WO1999043678A1 - Remedies/preventives for parkinson's disease - Google Patents

Remedies/preventives for parkinson's disease

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Publication number
WO1999043678A1
WO1999043678A1 PCT/JP1999/000828 JP9900828W WO9943678A1 WO 1999043678 A1 WO1999043678 A1 WO 1999043678A1 JP 9900828 W JP9900828 W JP 9900828W WO 9943678 A1 WO9943678 A1 WO 9943678A1
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Prior art keywords
group
1h
example
substituted
lower
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PCT/JP1999/000828
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French (fr)
Japanese (ja)
Inventor
Hiroshi Tsumuki
Akiko Nakamura
Shizuo Shiozaki
Michio Ichimura
Yoshihisa Kuwana
Junichi Shimada
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Kyowa Hakko Kogyo Co., Ltd.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Abstract

Drugs for treating and/or preventing diseases induced by the hyperenergia of adenosine A2A receptor such as Parkinson's diseases which contain as the active ingredient [1,2,4]triazolo[1,5-a]pyrimidine derivatives represented by general formula (I) or physiologically acceptable salts thereof, wherein Z represents oxygen or sulfur; and R represents formula (a) (wherein Y represents oxygen, sulfur, etc.; n is an integer of from 0 to 5; and X?1, X2, and X3¿ represent each hydrogen, halogeno, lower alkyl, etc.

Description

Treatment and prevention agents the art of Akira fine manual Parkinson's disease

The present invention has an antagonistic action on adenosine A 2A receptor relates invention of a medicament useful in the treatment and Z or prophylaxis of for example Parkinson's disease. Further, the present invention relates to a novel useful as an active ingredient of the aforementioned medicament [1, 2, 4] Toriazoro [1, 5-a] pyrimidine derivatives or related salts. BACKGROUND

Adenosine, adenosine A 2A receptor via known to attenuate the effects of the neurotransmitter [® sip Bien 'journal O Bed & Famako port G. (Eur. J. Pharmacol.), 168, 285 (1989)]. Thus, substances having an antagonistic action against the adenosine A 2A receptor, each species diseases resulting from hyperactivity of adenosine A 2A receptors, such as Parkinson's disease, dementia, or as therapeutic and Z or pre Bozai for such depression usefulness of it is expected.

On the other hand, [1,2,4] Toriazoro [l, 5-a] as pyrimidine derivatives, compounds having an inhibitory effect on atherosclerotic vascular hypertrophy (JP-A 4-99775 and JP-A No. 3 118 383 No. publication), vasodilating action, hypotensive action, a platelet aggregation inhibitory action, and cholesterol lowering compounds having an action (JP 57-35592 JP), compounds that have a anti-tumor action (JP 55-51089 JP ), as well as cardiovascular diseases, particularly compounds useful for the treatment of cerebral circulatory diseases (JP-2 - 212 488 JP) is that known. However, [1, 2, 4] Toriazoro [1, 5 - a] effect on adenosine receptor antagonism and the central nervous system of pyrimidine derivatives is not known in the prior art. Incidentally, as a Toriazoropiri thymidine derivatives show efficacy against Roh one Parkinson's disease, in W095 / 03,806 specification [1, 2, 4] Toriazoro [1, 5-c] describes pyrimidine derivatives les, that <

Disclosure of the Invention

An object of the present invention has a potent adenosine A 2A receptor antagonistic activity, adenosine A 2A diseases resulting from hyperactivity of the receptor, preferably in a therapeutically effective and Z or prevention of Parkinson's disease [1, 2, 4] Toriazoro [1, is to provide a medicament comprising as 5-a] pyrimidine derivative or a physiologically acceptable salt thereof as an active ingredient. Another object of the present invention is to provide a novel [1, 2, 4] Toriazoro [l, 5-a] pyrimidine-induced, or a salt thereof having the above characteristics.

The present inventors have was subjected to resolve Subeku intensive study of the above problems is represented by the following general formula [1,2,4] triazolo [1, 5-a] pyrimidine derivative strong adenosine It has a a 2A receptor antagonistic activity and were useful as an active ingredient of a medicament for the treatment and Z or prevention of Parkinson's disease. The present invention has been accomplished on the basis of the above findings.

That is, the present invention provides the following formula (I):

(I)

Wherein, Z is an oxygen atom or a sulfur atom; R is the following formula

Wherein, Upsilon represents an oxygen atom, (wherein, R 'represents a hydrogen atom or a lower alkyl group) a sulfur atom, NR 1, or a single bond; eta represents an integer of 0 to 5; X 1 , X 2, and X 3 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an amino group, a mono- or di-lower alkylamino group, a lower § Rukanoiru group, a substituted or unsubstituted Aroiru group, a substituted or unsubstituted Ari group, a substituted or unsubstituted heterocyclic group, a hydroxyl group, or a nitro group] with represented Ru group, or the following formula:

Wherein, m represents an integer of 0 to 5; k represents an integer of 0 to 5; Q is oxygen atom, a sulfur atom, - NH -, or represents a methylene group; R 2 is a hydrogen atom, a lower alkyl group, human de proxy lower alkyl group, amino lower alkyl group, a lower alkoxy group, a lower alkyl thio group, a mono- or di-lower alkylamino group, a substituted or unsubstituted Ari group, a substituted or unsubstituted heterocyclic group, or shows one CO- R 3 (wherein, R 3 is lower alkyl, lower alkoxy, lower alkylthio group, a substituted or unsubstituted Ariru group, a substituted or shows the unsubstituted heterocyclic group) a group represented by ] represented by indicate to] a group represented by [1, 2, 4] Toriazoro [l, 5-a] salts thereof and hydrates thereof and solvates pyrimidine derivatives and physiologically acceptable material selected from the group consisting of hydrate There is provided a medicament for the treatment及beauty / or prevention of diseases resulting from hyperactivity of adenosine A 2A receptor comprising as an active ingredient. By the preferred embodiment of the invention lever, the disease said medicament is provided is Parkinson's disease.

From another aspect of the present invention, acceptable formula (I) [1, 2, 4] Toriazoro [1, 5-a] pyrimidine derivatives and physiologically for manufacture of the aforementioned medicament a salt thereof, and the use of a substance selected from the group consisting of hydrates and solvates; diseases resulting from hyperactivity of adenosine a 2A receptor, preferably the treatment of Parkinson's disease及beauty Z or prevention there are, represented by the above formula (I) [1, 2, 4] Toriazoro [1,5 - a] pyrimidine derivatives and physiologically acceptable salts thereof and hydrates thereof 及 beauty solvent the method comprises projecting Azukasuru step the treatment and / or prophylactically effective amount of a substance selected from the group consisting of hydrate in human; and, the formula (I) [1, 2, 4] Toriazoro [1, 5 - a] or pyrimidine derivatives and physiologically acceptable salts thereof, as well as their hydrates and solvates Adenosine A 2A antagonist comprises a material selected from the Ranaru group is provided. From a further aspect of the present invention, in the above formula (I), Z is oxygen atom or sulfur atom; Y is an oxygen atom, a sulfur atom, one NR 1 - (In the formula, R 1 represents a hydrogen atom or It shows a lower alkyl group), or a single bond; n is the integer 5 from 0; X 1, X 2, and X 3 are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an amino group, a mono- or di-lower alkylamino group, a lower Arukanoiru group, a substituted or unsubstituted Aroiru group, a substituted or non-replacement of Ariru group, a substituted or unsubstituted heterocyclic group, a hydroxyl group, or a nitro group (provided that X 1, X 2, and except when X 3 is a hydrogen atom simultaneously); 111 is an integer from 5 to 1; k is an integer from 5 to 0; Q is oxygen atom , sulfur atom, - NH - Or be a methylene group; R 2 Gahi Dorokishi lower alkyl group, Amino lower alkyl groups, lower-grade alkoxy group, a lower alkylthio group, a mono- or di-lower alkylamino group, a substituted or unsubstituted Ariru group, a substituted or unsubstituted heterocyclic group, or one CO- R 3 (in the formula, R 3 is lower alkyl, lower alkoxy, lower alkylthio group, a substituted or unsubstituted Ariru group, or a substituted or unsubstituted heterocyclic group) ( If however k is 0, R 2 is a group represented by not unsubstituted Ariru group), [1, 2, 4] Toriazo port [1, 5-a] pyrimidine derivative or a salt thereof It is provided as a new substance.

Meaning of the terms used herein are as follows.

Lower alkyl group, or a substituent (e.g., a lower alkoxy group, including lower alkyl moiety, lower alkylthio group, lower alkylamino group, a di-lower alkylamino group, lower grade Arukanoiru group, human Dorokishi lower alkyl group, or an amino-lower alkyl group the lower alkyl moiety in Do etc.), rather it may also be either straight or branched chain, for example, one not atoms 6, it preferably using a four alkyl Le to one free atoms can. More specifically, as the lower alkyl group, a methyl group, Echiru group, a propyl group, an isopropyl group, butyl group, sec- butyl group, or a tert- butyl group, a pentyl group, and the like cyclohexyl group neopentyl group to, It can be, in substituents which contain a lower alkyl moiety is preferably lower alkyl groups constitute a alkyl portion minutes.

Examples of "lower alkoxy group", for example, there may be mentioned main butoxy group, an ethoxy group, pro epoxy group, an isopropoxy group, a butoxy group, etc. sec- butoxy, or tert- butoxy sheet group, "lower examples of alkylthio groups ", Mechiruchi O group, and the like can be illustrated Echiruchio group, or a propylthio group, examples of the" mono-lower alkylamino group ", Mechiruamino group, Echiruamino group, propylamino group, or n- etc. can be mentioned Buchiruamino group, examples of the "di-lower alkylamino group" may include Jimechiruamino group, Jechiruamino group, or Echirume Chiruamino group and the like.

Further, examples of "lower Arukanoiru group", for example, a formyl group, Asechiru group, a propionyl group, a butyryl group, an isobutyryl group, etc. can be mentioned pivaloyl group, to Kisanoi group, examples of the "Aroiru group" it is, and the like can be given Benzoiru group, Na Futoiru group. However, these substituents is not limited to the above specific example. Halogen atom, a fluorine atom, a chlorine atom, a bromine atom, or may be any of ® © atom. Two Al Kill groups in a di-lower Arukiruamino groups may be the same or different. In human Dorokishi lower alkyl group or an amino lower alkyl group, the substitution position of a hydroxyl group or amino group present in each group is not particularly limited. Although the number of hydroxyl or amino group is not particularly limited, it is preferably one.

The Ariru group, or Ariru portion that put the substituent (e.g. Aroiru group) containing Ariru moiety, for example, monocyclic 5-membered to 14-membered ring, the use of a bicyclic, or tricyclic Ariru group can. More, specifically, as Ariru group, phenyl group, naphthyl group, indenyl group, etc. anthryl group can be used, that the substituent containing a Ariru part these Ariru groups constitute Ariru portion preferable.

The heterocyclic group may be used one or two or more heteroatoms (e.g., oxygen atom, nitrogen atom, sulfur atom, etc.) 5- to 14-membered heterocyclic ring group containing as a ring-constituting atom . Examples of the heterocyclic group include monocyclic, bicyclic, or can be used tricyclic double heterocyclic group, in addition to the aromatic heterocyclic group, can also be used partially saturated heterocyclic group . More specifically, a furyl group, a thienyl group, a pyrrolyl group, Vila group, Chiopiraniru group, a pyridyl group, Okisazoriru group, a thiazolyl group, imidazolyl group, pyridyl Mijiniru group, Toriajiniru group, indolyl group, quinolyl group, purinyl group, benzo O hexa benzotriazolyl group, a benzothiazolyl group or a base Nzoimidazo Lil groups, can be used.

Further, in the definition of the above formula (I), when for a substituent of "substituted or unsubstituted" means that the substituent is further one to two or more, preferably by one to three functional groups means that may be substituted. If the substituent has two or more functional groups, these functional groups may be the same or different. Examples of such a functional group, for example, a lower alkyl group, a halogenated lower alkyl group (chloromethyl group, such as triflate Ruo ii methyl group), human Dorokishi lower alkyl group (such as a human Dorokishimechiru group), a lower alkoxy group, a lower alkenyl group, a lower alkynyl group, a hydroxyl group, a halogen atom, a carboxyl group, a lower Arukiruoki aryloxycarbonyl group, a lower Arukanoiru group, (such as triflate Ruoroasechiru group) a halogenated lower Arukanoiru group, Ariru group, Ararukiru group (benzyl group, Bok Fuenechi Le group , 2-phenethyl, 2-phenylpropyl group, Jifuenirumechiru group, etc. Nafuchinore methyl group), Ariruokishi group, Ararukiruokishi group, Aroiru group, a heterocyclic group, an amino group, a mono- or di-lower alkylamino group, a force Rubamoiru group, Toro group, Shiano group, Mechirenjiokishi group, a lower alkylsulfinyl group, lower alkyl Rusuruhoniru group, a thiol group, or a lower alkylthio group, but such Ru can be exemplified, without being limited thereto. Further, these functional groups may further have another functional group. As such an example, specifically, mention may be made of black port phenyl group, methylcarbamoyl group, black hole base Njiru group, and alkoxybenzyl groups.

In the above formula (I), Z is an oxygen atom or a sulfur atom, Y is an oxygen atom, a sulfur atom, - NR 1 - (wherein, R 1 represents a hydrogen atom or a lower alkyl group), or a single bond It is shown. When Y represents a single bond, [1,2,4] Toriazoro [l, 5-a] pyrimidine and one (CH 2) "- it means that it is bound with the group represented by direct and are. n is 0 force, it represents an integer of al 5, when n is 0, meaning that X 1, X 2, which and a benzene ring and Y which X 3 is substituted directly bonded to. Y represents a single bond, and when n is Ru 0 Dare, X 1, X 2, and X 3 is a benzene ring substituted [1, 2, 4] Toriazoro [l, 5-a] It means that it is bound directly to the pyrimidine. Incidentally, X 1, X 2, and substituted position location of X 3 is not particularly limited, and may each be substituted at any position.

In the above formula (I), m represents an integer of 0 to 5, Q is an oxygen atom, a sulfur atom, - NH -, or is a methylene group, in the case of m force 0 includes Q it means that the ring is a 5-membered ring. One (CH 2) k - group represented by R 2, any of the ring members ring containing Q (provided that [1, 2, 4] Toriazoro [1, 5-a] directly bonded to the pyrimidine skeleton is bound to except a nitrogen atom) you, k is an integer from 0 to 5. If k is 0, it means that the R 2 TogaTadashi contact coupling with the ring constituent atoms of the ring (except for the nitrogen atom mentioned above) containing Q. Of these, one (CH 2) k - is preferably a group represented by is attached to Q.

The salt of the compound represented by the physiologically acceptable formula (I), for example, can Rukoto include metal salts, Anmoniumu salts, organic amine addition salts, amino acid addition salts, acid addition salts and the like. As the metal salt, for example, there may be mentioned sodium salts, § alkali metal salts such as potassium salts, magnesium salts, alkaline earth metal salts such as calcium salts, Al Miniumu salts, etc., as the Anmoniumu salt, Anmoniumu, tetra It may be mentioned salts such as methyl ammonium Niu beam. As, for example morpholine, the addition salts of a base such as piperidine may be mentioned, as the physiologically acceptable acid addition salts physiologically acceptable Ru organic Amin addition salts, e.g., lysine, glycine, Hue as possible out of the addition salts of amino acids such as a secondary Ruaranin. Physiologically acceptable acid addition salts, such as hydrochloride, sulfate, inorganic salts such as phosphate, acetate, maleate, fumarate, tartrate, organic acids such as Kuen salt mention may be made of salt.

The compound represented by the above formula (I), for example, can be produced according to the method disclosed in schemes shown below.

<Scheme 1>

(Μ)

(IV)

Ι-Β)

(In the scheme, X 1, χ 2, the chi · \ and Ζ the same meanings as defined above.)

The above-mentioned scheme a compound represented by 1 (I- beta) can be accordance connexion produced in the above steps 1 and 2. 1 to be able to obtain the compound (IV) by reaction with 10 equivalents of a compound in the presence in an inert solvent of a base (II) with 2 to 10 equivalents of Compound (III) (Step 1). This reaction is, for example, temperatures up to 0 ° C~ 200 ° C, preferably completed in about 10 minutes to about 50 hours at room temperature. Type of a solvent inert to the reaction is not particularly limited, for example, dimethylformamidine de, di Mechiruase Bok Ami de, N - Mechirupiro Li, dimethyl sulfoxide, Te Bok Rahi de port furan, 2-Mechizorete Torahi Dorofuran, Jiokisan , Jechinoree one Tenore, benzene, toluene, xylene, acetic Echiru § Se Tonitoriru, pyridine, dichloro methane, dichloroethane, it is suggested Etanonore, Metanonore, Purono ヽ. Roh one / Les can be used Butanonore, or the like any mixture thereof, preferably dimethyl formamidine de, or the like as tetrahydrofuran can be used. The base carbonate sodium © beam, carbonate force Li © beam, hydrogen Kana Bokuri © beam, hydrogenated force Li © beam, potassium tert- butoxide, sodium tert- butoxide, Toryechiruamin, Jiisopu port Piruechiruamin, or 1, 8- Jiazabishikuro [4, 5, 0], etc. can be used Undese 7 E emissions (DBU), preferably can be used sodium hydride, potassium carbonate, or DBU.

Then, 1 equivalent to a large excess amount of saturated compounds (IV) in a suitable solvent, preferably a compound (I- B) is obtained and is reacted with a large excess of ammonia (step 2). The solvent can have use water, methanol, ethanol, propanol, isopropanoyl no Honoré, butanol, Asetonitoriru, pyridine, dimethylformamidine de, Jimechiruase Toami de, dimethyl sulfoxide, acetic Echiru, or any mixture thereof, it can be preferably used such as ethanol or Asetonitoriru. This reaction is, for example, completed in 0 ° C~100 ° about 10 minutes to about 50 hours at a temperature of up to C.

Ku Scheme 2>

) M

Step 3

(LC)

I-B1

(In the scheme, k, m, Q, R 2, and Z have the same meanings as defined above.)

Compound (I one B) in X 1, X 2, and X 3 are each independently a hydrogen atom, a halo gen atom, or compound a nitro group (I one B 1) one equivalent to a large excess amount of compound

By reaction with (V), to give compound (I one C) (Step 3). This reaction to 1 if necessary can be carried out 10 in the presence of equivalent of base without solvent or in an inert solvent, for example, between at 0 ° C~200 ° temperature for about 10 minutes to 50 up to C completed in degree. The type of inert solvent is not particularly limited, for example, dimethyl formamide, Jimechiruase Toami de, N- Mechirupirori pyrrolidone, dimethyl sulfoxide, Te Torahi Dorofuran, 2 Mechirute Torahi Dorofuran, Jiokisan, Jefferies Chiruetenore, benzene, Tonoreen, xylene, acetic Echiru, § Se Tonitorinore, pyridine, dichloromethane, Jikuroroetan, Etanonore, Metanonore, Puroha. Nord, butanol, or the like can be used any mixture thereof, preferable properly may be used as the dimethylformamidine de or as tetrahydrofuran. As the base, for example, carbonate Natoriumu, carbonate force Riumu, hydrogenated Natoriumu, water hydride force helium, potassium tert- butoxide, sodium tert- butoxide, tri Echiruamin, diisopropyl E chill § Min, or the like can be used DBU , it can be preferably used and hydrogenated Natoriumu or DBU.

<Scheme 3>

Ar- (CH -,) - COCH 2 C0 2 Et

Step 5

(IX) (lD)

(In the scheme, Ar is X ', X 2, and shows a substituted phenylene Le group X 3, n and Z, as well as the chi', chi and X 3 have the same meanings as defined above.)

Compound (VI) and approximately equivalent amount of compound and (VII), an acidic solvent such as formic acid, acetic acid, propionic acid, preferably acetic acid, for example, whenever the temperature to heating reflux room, preferably heated at reflux in to obtain the compound (VIII) by reacting 10 minutes to 50 hours (step 4). Then, the compound (VIII) to Okishi salt phosphorous, chlorinating agent, such as chloride Chioniru, preferably obtained compound and treatment child with Okishi phosphorus chloride (IX) (Step 5). The reaction can be carried out without solvent or in an inert solvent, 1 5 with an equivalent amount of Okishi phosphorus chloride, for example, completed in about 10 minutes to about 24 hours at a temperature of room temperature - 100 ° C. The inert solvent includes, for example, Te Bok Rahi Dorofuran, Jiokisan, dichloromethane, black hole Holm, benzene, Tonoreen, xylene, acetic Echinore, triethyl Chino rare Min, pyridine, N N-dimethyl § diphosphate, or any mixture thereof or the like can be used. Subsequently, the compound (IX) with 1 equivalent to a large excess amount of saturated in a suitable solvent, preferably to give compound by reaction with a large excess of ammonia (I-D) (step 6). This reaction is, for example, completed in about 10 minutes to about 50 hours at temperatures up to 0 ° C 100 ° C. As the reaction solvent, for example, water, methanol, ethanol, Puropanonore, Isopurono. Nonore, butanol, § Se Toni DOO Rinore, pyridine, di-methyl formamidine de, Jimechiruase Toami de, dimethyl sulfoxide, acetic acid E Chi le, can be preferably used ethanol, Asetonitoriru, or etc. any mixture thereof .

<Scheme 4>

(IF) (Ι-Ε)

(In the scheme, Hal represents a halogen atom, k,, and Z have the same meanings as defined above.)

Compound (I-F) solvent-free or to 1 in an inert solvent 20 equivalents of a compound compound by reaction with (X) (I- E) can be obtained (step 7) This reaction is necessary to in response it can be carried out in the presence of 1 5 equivalents of a base, for example, completed in about 10 minutes to about 50 hours at 0 ° C 150 ° C. Type of inert solvent is not particularly limited, for example, dimethylformamidine de, dimethyl § Seth Ami de, N - Mechirubi chloride, dimethyl sulfoxide, Te Torahi Dorofuran, 2 Mechirutetorahi mud furan, Jiokisan, GETS chill ether , benzene, toluene, xylene, acetic Echiru, § Se Toni Bok Lil, pyridine, dichloromethane, Jikuroroetan, Etano Lumpur, can methanol, propanol, butanol, or be used, for example any mixture thereof, preferably dimethylformamidine it is possible to use de, pyridine, and the like Jikurorome Tan. As the base, for example, cesium carbonate, Na Bok Riumu, carbonate force Riumu, hydrogenated Natoriumu, hydrogenated force Riumu, potassium tert- butoxide, sodium tert- butoxide, Bok Ryechiruamin, Jiisopuropiru Echiruamin, etc. can be used DBU , preferably the like can be used Toriechiruamin.

<Scheme 5>

X, NH,

ΝΗ 2

Click, N (XI) X 1,

Ya. X 2 - (ΟΗ 2) Π Υ Ν Λ Ν.

Step 8

(Ι-Β1) (IG)

(Scheme, eta, gamma, and Ζ is. Compounds representing the same meaning as defined above (that put in I-B 1) Χ ι ' , Χ 2', and X 3 'are each independently a hydrogen atom, a halogen atom, or a nitro group, X 1, X 2, and X 3 in the compound (XI) and compound (I-G) have the same meanings as defined in formula (I).)

Compound (I-B 1) one equivalent to a large excess amount of Compound more compounds that react with (XI) (I- G) can be obtained. This reaction is, for example, without solvent or in an inert solvent, if necessary can be carried out 1-5 in the presence of equivalent of base at temperatures up to room temperature ~ 200 ° C, from about 10 minutes to about 50 hours in completed. Type of inert solvent is not particularly limited, for example, dimethylformamidine de, dimethyl § Seth Ami de, N- main Chirupirori pyrrolidone, dimethyl sulfoxide, as tetrahydrofuran, 2 - methyltetrahydropyran arsenide Dorofuran, di old hexane, Jechinore Etenore, benzene, Honoré Kon, xylene, 醉酸 Echiru, § Se Bok two Torinore, pyridine, Etanonore, methanol, propanol Le, butanol and the like, preferably dimethyl formamidine de, Jimechirusu sulfoxide, or any it can be a mixture of. As the base, for example, sodium © Mue butoxide, Natoriumume Tokishido, carbonate force Riumu, hydrogenated Natoriumu, hydrogenated force Riumu, potassium tert- butoxide, sodium tert- Bed Tokishido, Toryechiruamin, diisopropyl E chill § Min, or DBU, etc. it can have use of, can be preferably used hydrogenation Natoriumu.

Compounds of formula (I) can also for example, can be prepared by the method disclosed in schemes shown below.

Ku Scheme 6>

(XV) (I)

(In the scheme, Z and R are as defined above definition.)

Compound (I) can be prepared the above Step 9, according to step 1 0 and step 1 1. That is, the compound (II) and 1 to 5 equivalents of 3, 4-dimethyl Tokishibenjirua Min (XII) and the non-solvent or in a solvent inert to the reaction, usually Ot: ~ 100 ° C, preferably 0 ° C to give compound (XIII) by reacting 10 minutes to 24 hours and room temperature (step 9). The reaction is 0.1 to 5 equivalents in some cases, preferably may be added to one equivalent of base. As the base to be added, such as tri Echiruamin, diisopropyl E Ji / Reamin, DBU, N, N-dimethyl Anirin, Pi lysine, quinoline, carbonate force Riumu, carbonate Na Bok Riumu, bicarbonate Natoriumu, hydroxide of force potassium, sodium hydroxide, potassium tert- butoxide, sodium hydride and the like. Although the kind of a solvent inert to the reaction is not particularly limited, and for example, ethanol, methanol one Honoré, propanol, butanol, water, dimethyl phosphono REM Ami de, dimethyl § Seth Ami de, N- Mechirupirori pyrrolidone, dimethyl sulfoxide , as tetrahydrofuran, 2-Mechirute Torahi Dorofuran, Jiokisan, Jechirue Tenore, benzene, Tonoreen, xylene, acetic Echinore, Asetoni tolyl, pyridine, dichloromethane, dichloroethane and the like, can have use and any mixture thereof, it can be preferably used ethanol or dimethyl formamidine de like.

Then, the compound (XIII) with one equivalent to a large excess amount, preferably 2-4 (wherein, R has the same meaning as defined above.) This amount of RH compound represented by the (XIV), no solvent or in a solvent inert to the reaction, to give compounds by reacting usually from room temperature to 10 minutes to 24 hours at 150 ° C (XV) (step 1 0). The reaction of 0.5 to 10 equivalents by case, the preferably carried out by adding 2-4 equivalents of a base C., as the base added, for example Toryechiruamin, diisopropyl E Ji Ruamin, DBU, N, N - dimethyl § diphosphoric, pyridine, quinoline, potassium carbonate, Natoriumu bicarbonate Na Bok Riumu, hydroxide force Riumu, hydroxide Natoriumu forces potassium tert- butoxide, butyl lithium, sodium hydride, potassium hydride and the like like, preferably DBU, potassium carbonate, sodium hydride. Although not the kind of inert solvent is not particularly limited in the reaction, for example, ethanol, Metanonore, Puropanonore, butanol / Les, water, dimethyl phosphono REM Ami de, dimethyl Asetoami de, N- Mechirupirori pyrrolidone, dimethyl sulfoxide, Tetorahi Dorofura down, 2 - Mechinorete Torahi Dorofuran, Jiokisan, Jefferies Chino Les ether Honoré, benzene, toluene, xylene, acetic Echinore, Asetonitoriru, pyridine, dichloromethane, dichloroethane and the like, can be used as any mixture thereof, preferably it can be used ethanol, dimethyl sulfoxide or dimethyl formamidine de like.

Subsequently, compound (XV) solventless or in a suitable solvent, 1 equivalent - or treated with a large excess of a strong acid, compound by treatment with one equivalent to a large excess amount of a suitable oxidizing agent (I) can be obtained (step 1 1). If treatment with a strong acid, strong triflumizole Ruo b methanesulfonic acid as the acid to be used, Nafuion (Nafion®), triflic O b acetic acid, hydrochloric acid, include sulfuric acid, 3 to preferably triflate Ruo b methanesulfonic acid, Nafuion like 6 can be used equivalents. The reaction is usually room temperature ~ 100 ° C, rather preferably is carried out at room temperature ~ 60 ° C, completed in about 10 minutes to about 24 hours. In this case, one equivalent to a large excess amount of Anisoru, dimethyl Tokishibenzen or Bok Increment Tokishibenzen addition or the like Then it records the,. Suitable solvents to be used, acetic acid, Torifuruoro acetate, trichloroacetic acid, dichloroacetic acid, Metansunorehon acid, Etanonore, methanol, prop Nonore, Butanonore, benzene, Tonoreen, xylene, Kurorohonoremu, dichloro methane, Jikuroroetan, carbon tetrachloride, Tetorahi Dorofuran, Jefferies chill ether, Jiokisan, acetic Echiru, E chill methyl ketone, dimethylformamidine de, and the like, can be used as any mixture thereof, it can be preferably used Torifuruoro acetate. When processing with an oxidizing agent, the oxidizing agent used, 2, 3-dichloro - 5, 6 Jishiano - p - base Nzokinon (DDQ), click port Rael etc. Ageraru. The reaction is usually 0 ° C~100 ° C, preferably can be carried out at room temperature, it is completed in about 10 minutes to about 24 hours. Suitable solvents to be used, benzene, toluene, xylene, black hole Holm, dichloromethane, Jikuroroetan, carbon tetrachloride, Tetorahi de port furan, Jefferies chill ether Honoré, Jiokisan, acetic Echiru, E Chino Les methyl ketone, dimethylformamide Ami de, § Se Bok nitrile and the like, can be used etc. any mixture thereof.

Furthermore, compounds of the formula (I) can also be produced by the method for example disclosed in schemes shown below. Ku Scheme 7>

(In the scheme, Z and R are as defined above definition.)

The compound obtained in Step 9 (XIII), Step 1 1 compound is subjected to processing similar to that leads to (I one H) with (Step 1 2), the compound (I one H), Step 1 0 to obtain the compound (I) by the same manner as in (step 1 3).

Intermediates and desired compounds in each process described above, using separation and purification methods as for normal in the field of organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, and various click port Matogurafi one it can be isolated and purified Te. Further, production intermediates may also be subjected to the next reaction without purification. When producing a salt represented by reduction compounds with formula (I) may be purified as it is when the final product in the reaction step to give et be in the form of a salt, the final product is a free form If resulting et al is as a compound, the compound is dissolved or suspended in a suitable solvent, the desired product may be isolated and purified after forming the salt by adding an acid or base. Further, after converting the final product obtained in the form of a salt to the compound of free form, it may also be further converted into the desired salt les.

Among the formula (I) compounds encompassed in Table 1 are shown in Table 4, the compounds used in the present invention the following specific examples of compounds suitable as the active ingredient of the medicament of the present invention to these It is not limited (in the table, Me represents a methyl group). Table 1 The first table More

The first table More The first table More

Of the above compounds encompassed by (I), Z is oxygen atom or sulfur atom; Y is an oxygen atom, a sulfur atom, NR 1 (wherein, the R 1 is a hydrogen atom or a lower alkyl group shown), or a single bond; n is the integer 5 from 0; X 1, X 2, and X 3 are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, amino groups, mono- or di-lower alkylamino group, a lower § Rukanoiru group, a substituted or unsubstituted Aroiru group, a substituted or unsubstituted Ari group, a substituted or unsubstituted heterocyclic group, a hydroxyl group, or a nitro group ( However X 1, X 2, and except when X 3 is a hydrogen atom simultaneously); m is Ri integer der 5 from 1; k is located at 5 integer from 0; Q is an oxygen atom, a sulfur atom, - NH -, or methylene A group; R 2 Gahi Dorokishi lower alkyl group, Amino lower alkyl group, a lower alkoxy group, a lower alkylthio group, a mono- or di-lower alkylamino group, a substituted or non-substituted Ariru group, a substituted or unsubstituted heterocyclic group, or a - CO- R 3 (wherein, showing R 3 is lower alkyl, lower alkoxy, lower alkylthio group, a substituted or unsubstituted Ariru group, a substituted or unsubstituted heterocyclic group) ( However, if k is Ru 0 der compounds R 2 is a group represented by not unsubstituted Ariru group) are novel compounds.

Applications of these novel compounds provided by the present invention is not limited to use as the active ingredient of the medicament of the present invention, for applications such as intermediates for the preparation of the active ingredient and other compounds of other pharmaceutical it can be used. The scope of the present invention according to the above novel compounds, it goes without saying that such other applications are included. As for the aforementioned novel compounds, addition of any salt, such as physiologically acceptable the salt, any hydrates or solvates are also included in the scope of the present invention. The type of Solvent that forms the solvate is not particularly limited, examples thereof include ethanol, as tetrahydrofuran, di Okisan the like. Furthermore, if one or the two or more asymmetric carbon exists, Isomers in pure form, such as any of the optically active or Jiasutereo isomers, any mixtures of isomers, or racemates present invention It is included in the scope of.

The medicament of the present invention, [1, 2, 4] represented by the formula (I) Toriazoro [1, 5 - a] pyrimidine derivative conductors and physiologically acceptable salts thereof and hydrates thereof, a substance selected from the group consisting of a solvate is characterized by containing as an active ingredient, various diseases resulting from hyperactivity of adenosine emissions a 2A receptor, for example, Parkinson's disease, senile dementia, such as depression it can be used in the treatment and / or prophylaxis. Particularly preferred subject of the medicament of the present invention is Parkinson's disease. The medicament of the present invention, may be directly administering the substance as an active ingredient, but generally, pharmaceutical compositions comprising the above substance and one or more pharmaceutical additives which is an active ingredient it is desirable to administer in the form. Such pharmaceutical compositions can be prepared according to how well known or conventional per se in the field of pharmaceutics. Further, the form of pharmaceutical compositions in the pharmaceutical of the present invention, the active ingredient of other medicament may be contained one or more. Incidentally, the drug of the present invention is applicable to a mammal including human.

Administration route of the medicament of the present invention is not particularly limited, Ru can be appropriately select the most effective route of administration for either or et treatment and / or prevention of oral or parenteral administration. Oral or, can be cited for example buccal, tracheal, rectal, subcutaneous, parenteral, such as intramuscular, and intravenous. Formulation Examples of formulations suitable for oral administration, for example, tablets, granules, fine granules, powders, syrups, solutions, capsules, or the like can be mentioned suspensions, suitable for parenteral administration examples of, for example, injections, drip infusions, inhalants, sprays, suppositories, percutaneous absorption agents, and the like transmucosal absorbents.

The production of liquid preparations suitable for oral administration are, for example, water, sucrose, Sorubi' bets, sugars such as fructose, polyethylene glycol, glycidyl copolymers one Honoré such as propylene da recalls; sesame, Oribu oil, oils such as soybean oil ; preservatives such as p- arsenate Dorokishi acid esters; scan Torobe Lee flavor, can be used pharmaceutical additives, such as flavors such as peppermint. Furthermore, capsules, tablets, in the manufacture of solid preparations such as powders, or granule agent, for example, lactose, dextrose, sucrose, Man'ni' bets of any excipients; magnesium stearate; starch, disintegrants such as sodium alginate , lubricants such as Tanoreku; can be used soluble plasticizer such as glycerin; surfactants such as fatty acid esters; polyvinylidine one alcohol, hydroxycarboxylic cellulose, binders such as gelatin.

Intravascular administration preparation such as injections or drip infusions of preparations suitable for parenteral administration may be formulated with an aqueous medium of good Mashikuwahi preparative isotonic with blood. For example, note Ysaÿe a salt solution, with water 4 medium selected from a mixture of glucose solution, or salt water and a glucose solution, a solution with suitable auxiliaries according to a conventional method, suspension, or dispersion and to prepare can do. Suppositories for enteral administration can be prepared, for example, cocoa butter, carriers such as hydrogenated fats or hydrogenated carboxylic acid Yore, Te. Sprays as possible out be prepared with carriers that can facilitate absorption dispersed does not stimulate oral and airway mucous membrane of the human Bok, and the above compound as an active ingredient as fine particles child . Such carriers include, for example, can be used such as lactose or glycerol. By the material and using the nature of the carrier as an active ingredient, it can be prepared as a preparation in the form of aerosols or de Raibauda. The preparation of formulations for parenteral, e.g., diluents, fragrances, preservatives, excipients, disintegrating agents, lubricants, binders, surfactants, one or more selected from plasticizers the pharmaceutical additives can and Mochiiruko.

The dosage and frequency of administration of the medicament of the present invention is not particularly limited, the type of the substance as an active ingredient, route of administration, the treatment and Roh or prophylactic purposes, the patient's age and weight, the nature and severity of the condition It can be appropriately selected depending on various conditions such as. For example, preferably administered in divided adult per day l~50mgZkg a 3-4 times. BEST MODE FOR CARRYING OUT THE INVENTION

Following is a more detailed explanation of the present invention through examples, but the scope of the present invention is not limited to these examples. In addition, the numbers of the compounds in the following examples Ru Oh in correspondence with the numbers of the compounds exemplified as preferred compounds in Tables 1 to 4 (EtOH represents ethanol). Example 1 (Reference Example): 5, 7 - dihydric Dorokishi 2- (2 - furyl) [1, 2, 4] Preparative Riazoro [1, 5 - a] Pi Li thymidine [Compound (1)]

Sodium hydride 3.0 was added ° C Deyutsuku Ri in ethanol 100 ml and 2 g (80 mmol). Then malonic acid Jechiru 12. 2 ml of this suspension (80 mmol), 3 were synthesized by the method described in JP-A-5 97,855 - Amino-5- (2-furyl) - 1, 2, 4 - after addition of bets Riazor 12 g (80 顏 ol), and the mixture was heated under reflux for 7 hours. The reaction was filtered and the precipitated solid was added ether returned to room temperature. The resulting solid washed with ether, dried, dissolved in water 200 ml. pH by the addition of concentrated hydrochloric acid to the solution was adjusted to be about 4. At 0 ° C was collected by filtration while standing precipitated solid. The resulting solid was washed with water, E one ether and then dried to the title compound (1) 12.4 g

(Yield: 71%) as a white solid.

Ή negation R (DMS0- d 6, δ ppm ): 7.90-7.75 (m, 1H), 7.08-6.79 (m, 1H), 6.70- 6.57 (m, 1H), 5.08 (s (br), 1H)

MS (m / e): 218 (M +) Example 2 (Reference Example): 5,7-dichloro - 2 - (2 - furyl) [l, 2,4] Toriazoro [1,5-a] pyrimidone Jin [compound (2)]

Example compound obtained in 1 (1) 20 g (91.7 employment ol) was heated at reflux for 4 hours in Okishi phosphorus chloride 50 ml of. The reaction was warmed to room temperature and the solvent was cast entering into ice water and the residue was distilled off under reduced pressure. As a pale brown solid: The precipitated solid was collected by filtration, washed with water to yield by drying (2) 15.1 g (73% yield).

¾ NMR (CDC1 3, δ ppm ): 7.66 (t, J = l.0Hz, 1H), 7.35 (t, J = 3.5Hz, 1H), 7.22 (s, 1H), 6.62 (dd, J = 3.5Hz , 1.5Hz, 1H)

MS (m / e): 256 , 254 (M +) Example 3 (Reference Example): 2- (2-furyl) - 5, 7 - Jifuenokishi [1,2, 4] Toriazoro [1,5-a] Pi Li spermidine [compound (3)]

Dissolved phenol 13.8 g of (147 mmol) in as tetrahydrofuran (THF), the solution of sodium hydride 5.88 g (147 mmol) Oyutsuku Ri was added., Then the compound obtained in Example 2 (2) 15 g ( 58.8 negation 0 1) was heated under reflux for 4 hours added. The reaction Ether was added back to room temperature, the precipitated solid was collected by filtration. Ether obtained solid was washed with water, then the title compound by drying (3) 26.8 g: (yield quantitative) as a white solid.

Ή NMR (DMS0- d 6, δ ppm): 7.65-7.13 (m, 12H), 6.59 - 6.54 (m, 1H), 5.82 (s, 1H) MS (m / e): 370 (M +) Example 4 (reference example): 7-Amino - 2- (2-furyl) - 5- phenoxy [1, 2, 4] Bok Riazoro [1, 5 - a] pyrimidine [compound (4)]

The compound obtained in Example 3 (3) 500 mg (1.39 mmol) in Asetonitoriru 10 ml, the § Nmonia 10 ml water was added, and the mixture was stirred for 5 hours at 40 ° C. The solvent was evaporated, and extracted by adding black port Holm and water to the residue. The organic layer was Drying over anhydrous magnesium sulfate and the solvent was distilled off, the residue was recrystallized from ethanol the title compound (4) 255 mg (yield: 62%) was obtained as a white solid.

'Η NMR (DMS0 - d 6 , δ ppm): 8.10 (s (br), 2H), 7.88 (d, J = 0.7Hz, 1H), 7.50- 7.21 (m, 5H), 7.06 (t, J = l.0Hz, 1H), 6.68 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.79 (s, 1H)

MS (m / e) 293 ( M +)

IR (KBr; cm "1) : 1649, 1600, 1585, 1564, 1461, 1322

Mp: 208.9-210.5 ° C Example 5 (Reference Example): 2- (2-furyl) - 5, 7-bis (2, 4-dichloro-phenoxyethanol) [1, 2,4] tri Azoro [1, 5 - a] pyrimidine [compound (5)]

The compound obtained in Example 2 (2) and 2, 4 - dichloro port phenol of Yore ,, Example 3 with title compound was synthesized in analogy (5) (yield: 58%) as a pale brown solid,

Ή NMR (CDC1 3, δ ppm ): 7.65-7.15 (m, 8H), 6.55 (dd, J = 3.5Hz, 2.0Hz, 1H), 5.81 (s, 1H)

MS (m / e): 507 (M +) Example 6 (Example): 7-Amino - 5- (2, 4-dichloro-off We Roh carboxymethyl) -2- (2-furyl) [1,2, 4 ] Toriazoro [1, 5-a] pyrimidine [compound (6)]

The compound obtained in Example 5 using (5), the title compound was prepared in analogy to Example 4 (6) (yield: 95%) was obtained as a pale yellow solid.

'Η NMR (DMSO- d 6, δ ppm): 8.22 (s (br), 2H), 7.88 (d, J = l.5Hz, 1H), 7.81 (d, J = 2.5Hz, 1H), 7.53 ( dd, J = 9.1Hz, 2.5Hz, 1H), 7.44 (d, J = 8.4Hz, 1H), 7.05 (d, J = 3.0Hz, 1H), 6.68 (dd, J = 3.5Hz, 2.0Hz, 1H ), 5.91 (s, 1H)

MS (m / e): 361 (M +)

IR (KBr; cm "1) : 1654, 1604, 1571, 1459

Mp:> 290 ° C Example 7 (Reference Example): 2 - (2-furyl) - 5, 7-bis (2, 4, 6-trichloro port phenoxy) [1, 2, 4] Toriazoro [1, 5- a] pyrimidine [compound (7)]

The compound obtained in Example 2 and (2) using 2,4,6-trichloro-off We Nord, the title compound was prepared in analogy to Example 3 (7) (yield: 49%) as a pale brown solid.

¾ NMR (DMSO- d 6, δ ppm): 7.65-7.15 (m, 8H), 6.55 (dd, J = 3.5Hz, 2.0Hz, 1H), 5.81 (s, 1H)

MS (m / e): 577 (M +) Example 8 (Example): 7 § Mi Bruno - 2 - (2-unfavorable Le) - 5- (2, 4, 6-Application Benefits black port Fuenoki sheet) [1,2, 4] Toriazoro [1, 5-a] pyrimidine [compound (8)]

The compound obtained in Example 7 using (7), the title compound was prepared in analogy to Example 4 (8) (yield: 59%) as a pale yellow solid:

¾ NMR (DMSO- d 6, δ ppm): 8.51 (s (br), 2H), 7.92 (d, J = l.0Hz, 1H), 7.18 (d,

J = 3.5Hz, 1H), 6.71 (dd, J = 3.5Hz, 2.0Hz, 1H), 6.27 (s, 1H)

MS (m / e): 395 (M +)

IR (KBr; cm "1) : 1645, 1594, 1326

Mp:> 290 ° C Example 9 (Reference Example): 2- (2-furyl) - 7-arsenide Dorokishi - 5- phenyl [1,2, 4] Toriazoro [1,5-a] pyrimidine [Compound (9 )]

3-Amino - 5- (2 - furyl) - 1,2, 4-preparative Riazo Ichiru 3 g of (20 mmol) and Benzoiru acetic acid Echiru 3.64 ml (21 negation ol) in acetic acid 30 ml, at 120 ° C and the mixture was stirred for 12 hours. The reaction mixture was allowed to warm to room temperature and extracted by adding black port Holm and water. The organic layer was dried over anhydrous sulfate Ma Guneshiumu title compound by distilling off the solvent (9) 2.78 g (yield: 50%).

Ή NMR (DMS0-d 6, δ ppm): 7.95- 7.86 (m, 3H), 7.60-7.52 (m, 3H), 7.16 (s (br), 1H), 6.72 (s (br), 1H), 6.34 (s, 1H)

MS (m / e): 278 (M +) Example 10 (Reference Example): 7-Chloro - 2- (2 - furyl) - 5 - Fuweniru [1,2, 4] Toriazoro [1,5-a] pyridinium Mi jin [compound (10)]

The compound obtained in Example 9 (9) was heated at reflux for 1.3 g (4.67 Yuzuru ol) the Okishi phosphorus chloride 15 ml of. The reaction was poured into ice water returned to room temperature, the precipitated solid was collected by filtration. The resulting solid washed with water and dried to the title compound (10) 1.27 g (yield: 92%).Ή NMR (DMS0-d 6, δ ppm): 8.40- 8.31 (m, 3H), 7.99 (d, J = l.0Hz, 1H), 7.63- 7.58 (m, 3H), 7.32 (d, J = 3.5 Hz, 1H), 6.76 (dd, J = 3.5Hz, 2.0Hz, 1H)

MS (m / e): 298 , 296 (M +) Example 11 (Reference Example): 7 - Amino - 2 - (2-furyl) - 5 - phenyl [1, 2, 4] Toriazoro [1,5-a ] pyrimidine [compound (11)]

The compound obtained in Example 10 (10) was heated to reflux for 3 hours 690 mg of (2.33 mmol) in ethanol saturated with ammonia. After evaporating the solvent, it was added to the residue black port Holm and water extraction. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off, the residue was recrystallized from ethanol the title compound (11) 380 mg (yield: 59%) was obtained.¾ NMR (DMS0- d 6, δ ppm): 8.23 (s (br), 2H), 8.08-8.04 (m, 2H), 7.93 (t, Jl.0Hz, 1H), 7.59-7.49 (m, 3H) , 7.18 (d, J = 3.0Hz, 1H), 6.79 (s, 1H), 6.72 (dd, J = 3.5Hz, 1.5Hz, 1H)

MS (m / e): 277 (M +)

IR (KBr; cm- Ri: 1643, 1637, 1592, 1968, 1384

Mp:> 270 ° C (decomposition) Example 12 (Example): 7 A Mi Roh - 5 - (3, 4 - dimethyl Tokishifuwe Bruno carboxymethyl) - 2- (2-unfavorable le) [1,2, 4 ] Toriazoro [1, 5-a] pyrimidine (compound 12)

3, 4 - the dimethyl Bok Kishifuenoru L17 g (7.58 mmol) was dissolved in dimethyl formamidine de (DMF) 15 ml, sodium hydride 404 mg of (10.12 mmol) was added Ri 0 ° C Deyutsuku. Then, the compound obtained in Example 8 (8) 1.0 g (2.53 mmol) was added to the mixture and stirred for 4 hours at 100 ° C. The reaction was allowed to warm to room temperature, water and then extracted by adding black port Hol beam. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off and the resultant residue using silica gel column chromatography was purified by (eluent black opening formal beam). The resulting solid was washed with ethanol the title compound (12) 1.0 g: (yield quantitative).

'Η NMR (DMS0-d 6 ) δ ppm): 8.08 (s (br), 1H), 7.89 (d, J = l.0Hz, 1H), 7.08- 6.67 (m, 5H), 5.73 (s, 1H ), 3.79 (s, 3H), 3.75 (s, 3H)

MS (m / e): 353 (M +)

IR (KBr; cm "1) : 1637, 1589, 1564, 1461, 1400

Mp: 263.5-264.5 ° C Example 13 (Example): 7-Amino - 2- (2-furyl) - 5- (4-Hue Yul phenoxy) [1, 2, 4] Toriazoro [1, 5 - a] pyrimidine [compound (13)]

4 Fuenirufueno one Honoré 1.29 g of (7.59 mmol) were dissolved in DMF 15 ml, hydrogen Kana thorium 404 mg of (10.12 mmol) was added Ri 0 ° C Deyutsuku. Then, the compound obtained in Example 8 (8) 1.0 g (2.53 mmol) was added to the mixture and stirred for 3 hours at 100 ° C. The reaction mixture was returned to room temperature, water and then extracted by adding black port Holm. The organic layer was dried over anhydrous magnesium sulfate, the solvent recrystallized from DMF- water evaporated to the resulting residue to the title compound (13) 580 mg (yield: 62%) was obtained "

Ή NMR (DMS0- d 6, δ pm): 8.15 (s (br), 2H), 7.89 (t, J = l.0Hz, 1H), 7.77-

7.69 (m, 4H), 7.52-7.30 (m, 5H), 7.07 (d, J = 3.3Hz, 1H), 6.68 (dd, J = 3.6Hz,

2.0Hz, 1H), 5.84 (s, 1H)

MS (m / e): 369 (M +)

IR (KBr; cm "1) : 1662, 1654, 1604, 1560, 1216

Mp:> 290 ° C Example 14 (Reference Example): 7 - Amino - 5 Benjiruokishi - 2- (2 - furyl) [1, 2, 4] Toriazoro [l, 5-a] pyrimidine [Compound (14) ]

Using a compound (8) 0.8 g preparative base down benzyl alcohol 0.63 ml obtained in Example 8, the title compound was obtained in analogy to Example 12 (14) (yield: 90%) was obtained.

¾ NMR (DMS0-d 6) δ ppm): 7.89 (s (br), 2H), 7.48-7.31 (m, 6H), 7.09 (d, J = 3.3Hz, 1H), 6.70 (dd, J = 3.3 Hz, 1.7Hz, 1H), 5.68 (s, 1H), 5.40 (s, 2H) MS (m / e): 307 (M +)

IR (KBr; cm- 1): 1654, 1608, 1473, 1336

Mp: 251.5-253.0 ° C Example 15 (Reference Example): 7 § Mi Bruno - 2- (2-off Lil) - 5 - Moruhori Bruno [1,2,4] Preparative Riazoro [1,5-a] pyridinium Mi jin [compound (14)]

Example compound obtained in 4 (4) 0.8 g of (2.73 negation ol) was dissolved in morpholine 5 ml, it was heated overnight under reflux with DBU 0.45 ml. The solvent was distilled off under reduced pressure, the residue added to E one Te Le, and the precipitated solid was collected by filtration. The obtained solid was washed with ether, the title compound was recrystallized from Etano Lumpur (15) (yield: 52%) was obtained.

lH NMR (DMSO- d 6, δ ppm): 7.85 (. t, J = l OHz, 1H), 7.52 (s (br), 2H), 7.02 (d, J = 4.0Hz, 1H), 6.66 (dd , J = 3.5Hz, 2. OHz, 1H), 5.66 (s, 1H), 3.69 (t, J = 4.0Hz, 4H), 3.52 (t, J = 4.6Hz, 4H)

MS (m / e): 286 (M +)

IR (KBr; cm "1) : 1654, 1604, 1569, 1490

Mp:> 290 ° C Example 16 (Reference Example): 7-Amino - 2- (2 - furyl) - 5- (4-methyl-bi Bae pyrazinyl) [2,4] Preparative Riazoro [1, 5- a] pyrimidine hydrochloride [compound (16)]

The compound obtained in Example 4 (4) 1.0 g (3.41 mmol) and N - using the Mechirubiperajin 5 ml, in the same manner as in Example 15 7-Amino - 2 - (2-furyl) -5- (4 - Mechirubiperaji sulfonyl ) [1, 2,4] Toriazo port [1, 5-a] pyrimidine 600 mg (yield: 59%). Resulting et a 7-Amino - 2 - (2-furyl) - 5- (4-methyl-bi Bae pyrazinyl) [1, 2, 4] Toriazoro [l, 5_A] pyrimidine 600 mg of (2.10 mmol) 4N It was stirred for 30 minutes with hydrochloric acid in one acetate Echiru. The solvent was evaporated, the solid was collected by filtration precipitated by adding ether to the residue. The resulting solid was dried title compound (16) 303 mg (yield: 25%, 2 steps).

¾ NMR (DMS0-d 6) δ ppm): 7.90 (d, J = l.5Hz, 1H), 7.81 (s (br), 2H), 7.13 (d, J = 3.5Hz, 1H), 6.69 (dd , J = 3.5Hz, 1.5Hz, 1H), 5.81 (s, 1H), 4.40-4.34 (m, 2H), 3.58-3.38 (m, 4H), 3.16-3.03 (m, 2H), 2.76 (d ( br), J = 4.0Hz, 3H)

MS (m / e): 299 (W)

IR (KBr; cm "1) : 1647, 1604, 1575, 1519

Mp: 224.0-226.5 ° C Example 17 (Reference Example): 7-Amino - 2- (2 - furyl) - 5- (4-off We two ruby ​​Bae pyrazinyl) [1, 2,4] Toriazoro [1, 5-a] pyrimidine [compound (17)]

Example compound obtained in 6 (6) was dissolved 800 mg of (2.21 mmol) dimethyl sulfoxide (DMS0) in 5 ml, N-phenylene Rubiperajin 1.07 ml (6.65 mmol) and DBU0.3 ml of (2.21 negation ol) was added and stirred for 6 hours at 140 ° C Te. The reaction mixture was allowed to warm to room temperature and extracted by adding black port Holm and 1N aqueous sodium hydroxide solution. The organic layer was dried over anhydrous magnesium sulfate, the solvent was purified residue obtained by removing at silica gel column chromatography scratch, the resulting purified product was recrystallized from ethanol notation compound (17) 430 mg (yield: 54%) was obtained.

Ή NMR (DMS0 - d 6, δ ppm): 7.86 (s, 1H), 7.52 (s (br), 2H), 7.28- 7.21 (m, 2H), 7.04-6.97 (m, 3H), 6.81 (t , J = 6.9Hz, 1H), 6.67 (dd, J = 3.3Hz, 1.7Hz, 1H),

5.71 (s, 1H), 3.79-3.69 (m, 4H), 3.28-3.21 (m, 4H) '

MS (m / e): 361 (M +)

IR (KBr; cm-: 1658, 1598, 1502, 1490

Mp: 277.5-280.0 ° C Example 18 (Reference Example): 7-Amino - 2- (2-furyl) - 5- piperazinyl [1,2,4] Preparative Riazoro [1,5-a] pyrimidine hydrochloride [compound (18)]

The compound obtained in Example 26 (26) 2.03 g (5.27 mmol) in 4N HCl one 1, was added to 4-Jiokisa down, the suspension was stirred at room temperature for 4 hours. After completion of the reaction, ether was added to the reaction mixture, and the precipitated solid was collected by filtration. After washing the solid with ether, dried under reduced pressure to give compound (18) 1.70 g: (yield quantitative).

¾ NMR (DMSO- d 6, δ ppm): 7.93 (t, J = 0.7Hz, 1H), 7.16 (d, J = 3.3Hz, 1H),

6.73 (dd, J = l.7Hz, 0.7Hz, 1H), 5.76 (s, 1H), 3.91-3.81 (m, 4H), 3 · 24 - 3.15 (m, 4H)

MS (ra / e): 361 (M +) Example 19 (Example): 7-Amino - 5- (4-benzyl-piperazinyl) -2- (2-furyl) [1,2, 4] Toriazoro [ 1, 5-a] pyrimidine [compound (19)]

The compound obtained in Example 6 (6) 800 mg (2.21 mmol) were dissolved in DMSO 5 ml, N-base Njirubiperajin L73 ml (9.94 mmol), was added to DBU 0.33 ml (2.21 mmol), the mixture 140 ° and the mixture was stirred overnight at C. The reaction mixture was allowed to warm to room temperature and extracted by adding water, the black hole Holm. The organic layer was washed with saturated brine and dried over anhydrous sulfate Ma. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography one (eluent: 1% methanol one black port Holm) to afford the resulting purified product ethanol one isopropyl ether (1: 5) from recrystallization title compound (19) 275 mg (yield: 33%) as a brown solid.

ΐ 丽 R (CDC1 ,, δ ppm): 7.56 (d, J = l.7Hz, 1H), 7.35- 7.30 (m, 5H), 7.17 (d, J = 3.3Hz, 1H), 6.54 (d, J = 3.3Hz, 1H), 5.55 (s, 1H), 5.33 (s (br), 2H), 3.72 (s (br), 4H), 3.56 (s (br), 2H), 2.53 (s (br) , 4H)

MS (m / e): 375 (M +)

IR (KBr, cm "1) : 2371, 1651, 1604, 1564, 1244

Mp:> 230 ° C (decomposition)

As C 20 H 21 N 7 0 0.2H 2 0 0.3Et0H: Elemental analysis

Found (%): C 62.99, H 5.77, N 25.05

Calculated (%): C 62.98, H 5.96, N 24.96 Example 20 (Example): 7 - § Mi Bruno - 2- (2-off Lil) - 5- (4-piperidines Ronirubiperajini le) [1,2 , 4] Toriazoro [1, 5 - a] pyrimidine [compound (20)]

N - using piperidines Ronirubiperajin title compound was prepared in analogy to Example 19 (20) (yield: 73%) was obtained as a brown solid.

Ή NMR (CDC1 3, δ ppm ): 7.56 (d, J = l.7Hz, 1H), 7.35-7.30 (m, 5H), 7.17 (d, J = 3.3Hz, 1H), 6.54 (d, J = 3.3Hz, 1H), 5.55 (s, 1H), 5.33 (s (br), 2H), 3.72 (s (br), 4H), 3.56 (s (br), 2H), 2.53 (s (br), 4H)

MS (m / e): 419 (M +)

IR (KBr, cm "1) : 3302, 2380, 1556, 1512, 1462, 1383

Mp: 265.5-267.0 ° C

As C 21 H 21 N 7 0 3 0.1¾0 0.2EtOH: Elemental analysis

Found (%): C 59.79, H 5.12, N 22.83

Calculated (%): C 59.71, H 5.24, N 22.78 Example 21 (Example): 7 - Amino - 5- [4- (3, 4-dimethyl Tokishibenjiru) piperidines Rajuru] -2 - (2-furyl ) [2,4] Toriazoro [1, 5 - a] pyrimidine [compound (21)]

Using N-(3,4-dimethyl Tokishibenjiru) piperidines Rajin, title of compounds in the same manner as in Example 19 (21) (yield: 85%) as a yellow solid:.

lH NMR (CDC1 3, δ ppm ): 7.56 (s, 1H), 7.18 (d, J = 3.3Hz, 1H), 6.88 (s, 1H), 6.76 (s, 2H), 6.54 (dd, J = 3.3 Hz, 1.7Hz, 1H), 6.00 (s, 2H), 5.56 (s, 1H), 5.34 (s, 2H), 3.70 - 3.68 (m, 4H), 3.45 (s, 2H), 2.51-2.48 (m , 4H)

MS (m / e): 435 (M +)

IR (KBr, cm- 1): 3446, 2366, 1649, 1560, 1230

Mp: 223.4-224.5 ° C

As C 22 H 25 N 7 0 3 : Elemental analysis

Found (%): C 60.38, H 5.92, N 22.12

Calculated (%): C 60.68, H 5.79, N 22.51 Example 22 (Example) · 7 § Mi Bruno - 5- [4- (4 - Anishiru) piperidines Rajuru] - 2- (2-off Li Le) [1,2, 4] Toriazoro [1, 5-a] pyrimidine [compound (22)]

N - (4 - Anishiru) with piperidines Rajin title compound was prepared in analogy to Example 19 (22): was obtained (yield quantitative) as a yellow solid:.

'Η NMR (CDC1 3, δ ppm): 7.57 (s, 1H), 7.19 (d, J = 3.3Hz, 1H), 6.95-6.84 (m, 4H), 6.55 (dd, J = 3.3Hz, 1.7Hz , 1H), 5.63 (s, 1H), 5.41 (s (br), 2H), 3.89- 3.85 (m, 4H), 3.78 (s, 3H), 3.16 - 3.12 (m, 4H)

MS (m / e): 391 (M +)

IR (KBr, cm "1) : 3115, 2382, 1655, 1601, 1570, 1508

Mp: 280.0-281.8 ° C

As C 20 H 21 N 7 0 2 0.2H 2 0: Elemental analysis

Found (%): C 61.02, H 5.50, N 24.52 Calculated (%): C 60.81, H 5.46, N 24.82 Example 23 (Example): 7-Amino - 2- (2-furyl) -5- [ 4 - (2 - pyridyl Mijiniru) piperidines Raju Le] [1,2, 4] Toriazoro [l, 5-a] pyrimidine [compound (23)]

N-- using (2 pyridinium Mijiniru) piperidines Rajin title compound was prepared in analogy to Example 19 (23) (yield: 62%) was obtained as a brown solid.

Ή NMR (CDC1 3, δ ppm ): 8.34 (d, J = 4.6Hz, 2H), 7.57 (t, J = l.0Hz, 1H), 7.19 (d, J = 3.3Hz, 1H), 6.56-6.53 (m, 1H), 5.61 (s, 1H), 5.40 (s (br), 2H), 3.97-3.93 (m, 4H), 3.84-3.81 (m, 4H)

MS (m / e): 363 (M +)

IR (KBr, cm- '): 3157, 2382, 1650, 1589, 1489, 1238

Mp:> 291 ° C Example 24 (Example): 7-amino - 2- (2-furyl) - 5- [4- (2-menu Tokishechiru) piperazinyl Le] [1,2, 4] Toriazoro [1, 5-a] pyrimidine (compound 24)

Using N-(2-menu Tokishechiru) piperidines Rajin title compound was prepared in analogy to Example 19 (24) (yield: 54%) as a yellow solid.

Ή NMR (CDC1 3) δ ppm ): 7.56 (s, 1H), 7.18 (d, J = 3.3Hz, 1H), 6.55 (dd, J-3.3Hz, 1.7Hz, 1H), 5.58 (s, 1H) , 5.41 (s (br), 2H), 3.77 (s (br), 4H), 3.57 (t, J = 5.3Hz, 2H), 3.37 (s, 3H), 2.63 (s (br), 6H)

MS (m / e): 343 (M +)

IR (KBr, cm "1) : 3160, 2384, 1661, 1606, 1560

Melting point: 163.5-165.5

Elemental analysis: as hexanes C 16 H 21 N 7 0 2 0.4H 2 0 0.1

Found (%): C 55.19, H 6.61, N 27.49

Calculated (%): C 55.51, H 6.51, N 27.30 Example 25 (Example): 7-Amino - 2- (2-furyl) - 5- [4- (3 - off Nirupuropiru) piperazine sulfonyl] [1, 2, 4] Toriazoro [1,5-a] pyrimidine [compound (25)]

With N- (3- phenylpropyl) piperidines Rajin title compound was prepared in analogy to Example 19 (25) (yield: 68%) was obtained as a brown solid.

¾ NMR (DMSO- d 6, δ ppm): 7.84 (s, 1H), 7.45 (s (br), 2H), 7.28 - 7.17 (m, 5H), 7.01 (d, J-3.3Hz, 1H), 6.66 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.65 (s, 1H), 3.55 (s (br), 4H), 2.65-2.59 (m, 2H), 2.43 (s (br), 4H) , 2.35-2.30 (m, 2H), 1.77 (s (br), 2H)

MS (m / e): 403 (M +)

IR (KBr, cm "1) : 3383, 2366, 1645, 1604, 1574

Mp: 165.0-167.5 ° C Example 26 (Example): 7-Amino - 2- (2-furyl) - 5-[4 - (tert-butoxycarbonyl) pin Perajiniru] [1,2, 4] Toriazoro [1 , 5-a] pyrimidine [compound (26)]

Using N- (tert- butoxycarbonyl) piperidines Rajin to give title of compounds in the same manner as in Example 19 (26) as a white solid.

Yield: 44%

Ή NMR (DMS0-d 6, δ ppm): 7.85 (. T, J = l OHz, 1H), 7.53 (s (br), 2H), 7.02 (d, J = 3.3Hz, 1H), 6.67 (dd , J = 3.3Hz, 1.7Hz, 1H), 5.64 (s, 1H), 3.57 (s (br), 4H), 3.44 (s (br), 4H), 1.43 (s, 9H)

MS (FAB): 386 (M + l)

IR (KBr, cm "1) : 3151, 2910, 2384, 1653, 1568, 1414, 1232

Mp: 223.4-224.5 ° C

As C 8 H 23 N 7 0 3 0.1H 2 0: elemental analysis!

Found (%): C 55.82, H 6.12, N 25.02

Calculated (%): C 55.83, H 6.04, N 25.32 Example 27 (Example): 7-Amino - 2- (2-furyl) - 5- {4- [2- (4-Furuo port base Nzoiru) E chill] piperazinyl} [1,2,4] Toriazoro [1,5-a] pyrimidine [compound (27)] the compound obtained in example 18 (18) 500 mg (1.55 thigh ol) was dissolved in 10 ml of ethanol and stirred for 5 minutes at room temperature by addition of carbonate Kariumu 860 mg (6.22 negation ol) to the solution. Then it stirred N- [2- (4- Full O b benzo I le) Echiru] 5 hours at room temperature was added a piperidines Rajin 870 mg (4.66 thigh ol). After completion of the reaction, and extracted by adding black port Holm and water to the reaction mixture. After drying the organic phase over anhydrous magnesium sulfate, the solvent was distilled off and the resultant residue using silica force gel strength column chromatography was purified by (eluent of 4% methanol one Roux chloroform), the resulting purified product title compound was recrystallized from ethanol (27) 151 mg (yield: 22%) was obtained.

Ή MR (DMS0 - d 6, δ ppm): 8.12- 8.01 (m, 2H), 7.85 (dd, J = l.7Hz, 1.0Hz, 1H), 7.48 (s (br), 2H), 7.39- 7.33 (m, 2H), 7.00 (d, J = 3.3Hz, 1H), 6.67 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.65 (s, 1H), 3.54 (s (br), 4H), 3.34 (s (br), 4H), 3.28-3.23 (m, 2H), 2.75- 2.73 (m, 2H)

MS (FAB): 436 (M + l)

IR (KBr, cm "1) : 3152, 2839, 2375, 1660, 1599, 1574

Mp: 199.4-202.5 ° C

As C 22 H 22 N 7 0 2 F 0.2H 2 0 0. lEtOH: Elemental analysis

Found (%): C 60.04, H 5.12, N 22.07

Calculated (%): C 60.10, H 5.22, N 22.10 Example 28 (Example): 7-Amino - 2- (2 - furyl) -5- {4- [4- (4-Furuo port base Nzoiru) Bed chill] piperazinyl} [1,2,4] Toriazoro [1,5-a] pyrimidine [compound (28)]

Using N-[4-(4-Full O b benzo I le) butyl] piperidines Rajin title compound was prepared in analogy to Example 27 (28) (yield: 19%) was obtained as a pale yellow solid.

¾ NMR (CDC1 3, δ ppm ): 8.01-7.97 (m, 2H), 7.56 (. D, J = l OHz, 1H), 7.18- 7.01 (m, 3H), 6.54 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.56 (s, 1H), 5.33 (s (br), 1H), 3.71-3.01 (m, 4H), 2.99- 2.96 (m, 2H), 2.53-2.49 (m, 4H), 2.45-2.40 (m, 2H), 1.82-1.76 (m, 2H)

MS (m / e): 463 (M +)

IR (KBr, cm "1) : 3295, 2955, 2384, 1647, 1599, 1560, 1232

Mp: 204.3-206.0 ° C

As C 24 H 26 N 7 0 2 F: Elemental analysis

Found (%): C 62.01, H 5.91, N 20.84

Calculated (%): C 62.19, H 5.65, N 21.15 Example 29 (Reference Example): 5 - Black hole - 7 - (3, 4-dimethyl-butoxy benzyl § Mi Roh) -2 - (2-pretended Le) [ 1,2, 4] Toriazoro [1, 5-a] pyrimidine [compound (29)]

The compound obtained in Example 2 (2) 17.4 g of (68.3 mmol) was suspended in ethanol 180 ml, was added with stirring Bella Toriruamin 30.9 ml at 0 ° C (205 negation ol). Anti JSAP was stirred for 2 hours returned to room temperature. The solvent was distilled off under reduced pressure, added black port Holm, dilute hydrochloric acid, then washed with water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent the title compound was distilled off under reduced pressure (29) 22.7 g (yield: 86%) as a white powder.

'H NMR (CDC1 3, δ ppm): 7.58 (. T, J = l OHz, 1H), 7.25 (d, J two 3.6Hz, 1H), 6.95-6.85 (m , 3H), 6.70 - 6.64 (m , 1H), 6.56 (dd, J = 3.6, 2. OHz, 1H), 6.21 (s, 1H), 4.53 (d, J = 5.6Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H )

MS (m / e): 387, 385 (W) Example 30 (Reference Example): 7- (3, 4-dimethyl-butoxy benzyl § Mi Roh) - 5 - [4- (4 - Kurorofuwe two Honoré) piperazinyl] - 2- (2-furyl) [1,2, 4] preparative Riazoro [1, 5-a] pyrimidine [compound (30)]

The compound obtained in Example 29 (29) 800 mg (2.08 mmol), 1 -. (4 - chlorophyll: ^ sulfonyl) pin Perazine dihydrochloride 2.24 g (8.32 mmol), and DBU 2.31 ml (16.6 mmol) of E pentanol was dissolved in 35 ml, it was heated under reflux overnight. The reaction was brought to room temperature, extracted added black port Hol arm and water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced distillation, silica gel column chromatography (elution solvent: 20% hexane monoacetate E chill) to give the title compound (32) 638 mg (yield: 56%) was obtained.

¾ NMR (CDC1 3, δ ppm ): 7.54 (s, 1H), 7.26-7.17 (m, 3H), 6 · 94- 9.80 (m, 5H), 6.54 (dd, J = 3.6Hz, 2.0Hz, 1H ), 6.25 (t, J = 5.3Hz, 1H), 5.41 (s, 1H), 4.47 (d, J = 5.3Hz, 2H), 3.92-3.78 (m, 10H), 3.30-3.20 (m, 4H)

MS (m / e): 545 , 543 (M +) Example 31 (Reference Example): 7- (3, 4-dimethyl-butoxy benzyl § amino) - 5- [4- (3-Kurorofuwe two Le) piperidines Rajuru ] - 2- (2-furyl) [l, 2,4] Toriazoro [1,5-a] pyrimidine [compound

(31)]

The compound obtained in Example 29 (29) 800 mg (2.08 mmol), 1- (3- Kurorofuweniru) pin Perazine 'hydrochloride L23g (5.29 mmol), and the same operation as in Example 30 using DBU 1.15 ml (8.32 mmol) title compound by performing (31) 673 mg (yield: 59%) was obtained as a click stream colored powder.

¾ NMR (DMS0-d 6, δ ppm): 8.40-8.33 (m, 1H), 7.95 (d, J = l.0Hz, 1H), 7.38- 6.85 (m, 8H), 6.77 (dd, J = 3.3 Hz, 1.7Hz, 1H), 5.89- 5.88 (m, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.95-3.75 (m, 4H), 3.40-3.25 (m, 4H)

MS (m / e): 545 (M +) Example 32 (Reference Example): 7- (3,4-dimethyl Bok Kishibenjiruami Roh) - 5- [4- (2-black port phenylene Le) piperidines Rajuru] 2- (2 - furyl) [l, 2,4] preparative Riazoro [1,5-a] pyrimidine [compound

(32)]

The compound obtained in Example 29 (29) 800 mg (2.08 negation ol), Bok (2 Kurorofuweniru) pin Perazine 1.23 g (6.24 mmol), and DBU 1.0 with ml (7.30 mmol), the same manner as in Example 30 It was obtained: title compound (32) 732mg (64% yield) of. Ή NMR (CDCI3, δ ppm): 7.54 (t, J = l.0Hz, 1H), 7.42-6.83 (m, 8H), 6.54 (dd, J = 3.3Hz, 2.0Hz, 1H), 6.25 (brt, J = 5.3Hz, 1H), 5.44 (s, 1H), 4.47 (d, J = 5.3Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.95-3.86 (m, 4H), 3.15-3.08 (m, 4H) example 33 (reference example): 7- (3,4-dimethyl-butoxy benzyl § amino) -5 - [4 - (2 - main Tokishifue two Honoré) piperidines Rajuru] - 2- ( 2- unfavorable Honoré) [1,2,4] tri Asolo [1, 5 - a] pyrimidine [compound

(33)]

The compound obtained in Example 29 (29) 800 mg (2.08 negation ol) and 1-- was heated to reflux overnight (2 main Tokishifue two Honoré) piperidines Rajin 1.10 ml (6.24 mmol) ethanol 30 ml of. The reaction was brought to room temperature, extracted added black port Holm and water, the organic layer was dried over anhydrous sulfate Magne Shiumu. The solvent was distilled off under reduced pressure, silica gel column chromatography

(Elution solvent: 20% black port Holm one hexane) to give the title compound (33) 574 mg

(Yield: 51%) as a yellow powder.

Ή NMR (DMS0-d 6, δ ppm): 8.27 (brt, J = 6.3Hz, 1H), 7.85 (d, J = 0.7Hz, 1H), 7.15-6.86 (m, 8H), 6 · 68 - 6.66 (m, 1H), 5.78 (s, 1H), 4.50 (d, J = 6.3Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 3.71 (s, 3H), 3.82-3.69 ( m, 4H), 3.06-2.90 (m, 4H)

MS (m / e): 541 (M Example 34 (Reference Example): 7- (3, 4-dimethyl-butoxy benzyl § amino) - 5 - [4 - (4 - fluorophenylcarbamoyl Honoré) piperazinyl] - 2 - (2 - full Li Le) [1,2,4] Application Benefits Asolo [1,5-a] pyrimidine [compound

(34)]

The compound obtained in Example 29 (29) 200 mg (0.52 mmol), and 1- (4-Furuorofe sulfonyl) using piperidines Rajin 374 mg (2.08 Hall ol), more notation The same operation as in Example 33 compound (34) 293 mg: was obtained (yield: quantitative) as a white powder.

Ή NMR (CDC1 ,, δ ppm.): 7.54 (. T, J = l OHz, 1H), 7.18 (d, J = 3.3Hz, 1H), 7.02- 7.85 (m, 7H), 6.54 (dd, J = 3.3Hz, 2.0Hz, 1H), 6.25 (t, J = 5.6Hz, 1H), 5.43 (s, 1H), 4.47 (d, J = 5.6Hz, 2H), 3.90- 3.75 (m, 10H), 3.20-3.06 (m, 4H)

MS (m / e): 529 (M) Example 35 (Reference Example) 5- (4-Buromofuenokishi) - 7- (3, 4-dimethyl-butoxy-benzyl amino) - 2 - (2-furyl) [1, 2, 4] Toriazoro [1,5-a] pyrimidine [compound (35)]

p- bromo phenol 675 mg of (3.90 mmol) were dissolved in DMF 15 ml, with stirring was added sodium et hydride (60% content) 156 mg (3.90 thigh ol). This compound obtained in Example 29 (29) 500 mg (1.30 negation ol) was added and stirred overnight at 100 ° C. The reaction was brought to room temperature, extracted by adding water and black hole Holm, and the organic layer was dried over anhydrous sulfate Maguneshiu beam. The solvent was distilled off under reduced pressure, silica gel column chromatography (elution solvent: 20% hexane one black port Holm) to give the title compound (35) 260 mg (yield: 38%) was obtained as a yellow powder.

Ή NMR (CDC1 3) δ ppm ): 7.56- 7.55 (m, 1H), 7.49 (d, J = 8.6Hz, 2H), 7.18 (d, J = 3.3Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H), 6.95-6.87 (m, 3H), 6 · 56 - 6.53 (m, 2H),

5.79 (s, 1H), 4.52 (d, J = 5.6Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H)

MS (m / e): 523, 521 (M +) Example 36 (Reference Example): 7- (3, 4 - dimethyl butoxy benzyl § amino) - 2- (2-furyl) -5- (4-pro Pokishifuenokishi) [2,4] Toriazoro [1,5-a] pyrimidine [compound (36)]

p- propoxy phenol 890 mg (5.84 mmol), hydrogen Kana Application Benefits um (60% including chromatic) 234 rag (5.84 mmol), and the compound obtained in Example 29 (29) 750 mg (1.95 mmol) using, eg title compound by the same procedure as 35 (36) 330 mg

(Yield: 34%) as a yellow powder.

¾ NMR (CDC1 3, δ ppm ): 7.55 (t, J = 0.7Hz, 1H), 7.16 (d, J = 3.3Hz, 1H), 7.10-

6.80 (m, 8H), 6.53-6.49 (m, 2H), 5.75 (s, 1H), 4.49 (d, J = 5.3Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.95 -3.80 (m, 2H), 1.87-1.75 (m, 2H), 1.08-0.98 (m, 3H) MS (m / e): 501 (M +) example 37 (reference example) 5- (4-butoxy phenoxy) -7- (3,4-dimethyl-butoxy-benzyl amino) - 2- (2-furyl) [l, 2,4] Bok Riazoro [1, 5-a] pyrimidine [compound (37)]

P - butoxide Schiff enol 1.04 g (6.23 negation ol), hydrogenated sodium (60% content) 250 mg (6.23 thigh ol), and the compound obtained in Example 29 (29) Les use the 800 mg (2.08 mmol) ,, example 35 title compound by the same procedure as (37) 377 mg (yield: 35%) as a yellow powder.

'Η NMR (CDC1 3, δ ppm): 7.55 (t, J = l.0Hz, 1H), 7.16 (d, J = 3.5Hz, 1H), 7.08 (d, J = 8.9Hz, 2H), 6.94- 6.83 (m, 5H), 6.57 - 6.52 (m, 2H), 5.81 (s, 1H),

4.49 (d, J = 5.9Hz, 2H), 3.96 (t, J = 6.4Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 1.83-1.72 (m, 2H), 1.55- 1.43 (m, 2H), 0.99 (t, J = 7.4Hz, 3H)

MS (m / e): 515 (M +) Example 38 (Reference Example): 7 - (3, 4-dimethyl-butoxy benzyl § amino) - 2 - (2-furyl) - 5- (3,4,5-Doo Li main Tokishifueno carboxymethyl) [1,2,4] preparative Riazoro [1,5-a] pyrimidone Jin [compound (38)]

3,4, 5-Application Benefits main Tokishifuenoru 1.19 g (6.48 mmol), hydrogen Kana Application Benefits um (60% content) 260 mg (6.48 mmol), and the compound obtained in Example 29 (29) 800 mg (2.08 was obtained 46%) as ocher powder: using mmol), the title compound by the same procedure as example 35 (38) 530 mg (yield.

Thigh (CDC1 3, δ ppm): 7.56 (. T, J = l OHz, 1H), 7.18 (d, J = 3.3Hz, 1H), 6.94- 6.85 (m, 3H), 6.54 (dd, J = 3.3 Hz, 1.7Hz, 1H), 6.57- 6.53 (m, 1H), 6.40 (s, 2H),

5.76 (s, 1H), 4.51 (d, J = 5.6Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.81 (s, 6H)

MS (m / e): 533 (M +) Example 39 (Reference Example): 7- (3, 4 - dimethyl Bok Kishibenjiruami Roh) - 2- (2 - furyl) - 5- Piperi Gino [1,2,4 ] Toriazoro [1,5-a] pyrimidine [compound (39)]

Piperidine 0.62 ml (6.23 mmol) and the compound obtained in Example 29 (29) using 600 mg (1.56 mmol), the title compound by the same procedure as Example 33 (39) 480 mg (yield: 71 %) of the title compound as an off-white powder.

Ή NMR (CDC1 3, δ ppm ): 7.53 (t, J = l.0Hz, 1H), 7.16 (d, J = 3.3Hz, 1H), 6.95- 6.84 (m, 3H), 6.52 (dd, J = 3.3Hz, 1.7Hz, 1H), 6.15 (t, J = 5.6Hz, 1H), 5.38 (s, 1H), 4.44 (d, J = 5.6Hz, 2H), 3.90 (s, 3H), 3.88 (s , 3H), 3.70-3.63 (m, 4H), 1.70-1.55 (m, 6H)

MS (m / e): 434 (M +) Example 40 (Reference Example): 7- (3,4-dimethyl-butoxy benzyl § amino) -2- (2-Furinore) - 5 - (the 1-key Samechirenimino) [2,4] Toriazoro [1, 5 - a] pyrimidine [compound (40)] hexamethylene I Min 0.54 ml (4.83 mmol) and the compound obtained in example 29 (29) 620 mg (1.61 mmol) using the title compound by the same procedure as example 33

(40) 510 mg (yield: 71%) as a white powder.

Anonymous R (CDC1 3, δ ppm) : 7.53 (. T, J = l OHz, 1H), 7.17 (d, J = 3.0Hz, 1H), 6.95- 6.83 (m, 3H), 6.52 (dd, J = 3.5Hz, 1.5Hz, 1H), 6.17 (t, J = 5.4Hz, 1H), 5.26 (s, 1H), 4.44 (d, J = 5.4Hz, 2H), 3.89 (s, 3H), 3.87 (s , 3H), 3.76 - 3.50 (m, 4H), 1.85- 1.70 (m, 4H), 1.55-1.48 (m, 4H)

MS (m / e): 448 (M +) Example 41 (Reference Example) 5- (4-base Njirupi piperidylpiperidine) -7- (3,4-dimethyl-butoxy-benzyl amino) - 2- (2 - furyl) [2,4] Toriazoro [l, 5-a] pyrimidine [compound (41)]

4 - benzylpiperidine L 10 ml (6.23 mmol) and the compound obtained in Example 29 (29) using 800 mg (2.07 negation 0 1), title of compounds by the same procedure as Example 33 (41) 726 mg (yield:. 67 ° /) was obtained. Ή NMR (CDCI3, δ ppm): 7.53 (t, J = 0.7Hz, 1H), 7.30- 7.12 (m, 6H), 6.94-6.83 (m, 3H), 6.52 (dd, J = 3.3Hz, 2.0Hz , 1H), 6.15 (t, J = 5.6Hz, 1H), 5.37 (s, 1H), 4.43 (d, J = 5.6Hz, 4H), 3.89 (s, 3H), 3.87 (s, 3H), 2.90 -2.80 (m, 2H), 2.56-2.53 (m, 2H), 1.84- 1.62 (m, 3H), 1.13- 1.21 (m, 2H)

MS (m / e): 524 (M +) Example 42 (Reference Example) 5- Benjiruamino - 7- (3, 4-dimethyl-butoxy benzyl § amino) - 2 - (2 - furyl) [1, 2, 4 ] Toriazoro [1, 5-a] pyrimidine (compound 42)

The compound obtained in Example 29 (29) 800 mg (2.07 mmol), Benjiruamin 0.71 ml (6.50 thigh ol), and DBU 0.29 ml of (2.16 mmol) was dissolved in ethanol 30 ml, and heated to reflux overnight. The reaction was brought to room temperature, extracted added black port Holm and water, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, silica gel column inlet Matogurafi one (elution solvent: black port Holm) purified to the title compound (42) 720 mg

(Yield: 73%) as a yellow powder.

Ή NMR (CDC1 3, δ ppm ): 7.52 (t, J = 0.7Hz, 1H), 7.35- 7.14 (m, 6H), 6.87- 6.82 (m, 3H), 6.52 (dd, J = 3.3Hz, 1.7 Hz, 1H), 6.30 - 6.20 (m, 1H), 5.16 (s, 1H), 4.61 (d, J = 5.9Hz, 2H), 4.37 (d, J = 5.3Hz, 2H), 3.88 (s, 3H ), 3.86 (s, 3H) MS (m / e): 456 (M +) example 43 (reference example): 7 - (3, 4-dimethyl-butoxy benzyl § amino) - 2- (2-furyl) - 5 - Fuwene Chiruamino [2,4] Toriazoro [1, 5 - a] pyrimidine [compound (43)]

The compound obtained in Example 29 (29) 800 mg (2.07 negation ol), Fuenechiruamin 0.78 ml (6.23 mmol), and DBU 0.28 ml using a (2.07 mmol), the title compound by the same procedure as Example 42 (43) 620 mg (yield: 64%) as a yellow powder.Ή NMR (CDC1 3, δ ppm ): 7.54 (. T, J = l OHz, 1H), 7.34-7.16 (m, 5H), 6.91- 6.82 (m, 3H), 6.53 (dd, J = 3.3Hz, 1.7Hz, 1H), 6.21-6.17 (m, 1H), 5.10 (s, 1H), 4.39 (d, J = 5.3Hz, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.71 ( q, J = 6.6Hz, 2H), 2.93 (t, J = 6.6Hz, 2H)

MS (m / e): 470 (M +) Example 44 (Reference Example): 7 - (3, 4-dimethyl-butoxy benzyl § amino) -2- (2-furyl) - 5- (3-Hue Nirupuropirua mino) [1, 2, 4] Toriazo port [1, 5-a] pyrimidine [compound (44)] the compound obtained in example 29 (29) 800 mg (2.07 mmol), and 3-Fuenirupuropi Ruamin 0.92 ml ( using 6.47 mmol), notation compound by the same procedure as example 33 (44) 617 mg (yield: 59%) was obtained.

Ή NMR (CDC1 3, δ ppm ): 7.52 (. T, J = l OHz, 1H), 7.28-7.13 (m, 6H), 6.90- 6.80 (in, 3H), 6.53 (dd, J = 3.3Hz, 1.7Hz, 1H), 6.21-6.15 (m, 1H), 5.08 (s, 1H), 4.87-4.79 (m, 1H), 4.39 (d, J = 5.6Hz, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.50-

3.40 (m, 2H), 2.70 (t, J = 7.6Hz, 2H), 1.95 (q, J = 7.3Hz, 2H)

MS (m / e): 484 (M one Example 45 (Reference Example): 7- (3, 4-dimethyl-butoxy benzyl § amino) -5- (3,4 - dimethyl Tokishifue Nechiruami Roh) - 2- (2- furyl) [1, 2,4] preparative Riazoro [1, 5 - a] pyrimidine [compound (45)]

The compound obtained in Example 29 (29) 800 mg (2.07 negation ol), and 3, 4 - dimethyl Tokishifu Enechiruamin 1.09 ml (6.47 mmol) using a more title compound The same operation as in Example 33 (45) 529 mg (yield: 48%) was obtained as a yellow powder.

Ή NMR (DMS0 - d 6, δ ppm): 8.91 - 8.10 (m, 1H), 7.84 (s, 1Η), 7.30-7.20 (m, 1H), 7.06-6.62 (m, 8H), 5.32 (s, 1H), 4.37 (d, J = 5.6Hz, 2H), 3.75- 3.42 (m, 14H), 2.74 (t, J = 7.6Hz, 2H)

MS (m / e): 530 (W) Example 46 (Example) 7-amino-5- [4 - (4-Kurorofuweniru) piperazinyl] -2- (2-pretended Le) [1,2,4] Toriazoro [1, 5-a] pyrimidine [compound (46)] the compound obtained in example 30 (30) 620 mg (1.14 mmol) was dissolved in Torifuruoro acetate 10 ml, Anisoru 0.5 ml, the Nafuion 1.2 g was added, It was heated to reflux for 1.5 hours. The reaction was brought to room temperature, filtered off Nafuion and washed well further methylamine one methanol solution Nafuion, then with methanol. After the filtrate and washings was evaporated under reduced pressure, silica gel force column chromatography was purified (eluent 0.2% Toryechiruamin one 3% methanol one black port Holm), the title compound by recrystallization from ethanol (46) 205 mg (yield: 45%) was obtained as a white powder.

'Η NMR (DMSO- d 6, δ ppm): 7.85 (s, 1H), 7.50 (s (br), 2H), 7.26 (d, J = 9.4Hz, 2H), 7.02 (d, J = 3.3Hz , 1H), 7.00 (d, J = 9.4Hz, 2H), 6.66 (dd, J = 3.3Hz, 2.0Hz, 1H), 5.71 (s, 1H), 3.78-3.66 (m, 4H), 3.30-3.22 (m, 4H)

MS (m / e): 395 (M

IR (KBr; cm- 1): 1659, 1601, 1570, 1495, 1234

Melting point:> 270 ° C

As C 19 H 18 N 7 0C1 0. lEtOH 0.2H 2 0: Elemental analysis

Found (%): C 57.12, H 4.64, N 24.20

Calculated (%): C 57.07, H 4.74, N 24.27 Example 47 (Example): 7 - Amino - 5 - [4 - (3-black port phenyl) piperazinyl] -2- (2-pretended Le) [1 , 2,4] Toriazoro [1, 5-a] pyrimidine [compound (47)]

Was obtained as a white powder: Using the compound obtained (31) 650 mg (1.20 negation ol) in Example 31, the title compound by performing the same operation as in Example 46 (47) 118 mg (25% yield) .

¾ negation R (DMSO- d 6, δ ppm ): 7.85 (s, 1H), 7.52 (s (br), 2H), 7.24 (t, J = 7.9Hz, 1H), 7.04-6.93 (m, 3H) , 6.81 (d, J = 7.9Hz, 1H), 6.66 (dd, J = 3.3Hz, 2.0Hz, 1H), 5.70 (s, 1H), 3.74-3.67 (m, 4H), 3.35-3.26 (m, 4H)

MS (m / e): 395 (M +)

IR (KBr; cm "1) : 1666, 1650, 1603, 1485 mp:> 300 ° C

Elemental analysis: C 19 H 18 N 7 0C1 0.3EtOH 0.4H, 0

Found (%): C 56.40, H 4.66, N 23.40

Calculated (%): C 56.47, H 4.98, N 23.52 Example 48 (Example): 7 - Amino - 5- [4- (2-Kurorofuweniru) piperazinyl] - 2- (2 - pretended le) [1,2 , 4] Toriazoro [1, 5-a] pyrimidine [compound (48)]

The compound obtained in Example 32 (32) using 700 mg (1.28 mmol), the title compound by performing the same operation as in Example 46 (48) 271 mg (yield: 53%) as a yellow powder.

¾ NMR (CDC1 3, 5 ppm ): 7.56 (. D, J = l OHz, 1H), 7.40 (dd, J = 7.6Hz, 1.3Hz, 1H), 7.26-7.20 (m, 1H), 7.18 (d , J = 3.3Hz, 1H), 7.01 - 6.97 (m, 2H), 6.54 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.63 (s, 1H), 5.49 (s (br), 2H), 3.90 - 3.86 (m, 4H), 3.14-3.09 (m, 4H)

MS (m / e): 395 (M +)

IR (KBr; cm "1) : 1654, 1605, 1483, 1443, 1331, 1225

Mp: 255.2- 256.4. C

As C 19 H 18 N 7 0C1 0.2EtOH : Elemental analysis

Found (%): C 57.57, H 4.65, N 24.21

Calculated (%): C 57.53, H 4.78, N 24.21 Example 49 (Example): 7 - Amino - 2- (2 - furyl) - 5 - [4- (2-menu Tokishifuweniru) piperazine sulfonyl] [1, 2,4] Toriazoro [1, 5-a] pyrimidine [compound (49)]

Was obtained as a white powder: the compound obtained in Example 33 using (33) 574 mg (1.06 mmol), the title compound by performing the same operation as in Example 46 (49) 188 mg (45% yield).

¾ NMR (CDC1 3, δ ppm ): 7.56 (. D, J = l OHz, 1H), 7.19 (d, J = 3.3Hz, 1H), 7.08-6.87 (m, 4H), 6.55 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.63 (s, 1H), 5.44 (s (br), 2H), 3.90 (s, 3H), 3.91 - 3.85 (m, 4H), 3.15-3.09 (m, 4H)

MS (m / e): 391 (M +)

IR (KBr; cm- 1): 1659, 1655, 1605, 1488, 1240

Mp: 269.8-271.2 ° C

As C 20 H 21 N 7 0 2 0.3Et0H: Elemental analysis

Found (%): C 61.08, H 5.61, N 24.16

Calculated (%): C 61.05, H 5.67, N 24.19 Example 50 (Example): 7-Amino - 5- [4- (4-Furuorofuweniru) piperazinyl] -2- (2-off Lil) [1,2 , 4] Toriazoro [1,5-a] pyrimidine [compound (50)]

Using the compound obtained (34) 620 mg (1.17 mmol) in Example 34, the title compound by performing the same operation as in Example 46 (50) 193 mg (yield: 44%) as a yellow powder.

¾ NMR (DMS0- d 6, δ ppm): 7.85 (t, J = l.0Hz, 1H), 7.49 (s (br), 1H), 7.13- 6.96 (m, 5H), 6.66 (dd, J = 3.3Hz, 2.0Hz, 1H), 5.72 (s, 1H), 3.77-3.65 (m, 4H), 3.25-3.13 (m, 4H)

MS (m / e): 379 (M +)

IR (KBr; cm "1) : 1659, 1651, 1605, 1568, 1508, 1230

Melting point:> 270 ° C

As C 19 H l8 N 7 0F 0.2EtOH 0.7H 2 0: Elemental analysis

Found (%): C 58.10, H 4.79, N 24.24

Calculated (° / o): C 58.08, H 5.17, N 24.44 Example 51 (Example): 7-Amino - 5 - (4-Buromofuwenokishi) -2 - (2-furyl) [1,2,4] tri Azoro [1,5-a] pyrimidine [compound (51)]

Was obtained as a white powder: the compound obtained in Example 35 (35) using 710 mg of (1.91 mmol), the title compound by performing the same operation as in Example 46 (51) 180 mg (25% yield).

Ή NMR (DMS0-d 6, δ ppm): 8.15 (s (br), 2H), 7.88 (d, J = L0Hz, 1H), 7.64 (dd, J = 8.9Hz, 2.0Hz, 2H), 7.21 ( dd, J = 8.9Hz, 2.0Hz, 2H), 7.06 (d, J = 3.3Hz, 1H), 6.68 (dd, J 3.3Hz, 2.0Hz, 1H), 5.82 (s, 1H)

MS (m / e): 373, 371 (M +)

IR (KBr; cm "1) : 1670, 1655, 1605, 1572, 1223

Melting point:> 270 ° C

As C I5 H 10 N 5 0 2 Br 0.2EtOH: Elemental analysis

Found (%): C 48.46, H 2.89, N 18.31

Calculated (%): C 48.50, H 2.96, N 18.36 Example 52 (Example): 7 § Mi Bruno - 2- (2-off Lil) - 5- (4 - propoxy off We Roh carboxymethyl) [1, 2,4] Toriazoro [1,5-a] pyrimidine [compound (52)]

Was obtained as a white powder: the compound obtained in Example 36 using (36) 600 mg (1.19 mmol), the title compound by performing the same operation as in Example 46 (52) 196 mg (47% yield).

Ή NMR (DMSO- d 6, δ ppm): 8.05 (s (br), 2H), 7.87 (d, J = 1.0Hz, 1H), 7.12 (d, J = 8.9Hz, 2H), 7.06 (d, J = 3.3Hz, 1H), 6.99 (d, J = 8.9Hz, 2H), 6.67 (dd, J = 3.3Hz, 2.0Hz, 1H), 5.73 (s, 1H), 3.95 (t, J = 6.6Hz , 2H), 1.82-1.68 (ra, 2H), 1.00 (t, J = 7.3Hz, 3H)

MS (m / e): 351 (M +)

IR (KBr; cnf 1): 1655, 1602, 1566, 1508, 1211

Melting point:> 270 ° C

As C 18 H 17 N 5 0 3 0.2EtOH: Elemental analysis

Found (%): C 61.44, H 5.11, N 19.40

Calculated (%): C 61.29, H 5.09, 19.42 Example 53 (Example): 7 - Amino - 5- (4-butoxide Schiff enoki sheet) -2 - (2-furyl) [l, 2,4] DOO Riazoro [1, 5 - a] pyrimidine [compound (compound 53)

Was obtained as a light brown powder: the compound obtained in Example 37 (37) using 377 mg of (0.73 ol), the title compound (53) 300 mg (56% yield) by performing the same operation as in Example 46 .

'Η NMR (DMS0 - d 6 δ ppm) 8.05 (s (br), 2H), 7.88 (t, J = L ΟΗζ, 1H 7.12 (dd, J = 9.0Hz, 2.3Hz, 2H 7.06 (d, J = 3.3Hz, 1H 6.99 (dd, J = 9.0Hz, 2.3Hz, 2H), 6.68 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.73 (s, 1H 3.99 (t, J = 6.3Hz, 2H) , 1.77- 1.66 (m, 2H), 1.53- 1.38 (m, 2H), 0.95 (t, J = 7.3Hz, 3H)

MS (m / e): 365 (M +)

IR (KBr; cm '1) : 1660, 1651, 1603, 1564, 1506, 1456, 1209

Mp: 257.5-258.4 ° C

As C, 9 H 19 N 5 0 3 0.3Et0H 0.1H 2 0: Elemental analysis

Found (%): C 61.75, H 5.48, N 18.30

Calculated (%): C 61.79, H 5.56, N 18.38 Example 54 (Example): 7 § Mi Bruno - 2- (2-furyl) -5 - (3,4, 5-Application Benefits main Tokishifuenoki sheet) [2,4] Toriazoro [1, 5 - a] pyrimidine (compound 54)

The compound obtained in Example 38 (38) using 450 mg (0.84 ol), the title compound by performing the same operation as in Example 46 (54) 157 mg (yield: 49%) as a yellow powder.

¾ NMR (DMS0 - d 6, δ ppm) 8.08 (s (br), 2H), 7.88 (d, J = l.0Hz, 1H), 7.07 (d, J = 3.5Hz, 1H 6.68 (dd, J = 3.5Hz, 1.5Hz, 1H), 6.58 (s, 2H), 5.76 (s, 1H) MS (m / e) 383 (M +)

IR (KBr; cm "1) : 1662, 1606, 1570, 1504, 1468

Mp:> 270 ° C Elemental analysis: as C 18 H 17 N 5 0 5 0.2Et0H

Found (%): C 56.28, H 4.56, N 17.83

Calculated (%): C 56.30, H 4.67, N 17.84 Example 55 (Reference Example): 7 § Mi Bruno - 2- (2-furyl) - 5 - Piperi Gino [1,2,4] Preparative Riazoro [1 , 5-a] pyrimidine [compound (55)]

As a pale yellow powder: the compound obtained in Example 39 (39) using 700 mg (1.61 mmol), the title compound (55) 399 mg (87% yield) by performing the same operation as in Example 46 .

Thigh (DMS0 - d 6, δ ppm ): 7.83 (d, J = l.5Hz, 1H), 7.35 (s (br), 2H), 7.00 (d, J = 3.5Hz, 1H), 6.65 (dd, J = 3.5Hz, 1.5Hz, 1H), 5.65 (s, 1H), 3.57 (t (br), 4H), 1.68- 1.48 (m, 6H)

MS (m / e): 284 (M ten)

IR (KBr; cm '1) : 1659, 1605, 1558, 1236

Melting point:> 270 ° C

As C 14 H 16 N 6 0 0. lEtOH: Elemental analysis

Found (%): C 59.00, H 5.90, N 28.97

Calculated (%): C 59.03, H 5.79, N 29.09 Example 56 (Reference Example): 7-Amino - 2- (2-Furinore) -5- (Kisamechireni Mino to Bok) [2,4] Toriazoro [ 1, 5-a] pyrimidine hydrochloride [compound (56)]

The compound obtained in Example 40 (40) 500 mg of (1.12 mmol) was dissolved in Torifuruoro acetate 10 ml, Aniso Ichiru 0.5 ml, the Nafuion 1.5 g was added and heated to reflux for 1.5 hours. The reaction was brought to room temperature, filtered off Nafuion and washed well further Mechiruaminme methanol solution Nafuion, then with methanol. After the filtrate and washings was evaporated under reduced pressure, silica gel column chromatography and purified (eluent hexane one chloroform to 20%). The resulting 7 - Amino - 2- (2-flip gray) -5 - (to 1 Kisamechiren'imi Roh) [1,2,4] triazolo in [i, 5-a] crude product of pyrimidine 4 M hydrochloric acid adding an acid Echiru 10 ml was stirred at room temperature for 1 hour. Then, ether 40 ml was added, precipitated were collected by filtration solid bodies, the title compound (56) 154 mg (yield: 41%) by washing with ether as a pale yellow powder.

Ή negation R (CDC1 3, δ ppm) : 7.55 (. T, J = l OHz, 1H), 7.18 (d, J = 3.3Hz, 1H), 6.53 (dd, J = 3.3Hz, 1.7Hz, 1H) , 5.47 (s, 1H), 5.34 (s (br), 2H), 3.90-3.55 (m, 4H), 1.82-1.50 (m, 8H)

MS (m / e): 298 (M +)

IR (KBr; cm "1) : 1678, 1614, 1568, 1548

Mp: 206.5-208.4 ° C

As C 15 H 18 N 6 0 1.0HC1 1.0H 2 0: Elemental analysis

Found (%): C 51.11, H 6.01, N 23.85

Calculated (%): C 51.06, H 6.00, N 23.82 Example 57 (Example): 7-Amino - 2 - (2-furyl) - 5- (4-benzyl-piperidinophenyl) [2,4] DOO Riazoro [1,5-a] pyrimidine [compound (57)]

Using the compound obtained (41) 650 mg (1.24 ramol) in Example 41, the title compound by performing the same operation as in Example 46 (57) 351 mg (yield: 75%) as a yellow powder.

Ή NMR (DMS0 - d 6, δ ppm): 7.83 (. D, Jl OHz, 1H), 7.37-7.17 (m, 7H), 7.00 (d, J = 3.3Hz, 1H), 6.65 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.65 (s, 1H), 4.32-4.21 (m, 2H), 2.90-2.80 (m, 2H), 2.54-2.49 (m, 2H), 1.85- 1.60 (m, 3H ), 1.28-1.06 (m, 2H)

MS (m / e): 374 (M +)

IR (KBr; cm- 1): 1655, 1606, 1558, 1490, 1236

Melting point:> 270 ° C

Elemental analysis: C 2I H 22 N 6 0 0.2H 2 0 as Found (%): C 66.88, H 6.09, N 21.85

Calculated (%): C 66.72, H 5.97, N 22.23 Example 58 (Reference Example): 7-Amino - 5 Benjiruamino - 2- (2 - furyl) [1,2, 4] Toriazoro [l, 5_A] pyridinium Mi jin [compound (58)]

It was obtained as a white powder: the compound obtained in Example 42 (42) using 600 mg (1.31 mmol), the title compound by performing the same operation as in Example 46 (58) 210 mg (52% yield).

Ή NMR (DMSO- d 6, δ ppm): 7.83 (s, 1H), 7.70 (t (br), J = 5.6Hz, 1H), 7.35- 7.22 (m, 5H), 6.98 (d, J = 3.3 Hz, 1H), 6.64 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.50 (s, 1H), 4.52 (d, J = 5.6Hz, 2H)

MS (m / e): 306 (M +)

IR (KBr; cm "1) : 1678, 1662, 1606, 1575, 1542, 1523, 1336

Mp: 244.5-245.0 ° C

As C 6 H 14 N 6 0 0. lEtOH: elemental analysis!

Found (%): C 62.11, H 4.51, N 27.05

Calculated (%): C 62.58, H 4.73, N 27.03 Example 59 (Reference Example): 7 - Amino - 2 - (2-furyl) -5- Fuwenechiruamino [1, 2, 4] Toriazo port [1, 5-a ] pyrimidine hydrochloride [compound (59)]

It was obtained as a white powder: the compound obtained in Example 43 (43) using 580 mg (1.23 mmol), the title compound by performing the same operation as in Example 56 (59) 211 mg (46% yield).

Ή NMR (CDC1 3, δ ppm ): 7.53 (. T, J = l OHz, 1H), 7.30- 7.12 (m, 6H), 6.52 (dd, J = 3.5Hz, 1.5Hz, 1H), 5.85 (s (br), 2H), 5.38 (s, 1H), 3.65-3.58 (m, 2H), 2.89 (t, J = 7.4Hz, 2H)

MS (m / e): 320 (NT) IR (KBr; cnf 1): 1686, 1678, 1578, 1560

Melting point: 164.1-170.2. C

As C I7 H 16 N 6 0 1.1HC1 0.9H 2 0: Elemental analysis

Found (%): C 54.07, H 4.94, N 22.45

Calculated (%): C 54.21, H 5.06, N 22.31 Example 60 (Reference Example): 7 § Mi Bruno - 2 - (2-off Lil) - 5- (3-phenylpropyl § Mi Roh) [1 , 2,4] Toriazoro [1, 5 - a] pyrimidine [compound (60)]

Was obtained as a brown powder: Using the compound obtained (44) 520 rag (1.07 mmol) in Example 44, the title compound by performing the same operation as in Example 46 (60) 280 mg (78% yield).

¾ NMR (DMSO- d 6, δ ppm): 7.92 (d (br), J = 1.0Hz, 1H), 7.77-7.55 (m, 2H), 7.38-7.13 (m, 6H), 6.71 (dd, J = 3.3Hz, 1.7Hz, 1H), 5.53 (s, 1H), 3.35-3.25 (m, 2H), 2.66 (t, J = 7.6Hz, 2H), 1.85 (q, J = 7.6Hz, 2H)

MS (m / e): 334 (M +)

IR (KBr; cm- 1): 1662, 1658, 1575, 1558

Mp: 114.2-114.9 ° C

As C 18 H 18 N 6 0 0.3H 2 0 0.3Et0H: Elemental analysis

Found (%) C 63.17, H 5.66, N 23.58

Calculated ( "¾): C 63.18, H 5.81, N 23.77 Example 61 (Example): 7-Amino - 5- (3,4-dimethyl Toki Schiff energy chill § amino) - 2- (2-pretended Le) [1,2, 4] Toriazoro [1, 5-a] pyrimidine hydrochloride [compound (61)]

Was obtained as a brown powder: Using the compound obtained (45) 500 mg (0.94 mmol) in Example 45, the title compound by performing the same operation as in Example 56 (61) 193 mg (47% yield).

Ή MR (CDC1 3, δ ppm ): 7.53 (s, 1H), 7.13 (d, J = 3.3Hz, 1H), 6.80- 6.68 (m, 3H), 6.53-6.51 (m, 1H), 5.86 (s (br), 2H), 5.40 (s, 1H), 5.26 (s (br), 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.65- 3.56 (m, 2H), 2.83 (t , J = 6.9Hz, 2H)

MS (m / e): 380 (M +)

IR (KBr; cm "1) : 1682, 1620, 1583, 1516

Mp: 125.4-127.6 ° C

As C 19 H 20 N 6 0 3 0.9HC1 1.1H 2 0: Elemental analysis

Found (%): C 52.81, H 5.39, N 19.19

Calculated (%): C 52.70, H 5.38, N 19.41 Formulation Example 1: Tablets

Compound 4 10 mg

Lactose 30 mg

Horse Author droppings 15 mg

Polyvinyl alcohol 1.5 mg

Maguneshiumu stearate 0.5 mg

By conventional methods, formulation examples 2 to produce tablets having the above composition: capsules

Compound 26 10 mg

Lactose 100 mg

Maguneshiumu stearic acid 2.5 mg

Usual manner by mixing the ingredients to produce capsules filled into gelatin capsules. Formulation Example 3: Injection

Compound 61 2 mg

Purified soybean oil 200 mg of purified egg yolk lecithin 24 mg

Glycerin for injection 50 mg

Distilled water for injection 1. 72 ml

By a conventional method, to produce an injection having the above composition. Test Example 1 Adenosine receptor antagonism (adenosine A 2A receptor binding test)

Bruns et al method [Molecular. Pharmacology (Mol. Pharmacol.), 29, 331 (1986)] using the method with minor modifications to, to evaluate the effect of the medicament of the present invention for the adenosine receptor. Using polytron homogenizer (Kinematica, Inc.) was suspended in rat striatum 50 mM Bok squirrel ice-cold (heat Dorokishimechiru) Aminometa down hydrochloride (Tris' HCl) buffer (pH 7. 7) . The suspension was centrifuged (50, OOOxg, 10 minutes), the resulting precipitate was resuspended in the 50 mM Tris' HCl buffer same amount was again added, were subjected to the same centrifugation. To the resulting final precipitate, 5 mM (wet weight) 50 mM Tris' HCl buffer so that the tissue concentration of ZML [10 mM chloride magnetic Shiumu, adenosine der transglutaminase 0.02 Yuni' concert mg tissue (Sigma Co. were suspended Etsu Chemical Co., Ltd.) was added to including].

CGS 21680 labeled with above cell suspension 1 ml 〖this tritium [adenosine A 2A receptor agonists: ¾- 2- [P- (2- Karubokishechiru) Fuwenechiruamino] - 5 '- (N- Echiruka Rubokisami de) adenosine:... 40 Curie one / mmol; New England Nuclear Corporation; The Jananore-O Bed & Famakoroji one 'and' E box Peri mental Serra Piyuuchikkusu (J. Pharmacol Exp Ther), 251, 888 (1989)] was added 50 ml (final concentration 4. 0 nM) and a test compound suspension 50 mu 1. After the mixed solution was left to stand for 120 minutes at 25 ° C, a glass fiber filter paper; rapid suction filtration on (GF / C Whatman Co.), in 50 mM Tris' HCl buffer 5 ml of ice-cold immediately It washed 3 times. The glass fiber filter was transferred to a server Iaru bottles, scintillator one coater -; added (EX II manufactured by Wako Pure Chemical Industries, Ltd.), and the radioactivity quantity was measured by a liquid scintillation one Chillon counter (manufactured by Packard).

Calculation of the inhibition rate for A 2A receptor binding of a test compound (¾- CGS 21680 binding) was calculated by the following PT JP equation. Inhibition rate = [1 i (binding amount one nonspecific binding under the test compound present) Z (total binding one non-specific binding amount)] x ioo [wherein, the total binding of the test compound in the absence in the presence drug; 3 H-CGS 21680 is a bond amount of radioactivity in; non-specific binding is 100 mM cyclopentyladenosine; be 3 H-CGS 21680 binding radioactivity in the presence (CPA Sigma Co.) the amount of binding is ¾- CGS 21680 bound radioactivity of the test compound the presence of various concentrations. The results are shown in Table 2. Wherein the compound included in the (I) either has a strong adenosine A 2A receptor antagonistic activity, treatment and Z of Parkinson's disease which medicament of the present invention is derived from hyperactivity of adenosine A 2A receptor or it has been shown to be effective in preventing.

Table 2 A 2 A receptor inhibition rate (%)

Compound No. 10 "8 10 one 7 M

4 48 87

6 31 80

11 11 53

14 68 94

17 0 47

21 13 56

25 38 76

26 21 61

27 37 78

53 NT 47

56 NT 53

57 NT 45

58 NT 65

59 NT 81

60 NT 62

61 NT 70

NT: not tested

Test Example 2: action on CGS 21680-induced catalepsy one

Parkinson's disease is a degenerative 'cell death based motor dysfunction nigra one striatal dopamine nerve. Adenosine A 2A the CGS 21680 is a receptor agonist GABA works働性inhibitory synaptic transmission in the middle- spiny nerve striatum via the adenosine A 2A receptor when administered (medium sized spiny neuron) intraventricularly There is directly inhibited [journal-O Bed 'Neuroscience (J. Neurosci.), 16, 605 (1996)]. This result, adenosine A 2A receptor is functioning accelerated manner with respect to the output of the GABA works働性nerves to globus pallidus outer segment from the striatum, the catalepsy one is induced by administration CGS 21680 It suggests.

5-week-old male ddY mice (body weight 22~25 g, Japan Sic) experiments were performed with 10 animals per one group. Was dissolved CGS 21680 and (RBI Co., Ltd.) in physiological saline (Otsuka Pharmaceutical Co., Ltd.), a 10 μ 8/20 μΐ was injected into the room mouse brain. Test compound was used suspended in 0. 3% Tween 80 [polyoxyalkylene (20) sorbitan mono-O-oleate] containing distilled water (Otsuka Pharmaceutical Co., Ltd.). The CGS 21680 30 minutes before injection into intraventricular, solution [0. 3% Tween 80 in distilled water: control] containing no suspension or the test compound containing the test compound were orally administered respectively (10 mg / kg , 0. 1 ml per mouse body weight 10 g). Test compounds administered by one animal height after between 1 hour 4, 5 cm, width 1.0 mice both forelimbs to Akuriru made platform stood vertically in cm only sequentially applying only both hind, measuring forces Tarepushi symptoms did.

Determination of effects, the catalepsy scores of 10 animals per group using criteria below was carried out total (50 points). Total score is determined that there is action where it becomes less than 40 points. Catalepsy one remission reaction number of animals showed the number of example catalepsy scores of 10 patients became less 4 points. Power Tarepushi remission rate was expressed as a percentage of the total score of the test compound administration group to the total score of the control group. The results are shown in Table 3. Ku catalepsy score>

"0": forelimbs, the duration of the leave that attitude was subjected to stand on hind both less than 5 seconds;

"1": while applying the forelimbs to the table that the duration of the posture for 5 seconds or more, in less than 10 seconds, the duration of the after the limb is less than 5 seconds;

"2": forelimb in a while applying to the table that the duration of the posture is 10 seconds or more, the duration of the hind limb is less than 5 seconds;

"3": (1) forelimb, while applying the base hind both the duration of the posture for more than 5 seconds, less than 10 seconds, or (2) the duration of intact posture multiplied forelimbs base is less than 5 seconds in, the duration of the after limb more than 5 seconds;

"4": (1) forelimb in the duration of leave that attitude was subjected to die is 10 seconds or more, the duration of the hind limb is more than 5 seconds, less than 10 seconds, or (2) while applying the forelimbs to the base its duration of the posture is 5 seconds or more, in less than 10 seconds, the time duration in hindlimbs 10 seconds or more;

"5": forelimbs, while applying to stand in hind both the duration of the posture is more than 10 seconds

Table 3

Compound No. used number of animals Total score remission reaction number of animals remission rate (%)

Control 10 48 2 4

(0. 3% Tween80)

4 10 14 10 66

6 10 9 10 78

12 10 21 8 56

16 10 30 9 36

17 10 14 10 68

19 10 15 9 66

21 10 13 8 70

26 10 22 9 54

27 10 19 8 60

46 10 30 8 38

48 10 18 9 62

49 10 28 8 42

54 10 7 9 84

56 10 22 8 56

59 10 15 9 70

61 10 29 10 40 Test Example 3 Action Against Haroperi Doll induced catalepsy one

The administration Haroperi Doll (the dopamine D1 / D2 antagonist) catalepsy one is triggered by D2 receptor blockade postsynaptic. [® bite Pian known as classical models that reproduce the Parkinson's disease by the Haroperi Doll induced catalepsy one drug administration 'journal. O Bed' Pharmacology (Eur. J. Pharmacol.), 182, 327 (1990 ) and U.S. Patent 3, 991, 207 Pat. According to the following method, it was studied the effect of the medicament of the present invention with respect to the needle bed gap Peri d'induced catalepsy scratch.

5-week-old male ddY mice (body weight 22~24g, Japan SIX) experiments were performed with 10 animals per one group. Haroperi Doll and (Janssen Corp.) were suspended in 0.3% carboxymethylcellulose port over scan (CMC), it was administered 1. 0 mg / kg intraperitoneally into mice. Test compound was used suspended in distilled water for injection was added Tween 80 (manufactured by Otsuka Pharmaceutical Co., Ltd.). Furthermore, L - dopa (L- D0PA; manufactured by Kyowa Hakko Kogyo) and hydrochloric acid benserazide (benserazide HC1; Kyowa Hakko Kogyo Ltd.) was used as a 3% CMC suspension 0.1. Haroperi Doll intraperitoneal free suspension is suspension or test compound comprising the administration 1 hour after the test compound [T wee n80 distilled water for injection was added (manufactured by Otsuka Pharmaceutical Co., Ltd.): control] were orally administered respectively ( 10 mg / kg, body weight of mouse 10 g per 0. 1 ml), each one animal one hour after the test compound administration height 4. 5 cm, to the base width 1. 0 cm mice both forelimbs only sequentially applying only both hind paws , to measure the force Tarepushi. The L- dopa 100 mg / kg and benserazide 25 mg / kg (for 併) was administered intraperitoneally as a control drug. Determination of the effect was performed in the same manner as in Test Example 2 using the same determination criteria as in Test Example 2. The results are shown in Table 4. From the results of Test Example 2 and Test Example 3, it is clear that the medicaments of the present invention has an excellent therapeutic or prophylactic effect against Parkinson's disease.

Table 4

Compound No. used number of animals Total score remission reaction number of animals remission rate (%)

Control 10 50 0 0

(0. 3% Tween80)

4 10 15 9 70

17 availability on 10 35 5 30 industry

The medicament of the present invention has an adenosine A 2A antagonism, various diseases resulting from function enhancement of adenosine Alpha 2 [lambda] receptors, for example the treatment and / or prevention of such paths one Parkinson's disease - is useful.

Claims

The scope of the claims
The following formula (I)
(I)
Wherein, Z is an oxygen atom or a sulfur atom; R is the following formula
[In the formula, Y is an oxygen atom, a sulfur atom, one NR 1 - (wherein, R 1 represents a hydrogen atom or a lower alkyl group), or a single bond; n is an integer from 0 to 5; X 1, X 2, and X 3 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an amino group, a mono- or di-lower alkylamino group, a lower § Rukanoiru group, a substituted or unsubstituted substituted Aroiru group, a substituted or unsubstituted Ari group, a substituted or unsubstituted heterocyclic group, a hydroxyl group, or a nitro group] with represented Ru group, or the following formula:
Wherein, m represents an integer of 0 Kakara 5; k represents an integer of 0 to 5; Q is oxygen atom, a sulfur atom, - NH -, or represents a methylene group; R 2 is a hydrogen atom, lower alkyl group, human de proxy lower alkyl group, § Mi-lower-alkyl group, a lower alkoxy group, a lower alkyl thio group, a mono- or di-lower alkylamino group, a substituted or unsubstituted Ari group, a substituted or unsubstituted heterocyclic ring group, or (wherein, R 3 is lower alkyl, lower alkoxy, lower alkylthio group, a substituted or unsubstituted Ariru group, a substituted or unsubstituted heterocyclic group) Single CO- R 3 is represented by [1 a group represented by a group] represented by shown to] that, 2, 4] Toriazoro [1, 5 - a] pyrimidine derivatives and physiologically acceptable salts thereof, as well as their water selected from the group consisting of hydrates and solvates Containing substance as an active ingredient, a medicament for the treatment and Z or prevention of diseases resulting from hyperactivity of adenosine A a receptor.
2. The medicament according to claim 1, wherein the disease is Parkinson's disease.
3. The formula (I) according to claim 1 [1, 2, 4] Toriazoro [1, 5-a] Pi Rimijin derivative and physiologically acceptable salts thereof, and their adenosine a 2A antagonist comprises a material selected from the group consisting of hydrates and solvent hydrate.
. 4 according formula (I) in the range described in the first term of [1, 2, 4] Toriazoro [1, 5 - a] Pi Rimijin derivative and physiologically acceptable salts thereof, and their for the manufacture of a medicament according to paragraph 1 or claim 2, wherein the substance selected from the group consisting of hydrates and solvent hydrate.
5. A therapeutic and Z or prevention of diseases resulting from hyperactivity of adenosine A 2A receptor, [1, 2,4] represented by formula (I) according to claim 1 Toriazoro [1, 5-a] administered pyrimidine derivatives and physiologically acceptable salts thereof, as well as the treatment and / or prophylactically effective amount of a substance selected from the group consisting of hydrates and solvates in patients the method comprising the step of.
6. The method according to claim 5 wherein the disease is Parkinson's disease.
. 7 in the formula (I) according to claim 1, Z is oxygen atom or sulfur atom; Y is an oxygen atom, a sulfur atom, one NR 1 - (In the formula, R 1 represents a hydrogen atom or a lower an alkyl group), or a single bond; n is an integer from 5 to 0; X ', X 2, and X 3 are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an amino group, a mono- or di-lower alkylamino group, a lower § Rukanoiru group, a substituted or unsubstituted Aroiru group, a substituted or unsubstituted Ari group, a substituted or unsubstituted heterocyclic group, a hydroxyl group, or a nitro group in it (provided that X 1, X 2, and except when X 3 is a hydrogen atom simultaneously); m force; 1 from Ri integer der of 5; k is located at 5 integer from 0; Q is oxygen atom , sulfur atom, - NH -, or-methylol Be alkylene group; R 2 Gahi Dorokishi lower alkyl group, Amino lower alkyl group, a lower alkoxy group, a lower alkylthio group, a mono- or di-lower alkylamino group, a substituted or non-substituted Ariru group, a substituted or unsubstituted substituted heterocyclic group, or a - CO- showing R 3 (wherein, R 3 is lower alkyl, lower alkoxy, lower alkylthio group, a substituted or unsubstituted Ariru group, or a substituted or unsubstituted heterocyclic group ) (provided that when k is 0, R 2 is a group represented by not unsubstituted Ariru group), [1, 2, 4] preparative Riazoro [l, 5_A] pyrimidine derivative or a salt thereof.
PCT/JP1999/000828 1998-02-24 1999-02-24 Remedies/preventives for parkinson's disease WO1999043678A1 (en)

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WO2003020723A1 (en) * 2001-08-30 2003-03-13 Kyowa Hakko Kogyo Co., Ltd. [1,2,4]TRIAZOLO[1,5-a]PYRIMIDINE DERIVATIVE
WO2003048163A1 (en) * 2001-11-30 2003-06-12 Schering Corporation [1,2,4]-TRIAZOLE BICYCLIC ADENOSINE A2a RECEPTOR ANTAGONISTS
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US9289400B2 (en) 2010-08-11 2016-03-22 Drexel University D3 dopamine receptor agonists to treat dyskinesia in parkinson's disease
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WO2003020723A1 (en) * 2001-08-30 2003-03-13 Kyowa Hakko Kogyo Co., Ltd. [1,2,4]TRIAZOLO[1,5-a]PYRIMIDINE DERIVATIVE
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WO2003048163A1 (en) * 2001-11-30 2003-06-12 Schering Corporation [1,2,4]-TRIAZOLE BICYCLIC ADENOSINE A2a RECEPTOR ANTAGONISTS
US6875772B2 (en) 2001-11-30 2005-04-05 Schering Corporation [1,2,4]-Triazole bicyclic adeonsine A2a receptor antagonists
EP2942082A2 (en) 2002-01-28 2015-11-11 Kyowa Hakko Kogyo Co., Ltd A2A receptor antogonists for use in the treatment of movement disorders
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EP2260850A2 (en) 2002-01-28 2010-12-15 Kyowa Hakko Kogyo Co., Ltd A2A receptor antogonists for use in the treatment of movement disorders
WO2004092171A3 (en) * 2003-04-09 2005-03-31 Biogen Idec Inc Triazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]pyrimidines useful as a2a adenosin e receptor antagonists
WO2004092173A3 (en) * 2003-04-09 2004-12-09 Biogen Idec Inc A2a adenosine receptor antagonists
WO2004092171A2 (en) * 2003-04-09 2004-10-28 Biogen Idec Ma Inc. Triazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]pyrimidines useful as a2a adenosin e receptor antagonists
WO2004092173A2 (en) 2003-04-09 2004-10-28 Biogen Idec Ma Inc. A2a adenosine receptor antagonists
US7285550B2 (en) 2003-04-09 2007-10-23 Biogen Idec Ma Inc. Triazolotriazines and pyrazolotriazines and methods of making and using the same
WO2004092177A1 (en) * 2003-04-09 2004-10-28 Biogen Idec Ma Inc. Triazolopyrazines and methods of making and using the same
US7674791B2 (en) 2003-04-09 2010-03-09 Biogen Idec Ma Inc. Triazolopyrazines and methods of making and using the same
US7834014B2 (en) 2003-04-09 2010-11-16 Biogen Idec Ma Inc. A2a adenosine receptor antagonists
EP2258372A1 (en) 2005-06-07 2010-12-08 Kyowa Hakko Kirin Co., Ltd. A2A antagonists for use in the treatment of motor disorders
US7851478B2 (en) 2005-06-07 2010-12-14 Kyowa Hakko Kirin Co., Ltd. Agent for preventing and/or treating movement disorder
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