WO2005002583A1

WO2005002583A1 - Use of thieno`2,3-d ! pyrimidines for the prophylaxis or treatment of hyperactivity disorder

Info

Publication number: WO2005002583A1
Application number: PCT/JP2004/009994
Authority: WO
Inventors: Junichi Eguchi; Yuji Inomata
Original assignee: Mitsubishi Pharma Corporation
Priority date: 2003-07-07
Filing date: 2004-07-07
Publication date: 2005-01-13

Abstract

In order to develop a method for the prophylaxis or treatment of hyperkinetic disorders or attention-deficit/hyperactivity disorder, the present invention offers a thieno[2, 3-d]pyrimidine derivative, an optical isomer thereof, a medicinally acceptable salt, a hydrate thereof or a solvate thereof.

Description

DESCRIPTION

USE OF THIENO*2,3-D!PYRIMIDINES FOR THE PROPHYLAXIS OR TREATMENT OF HYPERACTIVITY DISORDER Techn i cal Field The present invention concerns the invention of a medicament which is useful for the prophylaxis or treatment of hyper ac t i v i ty disorder or attention-defici t/hyperactivity disorder. Background Ar t Hyperkinetic disorders or t t en t i on-de i c i t/hyper c t i vi t y disorder (hereafter ADHD) is a psychiatric disorder which is characterized by hyper ac t i v i ty, impulsivity and inattention at developmental stages. Hyperkinetic disorders or ADHD initiates usually in infancy, tends to be unchanged during lifetime and is featured by excessive activity which is disproportional to his/her age and by failure to co^' trol his/her behavior. In the United States, approximately 5% of all children have been reported to suffer from ADHD. Regarding the etiologies of hyperkinetic disorders or ADHD, sorts of etiological theories, e.g., perinatal brain damage, inheritance, abnormalities in the CNS nor e inephr i ne and dopamine systems, and lead poisoning, have been proposed. However, the etiologies still remain unclear. Hyperkinetic disorders or ADHD develops in children before age 6. Pathologically, hyper ac t i v i ty itself tends to subside ith their age. However, hyperkinetic disorders or ADHD frequently progresses to oppositional defiant disorder, which warrants sufficient treatment at an early stage. The habilitation method is employed to treat hyper hyperkinetic disorders or ADHD. Psychotherapy, educational therapy and sensory integration therapy are conducted for patients to encourage their adequate soci l 1 i f e . Furthermore, pharmac o t her apy using psychos t i mu i an t s (e.g., me thy 1 hen i da t e) , an t i psycho t i cs (e.g., haloperidol) and other agents (e.g., atomoxetine) is also instituted. Ho ever, it still remains uncertain whether these pharmaceutical agents are sufficiently effective for the treatment of hyper hyperkinetic disorders or ADHD, and also these pharmaceutical agents exhibit serious adverse effect. The thieno[2, 3-d] py r imi d i ne derivative of claim 1 has been shown to be effective as a therapeutic medicament in the publications listed below. Namely, Patent Literature 1 has disclosed that the derivative is useful as a medicament hich improves sorts of depressive disorders including psychosomatic disorders and bipolar disorders. Patent Literature 2 has disclosed that the derivative is useful as a medicament which improves impaired high-level functions of the brain, e.g., presenile dementia and sequela of brain stroke. Patent Literature 3 has disclosed that the derivative has excellent anticonflict activity and is useful as an anxiolytic which improves anxiety disorders, stress-induced disorders, and somatoform disorders. However, these publications have neither suggested nor indicated that the abovementioned compounds are useful for the prophylaxis and treatment of hype hyperkinetic disorders or ADHD. Nonpatent Literature 1 has suggested that the compound of claim 3 is effective for the treatment of inattention because it improves eye tracking of cats in midpontine per i t r i e i n 1 preparation. However, the relevant literature did not show that methylphenidate, hich has been reported to be effective for the treatment of hyper hyperkinetic disorders or ADHD, was definitely effective in that animal model. These results show that the relevant animal model is not appropriate as a model for hyperkinetic disorders or ADHD. The t h i e n o [ 2 , 3-d] yr imi d i ne derivative of claim 1 has an advantage of allowing an expectation for therapeutic efficacywithout adverse effects, e.g., growth inhibition, or without a risk of drug dependence because the derivative does not inhibit dopamine reuptake as compared with psychosti ulants, e.g., methylphenidate, a therapeutic medicament for hyper hyperkinetic disorders or ADHD. As compared with an t i psycho t i c medicaments, e.g., haloperidol? a therapeutic medicament for hyper hyperkinetic disorders or ADHD which has a mechanism of action differing from that of psychostimulants, the t ieno [2, 3-d] py r imi d i ne derivative of claim 1 has an advantage of allowing an expectation for therapeutic efficacy without adverse effects due to dopamine D₂_r ecep t or i nhi b i t i on (e.g., ex t r apyr ami da 1 symptoms, dystonia, and acathisia) and to an t i cho 1 iner gi c activity (e.g., constipation, imbalance, and delirium) because it has neither dopamine D₂-receptor inhibitory activity nor an t i cho 1 i nerg i c acti it . Nonpatent Literature 1 has reported that the compound of claim 3 possesses no r adr ena 1 i ne r eup t ake- i nh i b i t o ry activity and antagonistic activity against the 5-HT₃ receptor. On the other hand, atomoxetine, a therapeutic medicament for hyperactivity disorder or ADHD, is a selective noradrenaline reuptake inhibitor. Furthermore, Nonpatent Literature 2 has reported that the administration of selective noradrenaline re-uptake inhibitor, desipramine and nisoxetine, reduces hyperactivity of 6-OHDA- t r ea t ed rats, a common model for hyperkinetic disorders or ADHD. However, nobody has reported that the medicaments which have both noradrenalin r eup t ake- i nh i b i t i on activity and 5-HT₃ antagonistic activity are effective for hyper hyperkinetic disorders or ADHD. Psychostimulants in current use as therapeutic medicaments for hyper kinetic disorders or ADHD, e.g., methyl henidate, are known to provoke drug dependence. On the other hand, Nonpatent Literature 3 has reported that 5 -HT ₃ antagonists reduce drug dependence. Therefore, the combined use of the thieno[2, 3-d]pyrimidine derivative of claim 1 and psychostimulants, e.g., methylphenidate, allows to expect that the 5-HT₃ antagonistic profile of a [2, 3-] th i enopyr imi d i ne derivative inhibits drug dependence which psychostimulants, e.g., methylphe idate, may provoke. In contrast, this effect is unexpectable for selective noradrenaline reuptake inhibitors, e.g., atomoxetine. Psychostimulants, e.g., methyl henid te, are known to occasionally provoke abdominal pain as an adve r s ee f f ec t . Alosetron, a 5-HT₃ antagonist, is a pharmaceutical drug which improves gastrointestin l functions and reduces abdominal pain. Therefore, the combined use of the thieno[2, 3-d] py r i m 1 d i ne derivative of claim 1 and psychostimulants, e.g., methylphenidate, allows to ex ect that the 5-HT₃ antagonistic activity of a thieno[2, 3-d]pyrimidine derivative reduces abdominal pain which psychostimulants, e.g., met yl henidate, may provoke. In contrast, this effect is unexpectable for selective noradrenaline reuptake inhibitors. Hyperkinetic disorders or ADHD is known to provoke symptoms of depression and anxiety as secondary impa i rmen t s . Patent Literature 1 has reported that the thieno[2, 3-d] pyr imi d i ne derivative of claim 1 has an t i depr es s an t like activity. Patent Literature 3, Nonpatent Literature 3 and Nonpatent Literature 4 have reported that a thieno[2, 3-d] pyr imi d i ne derivative has anxiolytic like activity which is based on 5-HT₃ antagonism. Therefore, the t h i e n o [ 2 , 3-d] pyr imi d i ne derivative of claim 1 allows to expect efficacy also for secondary impairments, depression and anxiety symptoms, in addition to efficacy for cardinal symptoms of hyperkinetic disorders or ADHD. In contrast, selective noradrenaline reuptake inhibitors, e.g., atomoxetine, allow to expect efficacy for a secondary impairment, symptoms of depression, but not for symptoms of anxiety, in addition to efficacy for cardinal symptoms of hyperkinetic disordersor ADHD. Furthermore, a selective serotonin reuptake inhibitor, fluvoxamine, and a s er o t on i n/nor adr ena 1 i n dua 1-r eu t ake inhibitor, ilnacipran, are used for secondary impairments of hyperkinetic disorders or ADHD? symptoms of depression and anxiety. In general terms, however, these therapeutic medicaments are unexpectable for improvement of cardinal symptoms of hyperkinetic disorders or ADHDThe invention has the following objectives: provision of a therapeutic medicament with superior therapeutic efficacy and less adverse effects than existing medicaments for cardinal symptoms and secondary impairments of hyperki ne t i c d i s or der s or ADHD; and provision of a therapeutic medicament which, through a combination with a psychos t i u 1 an t , allows a reduction in adverse effects of the psychos t imu 1 an t and acquisition of better therapeutic effects thereof.

(Prior literature)

(Patent Literature 1)

Examined Patent Application Publication No. H03-67071

(Patent Literature 2)

Examined Patent Application Publication No. H05-48028

(Patent Literature 3)

Examined Patent Application Publication No. H10-298078

(Nonpa t en t Literature 1)

Pharmacology Biochemistry and Behavior 1997 Vol. 56, No.

2, pp : 229-234

(Nonpa t ent Literature 2)

Journal of Pharmacology and Experimental Therapeutics 2002 Jun; 301(3) .1097-1102

(Nonpa tent Literature 3)

Pharmacology Biochemistry and Behavior 2003 Vol. 74,

PP297-302

(Nonpatent Literature 4)

Pharmacology Biochemistry and Behavior 2001, 68, 4,

677-683 Disclosure of the Invention The inventors were devoted themselves to investigations. Consequently, the inventors discovered that a thieno[2, 3-d] pyr i i d i ne der i v t i e, amedicinally acceptable salt thereof or a hydrate thereof could become a preventive or therapeutic medicament for hyperkinetic disordersor ADHD which provokes less adverse reactions, resulting in completion of the invention. The present invention o l i e r s a medicament which i s useful for the prophylaxis or treatment of hyperkinetic disordersor ADHD. Namely, the present invention is as described belo .

[1] A medicament for the prophylaxis or treatment of hyperkinetic disorders or a 11 en t i on-de f i c i t/hyper c t i v i ty disorder, which medicament comprises as anactive ingredient- a thieno[2, 3-d]pyrimidine derivative represented by the formula (I), an optical isomer thereof, a medicinally acceptable salt thereof, a hydrate thereof or a solvate thereof:

wherein R_[ and R₂ represent a hydrogen atom, a halogen atom or an alkyl of C, to C₆, and R₃ and R.₍ represent a hydrogen atom or an alkyl of C, to C₆, and R₅ represents a hydrogen atom or an alkyl of C, to C₆, or the formula (II)

(wherein m represents an integer of 1 to 3, and X represents a halogen atom), or the formula (III) C-NH-R⁶ II (ill) 0

(wherein R₆ represents an alkyl of C , to C₆), and Ar represents an optionally substituted phenyl or a 2-thienyl or 3-thienyl, and n represents an integer of 2 or 3.

[2] The medicament of claim 1, wherein Ar represents a phenyl, a 2-thienyl or a 3-thienyl: wherein phenyl can be substituted with a halogen atom, an alkyl of C, to C₅, an alkoxy of C, to C₆, a hydroxyl, a nitro, a cyano, alky 1-subs t i tut ed ami no.

[3] A medicament for the prophylaxis or treatment of hyperkinetic disorders or attention-deficit/hyperactivity disorder, which medicament comprises as an active ingredient - 4-(2-fluorophenyl)-6~methyl-2-(l-piperazinyl)thieno[2, 3-d]pyrimidine, an optical isomer thereof, a medicinally acceptable salt thereof or a hydrate or a solvate thereof.

[4] Use of a substance for the manufacture of a medicament for the prophylaxis or treatment of hyperkinetic disorders or t t en t i on-de f i c i t/hyper ac t i v i t y disorder, which substance comprises a thieno[2, 3-d] py r i mi d i ne derivative represented by the formula (I), an optical isomer thereof, a medicinally acceptable salt, a hydrate thereof or a solvate thereof:

(wherein, each symbol is synonymous to claim 1)

[5] Use of the substance of claim 4, wherein Ar represents a phenyl, a 2-thienyl or a 3-thienyl: wherein phenyl can be substituted with a halogen atom, an alkyl of C, to C₅, an alkoxy of C[ to C₆, a hydroxyl, a nitro, a cyano, al ky 1-subs t i t u t ed amino.

[6] Use of a substance for the manufacture of a medicament for the prophylaxis or treatment of hyperkinetic disorders or a t t en t i on-de f i c i t/hyper ac t i v i ty disorder, which substance comprises

4-(2-fIuorophenyl)-6-methyl-2-(l-piperazinyl)thieno[2, 3-d] py r i mi d i ne, an optical isomer thereof, a medicinally acceptable salt thereof or a hydrate or a solvate thereof

[7] A method for the prophylaxis or treatment of hype rkinetic disorders or a t t en t i on-de f i c i t/hype ac t i v i ty disorder, which met hod compri es administering a medicament to mammalian anim a 1 s at a prophylactic or t herapeu t i ca 11 y effective do s e, wherein the medicament comprises, as an active ingredi en t - a thieno[2, 3-d] py i m i d i ne derivative represented by the formula (I), an optical isomer thereof, a medi. cina lly acceptable salt, a hydrate thereof or a solvate there of:

(wherein, each symbol is syno.ny ous to claim 1).

[8] The method of claim 7, wherein Ar represents a phenyl, a 2-thienyl or a 3-thienyl: wherein phenyl can be substituted with a halogen atom, an alkyl of C, to C₅, an alkoxy of C, to C₆, a hydroxyl, a nitro, a cyano, a 1 ky 1 -subs t i t u t ed amino.

[9] A method for the prophylaxis or treatment of hyperkinetic disorders or a t t en t i on-de f i c i t/hyper ac t i vi ty disorder, which method comprises administering a medicament to mammalian animals at a prophylactic or t her apeu t i ca 1 ly effective dose, wherein the medicament comprises, as an active ingredient- 4- (2-fluorophenyi) -6-met yl-2- (1-piperaz inyl) th ieno [2- 3-d] pyr imi d i ne, an optical isomer thereof, a medicinally acceptable salt or a hydrate or a solvate thereof. Brief Description of the Drawings Fig.l is a drawing which shows the inhibitory effect of compound A on the enhanced motor activity of 6-OHDA- t rea t ed young rats. (Method 1) Best Mode for Embodying the Invent-ion A t h i e n o [ 2 , 3-d]pyrimidine derivative of the present invention, a medicinally acceptable salt thereof or a hydrate thereof show usefulness for the prophylaxis or treatment of hyperkinetic disorders or ADHD. Namely, they reducehyperactivity of 6-OHDA-treated rats, a common model for hyperkineticdisorders or ADHD,. 6-OHDA-treated rats, the most frequently investigated model among a number of models for hyperkinetic disorders or ADHD, are well evaluated by investigators in countries of the orld through its use for 20 or more years. Because of exhibition of its activity in the present model, a compound of the present invention is useful as a medicament which may be used to improve hyper kine t i cd i s or der s or ADHD. Medicinally acceptable salts include acid-added salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid) or organic acids (e.g., acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, me t hanesu 1 f on i c acid, benz enesu 1 f on i c acid, p- t o 1 uenesu 1 f on i c acid, camphor s u 1 on i c acid and ascorbic acid). In the case of using a compound of the present invention as a medicament, it is possible to administer it orally or parenterally in the form of tablets, pills, capsules, granules, po ders, syrups, emulsions, elixirs, suspensions, solutions, injections, drops, suppositories, etc. which can be obtained by the formulation of medicament components to be obtained by mixing a compound of the present invention with pharmaceutically acceptable carriers (e.g., excipients, binders, d i s i n t egr an t s , flavoring agents, emulsifying agents, diluents and solubilizing agents) according to conventional procedures. In the present patent specific tions, parenteral should include subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip i n f us i on me t hod, etc. An injection, e.g., sterile aqueous suspension for injection and sterile oily suspension for injection, can be prepared by using an appropriate dispensing agent, humectant or suspending agent according to the procedures which are known in the relevant art. Furthermore, a sterile injection may be a nontoxic parenterally admi n i s t r ab 1 e diluent (e.g., aqueous solution), a sterile injectable solution or a suspension in solvent. Water, the Ringer solution, isotonic saline and others may be mentioned as acceptable vehicles or solvents which can be used. Usually, in addition, a sterile nonvolatile oil can be used as a solvent or suspending medium. Any nonvolatile oil and a fatty acid may be used for this objective, and a natural, synthetic or s emi syn t he t i c fatty oil or a fatty acid, as well as a natural, synthetic or se isynthetic mono-, d i - or triglyceride is included. A suppository for rectal administration may be manufactured by mixing a medicament with an appropriate nonirritable excipient, e.g., cocoa butter and po I ye t hy I enegl yco 1 which are solid at room temperature but are liquid at an intestinal temperature and which are melt within the rectum and releases the med i camen t . Po ders, granules, tablets, pills, capsules and others which described above may be mentioned as solid dosage forms for oral administration. In such dosage forms, the active ingredient compound may be mixed with at least one additive, e.g., saccharose, lactose, cellulose, mannitol, multitol, dextran, starches, agar, arginates, chitins, chitosans, pectins, t r agacan t h gums, gumarabics, gelatins, chollagens, casein, albumin, synthetic or semi syn the t i c polymers, or glycerides. Furthermore, such dosage forms can contain further additives as usual. For example, inactive diluents, lubricants (e.g., magnesium stearate), preservatives (e.g., paraben, sorbic acid or its salt), antioxidants (e.g., ascorbic acid, ?-tocopherol and cysteine), d i s i n t egr an t s , binders, buffers, sweeteners, flavoring agents, and perfumes may be mentioned. In addition, tablets and pills can be manufactured after enteric coating. Regarding solutions for oral ad inistration, emulsions, syrups, elixirs, suspensions, solutions and others which are acceptable as medicaments can be mentioned. These may contain inactive diluents which are usually used in the relevant field, e.g., ater. According to age, body weight, general health condition, gender, diet, ad inistr tion period, administration method, excretion rate, medicament combination and the severity of symptoms of the patient at the moment, doses are determined in consideration of these or other factors. A compound of the pres nt invention, an optical isomer thereof, a medicinally acceptable salt thereof, a hydrate thereof or a solvate thereof present low toxicities and can be used safely. Their daily doses differ depending on the condition or body eight of the patient, class of compound, route of administration and others. For example, the following doses are desirable: parenterally (s ubcu t aneous ly, intr venously, intramuscularly or i n t r ar ec t a 11 y) , approximately 0.01 to 50 mg/per s on/day, and preferentially 0.01 to 20 mg/per s on/day ; and orally, approximately 0.01 to 150 g/person/day, preferentially 0.1 to 100 mg/pe r s on/day. Examp 1 es Preparation samples and results of pharmacology studies are shown below. However, these examples are for a better comprehension of the present invention and do not restrict the scope of the present invention. Exam le 1: Preparation After good mixing of the 0.5 parts compound of the present invention, 25 parts lactic acid, 35 parts crystallized cellulose, and 3 parts corn starch, knead them well with a binder which was made with 2 parts corn starch. Sieve this kneaded material with the 16 mesh. After drying at 50 ?C in an oven, sieve it with the 24 mesh. After good mixing of the kneaded po der obtained here with

8 parts corn starch, 11 parts crystalline cellulose and

9 parts talk, conduct compression tabletting to obtain tablets which contain 0.5 mg of the active ingredient per tablet.

Example 2: Inhibiton on the hyperactivity In 6-OHDA-treated rat pups Experimental examples are used to explain the pharmacological actions of a medicament of the present i nven t i on. The thieno[2, 3-d] py r im i d i ne derivative of claim 3 was used as a test compound. The relevant compound is hereafter termed compound A. (Methods) On days 3 and 6 after birth, male Wistar rats were pretreated with desipramine (20 g/kg, sc). Subsequently, 35 ?g of 6-hydr oxy dopam i ne (6-OHDA) were injected i n t raven t r i cu 1 ar ly into the right and left lateral ventricles on days 3 and 6, respectively. On each of days 14, 16, 18, 20, 22, and 25 after birth, spontaneous motor activity was measured for the adaptations the open field. On day 26 after birth, compound A (25 or 50 mg/kg) was administered orally to measure motor activity for 60 minutes from 1 hour after administration. (Results and Discussion) As shown in Fig. 1, the administration of compound A reduced the hyperactivity in 6-OHDA-treated rat pups. A significant difference was found against the vehicle treated control group at the following timings: regarding compound A 25 mg/kg, at 20 to 30 minutes and 30 to 40 minutes after measurement onset; and regarding compound A 50 mg/kg, at 30 to 40 minutes after measur emen t onset. The above pharmacology experiment indicates that a thieno[2, 3-d] py r im i d i ne derivative is useful for the prophylaxis and/or treatment of hyperkinetic disorders or ADHD.

Claims

Claims 1. A medicament for the prophylaxis or treatment of hyperkinetic disorders or a t t en t i on-de f i c i t/hyper ac t i v i ty disorder, which medicament comprises as an active ingredient, a thieno[2, 3-d]pyri idine derivative represented by the formula (I), an optical isomer thereof, a medicinally acceptable salt thereof or a hydrate or a solvate thereof:

wherein R, and R₂ represent a hydrogen atom, a halogen atom or an alkyl of C, to C₆, and R₃ and R represent a hydrogen atom or an alkyl of C_t to C₆, and R₅ represents a hydrogen atom or an alkyl of C, to C₆, or the formula (II)

(wherein represents an integer of 1 to 3, and X represents a halogen atom), or the formula (III) C-NH-R⁶ II (III) 0

(wherein R₆ represents an alkyl of C, to C₆) , and Ar represents an optionally substituted phenyl or a 2-thienyl or 3-thienyl, and n represents an integer of 2 or 3

2. The medicament of claim 1, wherein Ar represents a phenyl, a 2-thienyl or a 3-thienyl: wherein phenyl can be substituted with a halogen atom, an alkyl of C, to C₅, an alkoxy of C, to C₆, a hydroxyl, a nitro, a cyano, al yl-substituted amino.

3. A medicament for the prophylaxis or treatment of hyperkinetic disorders or a t t en t i on-de f i c i t/hyper ac t i v i ty disorder, which medicament comprises as an active ingredient - 4-(2-fluorophenyl)-6-methyl-2-(l-piperazinyl)thieno[2, 3-d] py r i mi d i ne, an optical isomer thereof, a medicinally acceptable salt thereof or a hydrate or a solvate thereof.

4. Use of a substance fo. ... e manufacture of a medicament for the prophylaxis or treatment of hyperkinetic disorders or a t t en t i on-de f i c i t/hyper ac t ivi ty disorder, which substance comprises a4-(2-fluorophenyl)-6-methyl-2-(l-piperazinyl) thieno [2, 3-d] py r imi d i ner ep r es en t ed by the formula (I), an optical isomer thereof, a medicinally acceptable salt or a hydrate or a solvate thereof: R3 R4. -< s CD

R2 Ar

(wherein, each symbol is synonymous to claim 1)

5. Use of the substance of claim 4, wherein Ar represents a phenyl, a 2-thienyl or a 3-thienyl: wherein phenyl can be substituted with a halogen atom, an alkyl of C, to C₅, an alkoxy of C, to C₆, a hydroxyl, .a nitro, a cyano, alky 1 -subs t i tut ed amino.

6. Use of a substance for the manufacture of a medicament for the prophylaxis or treatment of hyperkinetic disorders or t t en t i on-de f i c i t/hyper ac t i v i ty disorder, which substance comprises 4~(2-fluorophenyl)-6-methyl-2-(l-piperazinyl)thieno[^'2, 3-d]pyrimidine, an optical isomer thereof, a medicinally acceptable salt thereof or a hydrate or a solvate thereof.

7. A method for the . 'ophylaxis or treatment of hyperkinetic disorders or a t t en t i on-de i c i t/hyper ac t i v i ty disorder, which method comprises administering a medicament to ammalian animals at a prophylactic or ther apeu t i c a 11 y effective dose, wherein the medicament comprises, as an active ingredient- a thieno[2. 3-d] py r imi d i ne derivative represented by the formula (I), an optical isomer thereof, a medicinally acceptable salt or a hydrate or a solvate thereof:

(wherein, each symbol is synonymous to claim 1)

8. The method of claim 7, wherein Ar represents a phenyl, a 2-thienyl or a 3-thienyl: wherein phenyl can be substituted with a halogen ato , an alkyl of C, to C₅, an alkoxy of C, to C₆ , a hydro^' yl, a nitro, a cyano, a 1 ky 1 -s ubs t i t u t ed am i no.

9. A method for the prophylaxis or treatment of hyperkinetic disorders or attention-deficit/hyperactivity disorder, hich method comprises administering a medicament to ammalian animals at a prophylactic or t he r apeu t i ca 11 y effective dose, wherein the medicament comprises, as an active ingredient- 4-(2-fluorophenyl)-6-methyl-2-(l-piperazinyl)thieno[2, 3-d] py r imi d i ne, an optical isomer thereof, a medicinally acceptable salt or a hydrate or a solvate thereof.