Claims
- 1. A compound of the following formula (3), or a pharmaceutically acceptable salt thereof, ##STR57## wherein A represents a group of the formula ##STR58## or a group of the formula ##STR59## R.sup.22 represents a lower alkyl group; R.sup.21 represents a group of the formula ##STR60## wherein R.sup.23 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group, and
- R.sup.24 represents a hydrogen atom, a lower alkyl group, a cyclohexyl group, a phenyl group,
- a 4-halogenophenyl group, a p-diphenyl group
- a 2-pyridyl group or a 2-thiophenyl group,
- provided that R.sup.23 and R.sup.24 are not hydrogen atoms at the same time, and R.sup.24 is not a lower alkyl group when R.sup.23 is a hydrogen atom; and
- l is a number of 0 or 1.
- 2. The compound according to claim 1, wherein A represents a group of the formula ##STR61##
- 3. The compound according to claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochlorides, hydrobromides, bisulfites, phosphates, acidic phosphates, acetates, maleates, fumarates, succinates, lactates, tartrates, benzoates, citrates, glucanates, methansulfonates, p-toluenesulfonates, naphthalenesulfonates, and quaternary ammonium salts.
- 4. A pharmaceutical composition for treatment of neurological diseases induced by injury to nerve per se comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
- 5. A method for the treatment of neurological diseases induced by injury to nerve per se which comprises administering to a patient in need thereof a pharmacologically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
Priority Claims (3)
| Number |
Date |
Country |
Kind |
| 63-333670 |
Dec 1988 |
JPX |
|
| 1-41728 |
Feb 1989 |
JPX |
|
| 1-41729 |
Feb 1989 |
JPX |
|
Parent Case Info
This is a division of application Ser. No. 07/459,376, filed Dec. 29, 1989, now U.S. Pat. No. 5,147,876.
This invention relates to novel pyrimidines or their pharmaceutically acceptable salts, and novel therapeutic agents for neurological diseases of the peripheral and central nervous systems of animals containing the above compounds as active ingredients. Japanese Patent Publication No. 23,394/1971 discloses that aminopyrimidines represented by the following formula ##STR1## wherein A represents an alkylene group having up to 16 carbon atoms, or a lower alkylene group substituted by an amino group or a C.sub.2-5 acylamino group, M represents H, Na, K, NH.sub.4, Mg, Ca or an organic basic ammonium salt, and n is a value equal to the atomic valency of M,
Japanese Patent Publication No. 22044/1976 discloses that dichloro-lower aliphatic carboxylic acid salts of 2-isopropylaminopyrimidine, such as 2-isopropylaminopyrimidine dichloroacetate, are useful as a therapeutic agent for a neurological disease.
Japanese Laid-Open Patent Publication No. 100477/1977 (Patent Publication No. 28548/1984) discloses that 2-isopropylaminopyrimidine phosphate is useful as a therapeutic agent for a neurological disease.
Japanese Laid-Open Patent No. 157575/1979 discloses a process-for producing 2-chloropyrimidine in a high yield. A working example in this patent publication describes the preparation of 2-chloropyrimidine in a yield of 69%.
Japanese Laid-Open Patent Publication No. 393/1980 discloses a process for producing 2-isopropylaminopyrimidine in a high yield. A working example of this patent publication describes the preparation of 2-isopropylaminopyrimidine in a yield of 60%.
Japanese Laid-Open Patent Publication No. 122768/1980 discloses that a hydroxy derivative of 2-isopropylaminopyrimidine represented by the following formula ##STR2## wherein A.sup.4, A.sup.5 and A.sup.6 each represent H or OH, and at least one of them represents OH,
Japanese Laid-Open Patent Publication No. 145670/1980 discloses that 2-isopropylaminohalogenopyrimidines represented by the following formula ##STR3## wherein A.sub.4 ', A.sub.5 ' and A.sub.6 ' each represent H or a halogen atom, and at least one of them is a halogen atom,
Japanese Laid-Open Patent Publication No. 145,671/1980 discloses a process for producing a hydroxy derivative of 2-isopropylaminopyrimidine.
Japanese Laid-Open Patent Publication No. 151,571/1980 discloses that 2-isopropylamino-5-halogenopyrimidines are interesting in the treatment of neurological diseases.
Japanese Laid-Open Patent Publication No. 10177/1981 discloses a process for producing 2-isopropylaminopyrimidine substantially in a quantitative yield by aminolyzing 2-methylsulfonylpyrimidine with isopropylamine.
Japanese Laid-Open Patent Publication No. 26880/1981 discloses a process for producing 2-isopropylaminopyrimidine which comprises reacting bis(isopropylguanidine) sulfate with 1,1,3,3-tetraethoxypropane.
Japanese Laid-Open Patent Publication No. 90,013/1981 describes a therapeutic agent for myodystropy, myopathy, muscle rigidity and/or dysfunction of neuro-musclar transmission comprising substituted derivative of pyrimidine or its therapeutically acceptable salt or its metabolite as an active ingredient. However, it merely discloses various salts such as an orthophosphate, of 2-isopropylaminopyrimidine as an active compound.
Japanese Laid-Open Patent Publication No. 65873/1986 discloses that 2-piperazinopyrimidines of the following formula ##STR4## wherein R.sup.1 is H or aralkyl, and Y is a divalent organic group defined in the claim of this patent publication,
The present inventors previously provided a novel therapeutic agent for treatment of neurological diseases comprising a specific 2-piperazinopyrimidine derivative or its pharmaceutically acceptable salt (International Laid-Open No. W087/04928).
It is an object of this invention to provide novel pyrimidines and their pharmaceutically acceptable salts.
Another object of this invention is to provide therapeutic agents for neurological diseases and spinal breakdown comprising the above novel compounds.
Another object of this invention is to provide a novel therapeutic agent for neurological diseases having the effect of regenerating and repairing nerve cells.
Another object of this invention is to provide a novel therapeutic agent for neurological diseases which can be applied to disorders of peripheral nerves, cerebrospinal injury, etc.
Another object of this invention is to provide a novel therapeutic agent for neurological diseases which can be applied to diseases of central nerves which are different from psycosis and in which abnormality in the operating system or the metabolic system of chemical transmitters is regarded as being primarily involved.
Another object of this invention is to provide a novel therapeutic agent for cerebral diseases which has the effect of improving and restoring learning and memory.
Another object of this invention is to provide a novel therapeutic agent for neurological diseases or cerebral diseases, which comprises a comprehensively excellent and useful compound having pharmacological actions suitable for treatment of neurological diseases or cerebral diseases with little side effects such as liver trouble.
Further objects of this invention along with its advantages will become apparent from the following description.
According to this invention, there is first provided a pyrimidine represented by the following formula (1), or its pharmaceutically acceptable salt ##STR5## wherein R.sup.1 represents a hydrogen atom or a lower alkyl group; X represents a group of the formula ##STR6## a group of the formula ##STR7## in which R.sup.2 represents a hydrogen atom, a lower alkyl group, a phenyl group, a benzyl group or an alpha-(p-chlorophenyl)benzyl group,
In formula (1), R.sup.1 is a hydrogen atom or a lower alkyl group. The lower alkyl group may be linear or branched, and preferably has 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl n-butyl, sec-butyl, isobutyl and t-butyl groups.
In formula (I), X represents a group of the formula ##STR27##
In the above formulae, R.sup.2 represents a hydrogen atom, a lower alkyl group, phenyl group, benzyl group or an alpha-(p-chlorophenyl)benzyl group. Examples of the lower alkyl group may be the same as those exemplified for R.sup.1.
R.sup.3 corresponds to a substituent replacing the hydrogen atom of the methylene group, and represents a lower alkyl group, a hydroxyl group, a phenyl group optionally substituted by nitro, a benzyl group, a benzoyloxy group, a benzoylamino group, a lower alkylamino group, a di-lower alkylamino group, the HO(C.sub.6 H.sub.5).sub.2 C-group, a piperidino group, a hydroxy(lower alkyl) group, the C.sub.6 H.sub.5 SO.sub.2 O-- group, a benzoyl group optionally substituted by halogen, a lower alkylsulfonylamide group, or a lower alkoxycarbonyl group. n is a number of 4, 5, 6 or 7. Examples of the lower alkyl groups may be the same as those exemplified above with regard to R.sup.1.
R.sup.4 represents a hydrogen atom, a lower alkyl group or a benzyl group, and R.sup.5 represents a lower alkyl group, a lower acyl group, a 2-furoyl group, a benzyl group, a 4-piperidyl group optionally substituted by benzoyl, a phenethyl group or the group ##STR28## or a benzoyl group optionally substituted by halogen or nitro.
Examples of the lower alkyl groups for R.sup.4 and R.sup.5 may be the same as those R.sup.5.
The alkyl moiety of the lower acyl group for R.sup.5 may be linear or branched.
Acyl groups having 2 to 6 carbon atoms are preferred, and examples include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and hexanoyl groups.
In formula (I), Y represents a group of the formula ##STR29##
R.sup.9 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, or a di-lower alkylamino group. R.sup.6 represents a hydrogen atom, a lower alkyl group, a phenyl group, a benzyl group, a lower alkoxy group or a 2-(N,N-dimethylamino)ethyl group. R.sup.7 represents a lower alkyl group, a lower acyl group, a cyclohexylcarbonyl group, a 2-furoyl group, a lower alkoxycarbonyl group, a cinnamoyl group, a benzyl group, a benzylcarbonyl group, a tosyl group, a phenoxyacetyl group, a di-lower alkylcarbamoyl group, a 2-thienyl group, a group of the formula ##STR30## a group of the formula ##STR31## a group of the formula ##STR32## a group of the formula ##STR33## a group of the formula ##STR34## a 4-lower alkylpiperazyl group, or a benzoyl group which may be substituted by halogen, lower alkoxy, nitro, amino, benzoylamino or phenyl.
Examples of the lower alkyl groups for R.sup.9, R.sup.6 and R.sup.7 may be the same as those exemplified with respect to R.sup.1.
Examples of the lower acyl group for R.sup.7 may be the same as those exemplified above for R.sup.5.
Examples of the halogen and lower alkoxy group as substituent for the benzoyl group R.sup.7 are fluorine, chlorine, bromine and iodine, and alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and sec-butoxy. When R.sup.6 is a hydrogen atom, R.sup.7 is a benzoyl group.
Furthermore, in formula (1), Z represents a hydrogen atom, a halogen atom, a lower alkoxycarbonyl group or a lower alkyl group.
Examples of the halogen atom are fluorine, chlorine, bromine and iodine. Examples of the lower alkyl group may be the same as those exemplified with respect to R.sup.1.
According to this invention, there is further provided a compound represented by the following formula (2), or its pharmaceutically acceptable salt, ##STR35## wherein A.sub.1 represents .dbd.CH-- or --N.dbd.; A.sub.2 is .dbd.CH--, --N.dbd., or ##STR36## A.sub.3 represents .dbd.CH-- or --N.dbd.; R.sup.11 represents a lower alkyl group; R.sup.12 represents a phenyl group optionally substituted by halogen, lower alkyl or lower alkoxy, a 2-furyl group, or a 2-thienyl group; provided that
when A.sub.1 is --N.dbd., A.sub.2 is ##STR37##
when A.sub.1 and A.sub.2 are .dbd.CH--, A.sub.3 is .dbd.CH--, and
when A.sub.2 is --N.dbd., A.sub.1 and A.sub.3 are .dbd.CH--.
In formula (2), R.sup.11 is a lower alkyl group. R.sup.12 represents a phenyl group optionally substituted by halogen, lower alkyl or lower alkoxy, a 2-furyl group or a 2-thienyl group.
Examples of the lower alkyl groups for R.sup.11 and R.sup.12 may be the same as those exemplified above with regard to R.sup.1.
A.sub.1 is .dbd.CH-- or .dbd.N--, and A.sub.2 is .dbd.CH--, --N.dbd., or ##STR38## A.sub.3 is .dbd.CH-- or --N.dbd.. When A.sub.1 is --N.dbd., A.sub.2 is ##STR39## When A.sub.1 and A.sub.2 are .dbd.CH--, A.sub.3 is .dbd.CH--. When A.sub.2 is --N.dbd., A.sub.1 and A.sub.2 are .dbd.CH--.
According to still another aspect, there is also provided a novel compound of the following formula (3) having the same pharmacological efficacy.
A pyrimidine of formula (3), or its pharmaceutically acceptable salt, ##STR40## wherein A represents a group of the formula ##STR41## or a group of the formula ##STR42## R.sup.21 represents a group of the formula (a) ##STR43## wherein R.sup.23 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group and R.sup.24 represents a hydrogen atom, a lower alkyl group, a cyclohexyl group, a phenyl group, a 4-halogenophenyl group, a p-diphenyl group, a 2-pyridyl group or a 2-thiophenyl group, provided that R.sup.23 and R.sup.24 are not hydrogen atoms at the same time;
In formula (3), A represents a group of the formula ##STR45## R.sup.21 represents a group of the following formula (a) ##STR46## or a group of the following formula (b) ##STR47## which is a 9-fluorenyl or triphenylmethyl group.
R.sup.23 in formula (a) is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group, and R.sup.24 represents a hydrogen atom, a lower alkyl group, a cyclohexyl group, a phenyl group, a 4-halogenophenyl group, a p-diphenyl group, a 2-pyridyl group, or a 2-thiophenyl group. R.sup.23 and R.sup.24 are not hydrogen atoms at the same time.
The lower alkyl groups for R.sup.23 and R.sup.24, independently from each other, may be linear or branched and preferably contain 1 to 4 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and isobutyl groups.
The lower alkoxy group for R.sup.23 may be linear or branched, and those having 1 to 4 carbon atoms are preferred. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and t-butoxy groups. Examples of the 4-halogenophenyl group for R.sup.24 are 4-fluorophenyl, 4-chlorophenyl or 4-bromophenyl.
In formula (3), R.sup.22 is a lower alkyl group examples of which may be same as those given for R.sup.23. l is a number of 0 or 1.
Examples of formulae (1), (2) and (3) provided by this invention are given below. ##STR48##
The compounds of formulae (1), (2) and (3) may be produced by known methods, particularly the methods described in Japanese Laid-Open Patent Publication Nos. 140568/1986 and 87627/1986, or by treating the intermediates obtained by these methods in accordance with known methods (for example, the elimination of the protecting group by reduction). Examples 1 to 9 given hereinafter describe the production of these compounds in detail.
For example, compounds of formula (I) in which Y is --NR.sup.6 R.sup.7 and R.sup.6 is other than hydrogen may be produced by the following reaction scheme 1. ##STR49##
Compounds of general formula (1) in which X is --NR.sup.4 R.sup.5 may be produced by the following reaction scheme 2. ##STR50##
The starting compounds of formulae (II) and (III) in the reaction schemes 1 and 2 may be produced by the method described at J. Chem. Soc., 1965, pages 755-761, from ##STR51## as a starting material. The reactions in the reaction schemes 1 and 2 are conveniently carried out at a temperature of 20.degree. to 150.degree. C. in a solvent such as toluene, dioxane, pyridine or water in the presence of, as required, a basic compound. The basic compound may conveniently be, for example, an organic base (such as triethylamine, pyridine and 4-dimethylaminopyridine), and an inorganic base (such as sodium carbonate and potassium carbonate).
Compounds of general formula (1) in which Y is CH.sub.2 R.sup.9, R.sup.9 is hydrogen or a lower alkyl group and Z is a lower alkoxycarbonyl group may be produced in accordance with the following reaction scheme 3. ##STR52##
Specifically, by reacting compounds (IV) with (V) at a temperature of 20.degree. to 100.degree. C. in a reaction medium such as water, methanol, ethanol, THF and DMF, compounds of formula (I) In which Y.dbd.R.sup.10, and Z.dbd.COOR.sup.13 are obtained.
Compounds of general formula (I) in which Y is CH.sub.2 R.sup.9, R.sup.9 is other than hydrogen and lower alkyl group and Z is a lower alkoxycarbonyl group may be produced in accordance with the reaction scheme 4. ##STR53##
Compound (VI) may be prepared in the same way as in Production Method No. 7] of Japanese Laid-Open Patent Publication No. 65873/1986 except that X is used instead of benzylpiperazine. Compounds of formula (I) in which Y is CH.sub.2 R.sup.9 and Z is COOR.sup.10 are obtained by reacting compound (VI) with R.sup.9 H in the presence of an organic base and as pyridine or triethylamine, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride or sodium hydride in the presence of an inert solvent such as toluene or tetrahydrofuran or in the absence of solvent.
The compounds of general formula (2) can be synthesized by the same methods as in the synthesis of the compound of general formula (1).
The compounds of general formula (3) can be produced by the methods shown in the following schemes 5 and 6. ##STR54##
The starting material (VII) may be produced by the method described in J. A. C. S., 71, 2731 (1949). The reaction of the compound (VII) with N-formylpiperazine in a solvent such as acetonitrile or dimethylformamide or in the absence of solvent, optionally in the presence of a basic compound, at a temperature of 20.degree. to 150.degree. C., preferably 20.degree. to 100.degree. C., to form the compound (VIII). An inorganic base such as sodium carbonate or potassium carbonate, or an organic base such as triethylamine or pyridine may be used as the basic compound. Compound (III) is then hydrolyzed in the presence of an acid or an alkali to yield compound (IV). The hydrolysis is carried out in a solvent such as water, methanol or ethanol at a temperature of 0.degree. to 150.degree. C., preferably 20.degree. to 100.degree. C. ##STR55##
Compounds of formula (3) are produced from compound (IV) or (X) in accordance with scheme 5 by known methods, particularly the methods described in Japanese Laid-Open Patent Publications Nos. 140568/1986 and 87627/1986 or by treating the intermediates obtained by these methods in accordance with known methods (for example, the reductive elimination of the protective group). Examples 7 to 9 given below illustrate the production of the compounds of formula (3) in detail.
Investigations of the present inventors show that the compounds of formulae (1), (2) and (3) are useful as therapeutic agents for treatment of neurological diseases.
The compounds of formulae (1), (2) and (3) are normally used in the form of a pharmaceutical composition, and are administered by various routes (e.g., oral, subcutaneous, intramuscular, intravenous, intrarhinal, skin permeation and through the rectum).
The present invention also embraces a pharmaceutical preparation comprising a compound of general formula (1), 2) or (3) or its pharmaceutically acceptable salt. The pharmaceutically acceptable salt includes, for example, acid addition salts and quaternary ammonium (or amine) salts.
Examples of the pharmaceutically acceptable salts of the compounds (1), (2) and (3) include salts formed from acids capable of forming pharmaceutically acceptable non-toxic acid-addition salts containing anions, such as hydrochlorides, hydrobromides, sulfates, bisulfites, phosphates, acid phosphates, acetates, maleates, fumarates, succinates, lactates, tartrates, benzoates, citrates, gluconates, glucanates, methanesulfonates, p-toluenesulfonates and naphthalenesulfonates or their hydrates, and quaternary ammonium (or amine) salts or their hydrates.
The composition of this invention may be formulated into tablets, capsules, powders, granules, troches, cachet wafer capsules, elixirs, emulsions, solutions, syrups, suspensions, aerosols, ointments, aseptic injectables, molded cataplasmas, tapes, soft and hard gelatin capsules, suppositories, and aseptic packed powders. Examples of the pharmaceutically acceptable carrier include lactose, glucose, sucrose, sorbitol, mannitol, corn starch, crystalline cellulose, gum arabic, calcium phosphate, alginates, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, tragacanth gum, gelatin, syrup, methyl cellulose, carboxymethyl cellulose, methylhydroxybenzoic acid esters, propylhydroxybenzoic acid esters, talc, magnesium stearates, inert polymers, water and mineral oils.
Both solid and liquid compositions may contain the aforesaid fillers, binders, lubricants, wetting agents, disintegrants, emulsifying agents, suspending agents, preservatives, sweetening agents and flavoring agents. The composition of this invention may be formulated such that after administration to a patient, the active compound is released rapidly, continuously or slowly.
In the case of oral administration, the compound of formula (1), (2) or (3) is mixed with a carrier or diluent and formed into tablets, capsules, etc. In the case of parenteral administration, the active ingredient is dissolved in a 10% aqueous solution of glucose, isotonic salt water, sterilized water or a like liquid, and enclosed in vials or ampoules for intravenous instillation or injection or intramuscular injection. Advantageously, a dissolution aid, a local anesthetic agent, a preservative and a buffer may also be included into the medium. To increase stability, it is possible to lyophilize the present composition after introduction into a vial or ampoule. Another example of parenteral administration is the administration of the pharmaceutical composition through the skin as an ointment or a cataplasm. In this case, a molded cataplasm or a tape is advantageous.
The composition of this invention contains 0.1 to 2000 mg, more generally 0.5 to 1000 mg, of the active component for each unit dosage form.
The compound of formula (1), (2) or (3) is effective over a wide dosage range. For example, the amount of the compound administered for one day usually falls within the range of 0.03 mg/kg to 100 mg/kg. The amount of the compound to be actually administered is determined by a physician depending, for example, upon the type of the compound administered, and the age, body weight, reaction condition, etc. of the patient and the administration route.
The above dosage range, therefore, does not limit the scope of the invention. The suitable number of administrations is 1 to 6, usually 1 to 4, daily.
The compound of formula (1), (2) or (3) by itself is an effective therapeutic agent for disorders of the peripheral nervous system and the central nervous system. If required, it may be administered in combination with at least one other equally effective drug. Examples of such an additional drug are gangliosides, mecobalamin and isaxonine.
The formulations of the compounds (1), (2) and (3) in accordance with this invention and their biological activities will be illustrated in detail by a series of Examples B and Examples given below. It should be understood however that they do not limit the scope of the invention. Each of the following examples showing the composition of the invention uses one of the compounds described hereinabove or one of other pharmaceutically active compounds encompassed within general formula (1), (2) and (3).
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Divisions (1)
|
Number |
Date |
Country |
| Parent |
459376 |
Dec 1989 |
|
Patent Grant
5264435
