured in chloroform-d (CDCl 3 ).
  • CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm ( ⁇ ) downfield from tetramethylsilane and are measured in chloroform-d (CDCl 3 ).
  • ⁇ refers to phenyl (C 6 H 5 ).
  • Ether refers to diethyl ether.
  • Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • Treatment or treating refers to and includes both treatment of an existing condition as well as preventing the same condition from occurring where such is possible as is well known to those skilled in the art.
  • the amino-substituted heteroaryl amines (I) can be used to treat existing asthma conditions and to prevent future ones from occurring.
  • the amino-substituted heteroaryl amines (I) treat spinal trauma and prevent rejection of skin grafts.
  • the ratios of solvents used are volume/volume (v/v).
  • the gum is chromatographed on silica gel eluting with ethyl ace tate/hexane (50/50), the appropriate fractions are pooled and concentrated to give the title compound, CMR 162.29, 162.1, 160.0, 71.25, 70.66, 58.71, 48.35, 46.01, 45.91, 25.45 and 25.20 ⁇ .
  • a sample is crystallized from acetone, mp 136.5-137°; CMR 150.23, 137.27, 135.06, 119.81, 115.86, 64.22, 61.59, 53.61, 48.56, 37.97, 27.03 and 14.64 ⁇ .
  • Methanesulfonyl chloride (0.4 ml) is added slowly to a solution of 4-(3-ethyla- mino)-2-pyridinyl-piperazine (1.11 g) in pyridine (5 ml). The mixture is allowed to warm to 20-25°, then is mixed with ice and allowed to stand overnight. The mixture is diluted with ethyl acetate, the phases are separated, the organic phase is washed with water and saline, then dried and concentrated to give a yellow oil.
  • EXAMPLE 12 Benzyl 4-(3-(ethylamino)-2-pyridinyl)piperazine ethanoate (I) Following the general procedure of EXAMPLE 10 and making noncritical variations but reacting 4-(3-(ethylamino)-2-pyridinylpiperazine (0.84 g) with benzyl bromoacetate (1.14 g), crude title compound is obtained. Chromatography on silica gel, eluting with methanol/methylene chloride (5/95) gives the title compound, mp 54°; NMR 7.7, 7.47, 6.9, 6.8, 5.19, 4.1, 3.38, 3.15, 2.8 and 1.29 ⁇ .
  • a solution of the 2-morpholino-3-nitropyridine in methanol (150 ml) is hydrogenated in the presence of palladium/carbon (5%, 1 g) in a Parr apparatus (45 1b, 2 hr).
  • the mixture is filtered and the filtrate containing 2-morpholino-3-aminopyridine is concentrated to 50 ml and cooled in an ice bath.
  • Acetaldehyde (4 ml) is added followed by the portion-wise addition of sodium cyanoborohydride (1.4 g). The mixture is stirred for 1 hr with continued cooling, is allowed to stand overnight at 20-25° and then is concentrated under reduced pressure.
  • This nitro compound is hydrogenated and the resultant primary amine treated with acetaldehyde/sodium cyanoborohydride essentially as described in EXAMPLE 15 to give an oil which is chromatographed on silica gel eluting with acetone/methylene chloride (10/90). The appropriate fractions are pooled and concentrated to give the title compound, NMR 7.7, 6.9, 6.8, 4.42, 4.23, 3.27, 3.13, 2.76, 2.06 and 1.31 ⁇ .
  • 2-Di(2-methoxyethyl)amino-3-nitropyridine (2.6 g) is hydrogenated as described in EXAMPLE 15 to give 2-di(2-methoxyethyl)amino3-aminopyridine.
  • a methanolic solution (25 ml) of this amine is treated with 2 ml of acetaldehyde (exotherm). The mixture is cooled to 10° and additional acetaldehyde (2 ml) is added (no exotherm) followed by the addition of sodium cyanoborohydride (0.7 g). The mixture is cooled for 1 hr, stirred overnight at 20-25° and then concentrated at reduced pressure.
  • EXAMPLE 26 4-(2,6-Di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinepropanol (I) Following the general procedure of EXAMPLE 24 and making noncritical variations but replacing 1-methoxy-2-mesyloxyethane with 3-bromo-1-propanol, crude title compound is obtained.
  • EXAMPLE 30 Ethyl 4-(3-(ethylamino)-2-pyridinyl)-1-piperazine butanoate (l) Following the general procedure of EXAMPLE 14 and making noncritical variations but reacting 4-(3-ethylamino)-2-pyridinyl)piperazine (1.04 g) with ethyl 4-bromobutyrate (0.98 g), crude title compound is obtained.

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Abstract

On décrit des amines d'hétéroaryle substituées par amino dont la formule est (I) et qui sont utiles comme agents pharmaceutiques.
PCT/US1990/005645 1989-10-25 1990-10-10 Amines d'heteroaryle substituees par amino et a activite pharmaceutique Ceased WO1991006542A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993025539A1 (fr) * 1992-06-09 1993-12-23 Richter Gedeon Vegyészeti Gyár Rt. Nouveaux derives de piperazinil-bis(alkylamino)pyrimidine et procede pour leur preparation
US5502187A (en) * 1992-04-03 1996-03-26 The Upjohn Company Pharmaceutically active bicyclic-heterocyclic amines
US7622486B2 (en) 2004-09-23 2009-11-24 Reddy Us Therapeutics, Inc. Pyridine compounds, process for their preparation and compositions containing them
AU2006327876B2 (en) * 2005-12-20 2010-12-16 Ziarco Inc. Pyrimidine derivatives

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005118543A1 (fr) * 2004-06-03 2005-12-15 Ono Pharmaceutical Co., Ltd. Inhibiteur des kinases et utilisation de cet inhibiteur

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3720671A (en) * 1970-10-05 1973-03-13 Ciba Geigy Ag Polycyclic dyestuffs
DE2355967A1 (de) * 1973-11-09 1975-07-24 Hoechst Ag Polycyclische farbstoffe, verfahren zu ihrer herstellung und ihre verwendung
WO1988008424A1 (fr) * 1987-04-27 1988-11-03 The Upjohn Company Amines pharmaceutiquement actives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3720671A (en) * 1970-10-05 1973-03-13 Ciba Geigy Ag Polycyclic dyestuffs
DE2355967A1 (de) * 1973-11-09 1975-07-24 Hoechst Ag Polycyclische farbstoffe, verfahren zu ihrer herstellung und ihre verwendung
WO1988008424A1 (fr) * 1987-04-27 1988-11-03 The Upjohn Company Amines pharmaceutiquement actives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Journal of Medicinal Chemistry, volume 23, 1980, American Chemical Society, (Washington, DC, US), B. Roth et al.: "2,4-Diamino-5-benzyl-pyrimidines as antibacterial agents. 4. 6-substituted Trimethoprim derivatives from phenolic mannich intermediates. Application to the synthesis of Trimethoprim and 3,5-dialkylbenzyl analogues", pages 535-541 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5502187A (en) * 1992-04-03 1996-03-26 The Upjohn Company Pharmaceutically active bicyclic-heterocyclic amines
WO1993025539A1 (fr) * 1992-06-09 1993-12-23 Richter Gedeon Vegyészeti Gyár Rt. Nouveaux derives de piperazinil-bis(alkylamino)pyrimidine et procede pour leur preparation
US7622486B2 (en) 2004-09-23 2009-11-24 Reddy Us Therapeutics, Inc. Pyridine compounds, process for their preparation and compositions containing them
AU2006327876B2 (en) * 2005-12-20 2010-12-16 Ziarco Inc. Pyrimidine derivatives
US7943628B2 (en) 2005-12-20 2011-05-17 Pfizer Limited Pyrimidine derivatives

Also Published As

Publication number Publication date
KR927003545A (ko) 1992-12-18
CA2065305A1 (fr) 1991-04-26
AU638286B2 (en) 1993-06-24
AU6503590A (en) 1991-05-31
JPH05501248A (ja) 1993-03-11
EP0496746A1 (fr) 1992-08-05

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