JPS59148780A - Antipsychotic 5-fluoro-pyrimidin-2-yl piperazine compound - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a drug using a pyrimidine-based heterocyclic organic compound as an active ingredient, a composition for treating a disease by affecting an organism, and a method for using the same.

The related technology is the following structural formula: (in the formula, n represents 4 or 5, W and Y are different, υ1 is C
H and the other represents N, and R1 and R2 are independently selected from the substituents consisting of hydrogen and halogen among other moieties.

Tsuhara J, Med, Chem, 1515, 4
No. 77-479 (1972) and US Pat. In addition, three types of 5-substituted pyrimidinyl derivatives have been announced. In the above formula, W is N and Y is C-NO2, C-N HS 02 C4
Corresponds to compounds where R9 and C-9H. 5-halogenopyrimidines are not specifically disclosed or claimed.

The following documents are related, but not all columns are appropriate.

Icicle U.S. Patent No. 3.90, published September 23, 1975
No. 7゜801 is the above-mentioned W et al. patent No. 3,717,634.
It is part of the issue. US Pat. No. 3,907,801 claims materials based on pyridinyl compounds (eg, W and Y are both CH).

Icicle U.S. Patent No. 5.9', published August 24, 1976
76.77June is also claiming %y (%y) for the tranquilizing use of these compounds in some parts as well as soil.

U.S. Pat. No. 4,182,763 to Kasten et al., published January 8, 1980, discloses and claims the use of buspirone having formula (2), a test compound of the above type for the treatment of anxiety. There is.

No. 3,398, published August 20, 1968,
No. 151 discloses and claims related compounds in which the pyrimidine ring is substituted with sj', substituted (eg, halogen), or centered with an unsubstituted phenyl group.

Tsura J, MedicinalChem, 12
/ 4.876-881 (1969) reports on those having these phenyl homologs. However, neither the examples nor any of the tables honor the fluoro-substituted phenyl congeners.

In the end, on December 28, 1981, Bamboo Permit Application No. 06/
Attention is drawn to No. 334.688. This patent application discloses that 1-[4-(4,4-dialkyl-2,6-biperidinedione-1-yl)phthyl] with a 2-pyridinyl substituent in the 4-position exhibits convenient mental stability. Published a piperazine series and claimed a patent. The pi IJ midine ring of this compound thread can be unsubstituted or fluoro, chloro, hydroxyl, or id
Any one having trifluoromethyl 1tlL-1 may be used.

The present invention includes a compound 8-(4-[4
-(5-fluoro-pyrimidin-2-yl)-i-piperazinyl]butyl]-8-azaspiro[: 4,5]
] Includes findings that further demonstrate Tecan-Z9-Geo's long-acting psychotic therapeutic activity. This pharmacological activity sets the invention apart from related pyrimidinyl compounds of the above-mentioned literature. This literature compound primarily acts as an anxiolytic, but its psychotic action is poor and its duration is short.

a-(+-[+-(s-fluoro-pyrimidin-2-yl)-1-piperazinyl]butyl]-8-azaspiro[
45] Decane-Z9-dione (1, hereafter MJ14594
) and its pharmaceutically acceptable salts have useful psychotherapeutic activity with good duration of action. This compound has the following structural formula (1): Formula I A single method including several methods (A, B and C) can be used to prepare compound MJ14594. Various methods of producing the same method in slightly different ways will also be apparent to those skilled in the art. The Examples will describe specific examples of preferred embodiments.

Single method ■■ or H may be used. The relationship between W and Y is as follows: X represents a suitable substituent such as chloride, bromide, iodide, sulfate, phosphate, tosylate or mesylate. The intermediate compound 11b is easily converted into Sum 1 class 2b', which is the only compound that can be easily separated. The two compounds must be equivalent for use as intermediates.

Method Person 11a [la Method B I [1b' Method C] 1 c ■c The condensation process of Method A is carried out by refluxing the reactants in a forcefully dry inert reaction medium of pyridine or xylene. Processes B and C are carried out under reaction conditions that produce tertiary amines by alkylation of secondary amines. The reactants are heated to about 60 to about 150°C in the presence of an acid binder in a suitable organic liquid. Benzene, dimethylformamide, ethanol, a7tonitrile, toluene, and n-butyl alcohol are preferred examples of organic reaction liquid media. The preferred acid binder is potassium carbonate, but other unrooted and tertiary organic bases, other alkali and alkaline earth metal carbonates, bicarbonates, or hydrides and tertiary amines, etc., can also be used. [ :4-(j-piperazinyl)
-butyl] azaspirodecanedione (V) can be reacted with a suitable pyrimidine system to give a compound of formula I as follows: (v) This variant is derived from the preferred method of preparing I below. .

The intermediate spiroglutaric anhydride or imide with formula ■ can be found in the above literature. It is either commercially available or described in Specification 1.

Pyrimidinylpiperazine intermediates (In) are described in the above-mentioned patents or literature. Although these methods are not specifically described in this specification, they can be used to prepare the 5-fluoropyrimidinylpiperazine intermediate required as an intermediate in the present invention, and for further illustration, a representative synthesis method for ll1c is provided as a practical example. shows.

Intermediate ■a, l! :I! Ib and nlc can be easily obtained by the standard method shown by Tsura.

This synthetic method begins with 5-pluorouracil and proceeds through known reactions to the desired piperazine intermediate. There is also a method using carbethoxypiperazine, but it is a by-product (lIT
It is somewhat superior because it has a higher yield than that of 'c.

In fact, it has been found that it is convenient to produce I from Hv and V as shown in the following reaction equation: The unique psychotropic tendency exhibited by MJ 14594 was determined as a result of the following screening tests. M.J.
14594 is approximately three times more effective than buspirone in the conditioned avoidance response test using the methods described in the above-mentioned patents and literature.

This test method is administered orally to fasted mice and generally reflects psycholeptic activity without necessarily distinguishing Fukujin tranquilizers from psychotherapeutic compounds. What is even more interesting is MJ1
10 when 4594 was orally administered at 35 my/Kg
It was found that the effect was approximately three times longer than when buspirone (0 mg/Kt) was orally administered.

A more definitive test of psychotherapeutic efficacy is the apomorphine stereotypy behavioral test in fasted Hikoi mice. This test determines the ability of the central active compound to prevent the ``symptomatic behavior'' caused by apomorphine. The more effective this clinical trial is, the more effective it becomes as a guideline for the treatment of psychotic diseases.
Arzneimittel-Farsc of Jansen et al.
h, 17.841 (1966)).

MJ14594 was approximately as potent as buspirone in this reversal of the avomorph instereotopy test, with activity lasting as long as 6 hours versus 1-2 hours for buspirone in this test.

The psychosis treatment drug is postsyn
aptic) is believed to modulate psychotic symptomatology by acting as a dopamine receptor inhibitor. Since the stereotopic reversal test reflects dopamine suppressive activity, 2
A comparison of the duration of action of the drugs shows that the inhibitory component (psychotic therapeutic action) of MJ14594 is long-lasting, but that of buspirone disappears rapidly.

Further reasons for classifying MJ14594 as a psychotic drug derive from radioreceptor binding studies. The radioreceptor binding test measures the binding inhibition of neuronally active molecules in the brain and is particularly used to measure tranquilizing activity. Although it only lasts from to-20,
Its properties seem much more like an inhibitor. The binding affinity of buspirone at the [H3]spiberone-tagged receptor is reduced in the presence of 5 μM guanine triphosphate (GTP), whereas that of MJ14594 is essentially unchanged. GTP-induced changes in the binding to indicate agonist activity, whereas no change is consistent with an inhibitory effect. Literature related to dopamine receptor binding tests and their reflection of psychotherapeutic activity includes: Molecular Pharmacolo by Burt, Freeze and Snyder.
gy, 12.800 (197s; Burt, Freeze and Snyder's 5science, 196°326
(1977); Freeze, Peart and Snyder 5
Freeze, Prosser and Snyder, Life 5ci.
ence, 23.495 (1978); Freeze and Snyder, European Journal
of Pharmacology, 50.459
(1978); Freeze, Asgin and Snyder, Nature, 278.577 (1979).

MJ 14594's mouse Vogel model anxiolytic behavioral example test shows that this compound has no activity at doses below 5η/Kq;
．． Buspirone at 0η/'Ky shows activity. The murine Fonigel model is a modification of the Vogel fight test, a reliable fight test for testing anxiolytics (Vogel,
Biya and Claudie Psychopharmaco
logia (Berl) 21.1-7 (197
1)).

Further data has been added from comparative studies in other CNS examination methods. Although MJ 14594 does not show catalepsy at doses of 70 η/Kq (higher doses cause toxicity), buspirone does not reverse the catalepsy caused by trifluoperazine. Recently developed monkey motels (Kobacic, Domino's J, C11n, Ps
ycho harmacol,, 2.305-30
7 (1982)], MJ14954 appeared to be ineffective against the development of clinical side effects such as extrapyramidal symptoms.

Therefore, MJ14594 appears to have significantly more therapeutic properties than most conventional psychotic drugs. MJ1459
4 indicates a cat central electroencephalogram type that is similar to buspirone but shows better efficacy than buspirone.

Taken together, the in vivo efficacy, long duration of action, and depressant-like binding properties of MJ14594 clearly demonstrate that the pharmacological activity of this psychotherapeutic compound is distinct from that of buspirone and its related compounds.

Depending on the pharmacological properties established by the above tests, the formula (1
, 1 has a pleasant effect as a therapeutic agent for psychosis. Therefore, another form of the invention involves systemically administering to a mammal in need of psychiatric treatment an effective dosage of about 0.01 to 40 μg per kilogram of body weight of a compound having the formula (2) or a pharmaceutically acceptable acid addition salt thereof. The present invention relates to a method for treating mental illness in mammals, comprising:

As used herein, systemic administration refers to oral, rectal and parenteral (i.e. intramuscular, intravenous and subcutaneous) administration methods.
Oral administration of the compounds of this invention, which is the preferred method, requires a much larger amount of active agent to produce the same effect as a smaller amount given parenterally. In clinical practice, the compounds of the present invention may be administered at concentrations that effectively produce psychosis treatment effects without causing harmful or troublesome side effects.

In general therapy, the compounds of this invention are provided in a pharmaceutical composition comprising a psychotherapeutically effective amount of MJ14594 or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.

Pharmaceutical compositions containing from about 1 to 500 μl of active ingredient per unit dose are preferably conveniently prepared as tablets, buccal tablets, capsules, powders, aqueous and oily suspensions, syrups, elixirs, and aqueous solutions.

Preferred oral compositions are tablets and capsules containing common excipients, such as binders (such as syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone), fillers (lactose, sugar, cornstarch, calcium phosphate, sorbitol). or glycine], lubricant (
For example, magnesium stearate, Merck, polyethylene glycol or silica], disintegrating agents (eg starch) and wetting agents (eg sodium lauryl sulfate), etc. may also be included.

Solutions or suspensions of MJ14594 and common pharmaceutical excipients can be used in parenteral compositions, such as aqueous solutions for intravenous injection or oil suspensions for intramuscular injection. This composition of desired clarity, stability and suitability for parenteral use can be prepared in excipients consisting of water or polyhydric aliphatic alcohols such as glycerin, polypyrene glycol, and polyethylene glycol or mixtures thereof. It is obtained by dissolving 0.1 to 10% by weight of the active compound. Polyethylene glycol consists of a mixture of non-volatile, normally liquid polyethylene glycols that are soluble in both water and organic liquids and have a molecular weight of about 200 to 1500.

The compounds constituting the present invention and their preparation will become fully clear from the following examples. The examples are for illustrative purposes only and should not be construed as limiting the scope of the invention. All temperatures are in degrees Celsius (°C).

Nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (δ) in ppm relative to tetramethylsilane (TMS) as a comparison standard. The comparative areas reported for various shifts of the proton NMR spectrometer correspond to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shift regarding plurality is medium-broad singlet (BS), singlet (S),
Reported as multiple rings (m, l or doublet (+1). Symbols used are DMSO-d6 (deuterodimethylsulfoxide), CDCl3 (deuterochloroform)
The rest is normal. The infrared (IR) spectral description is only absorption wavenumbers (crn-') with functional group identification values. The IR measurements were carried out using potassium bromide (KBr) as a diluent. Elemental analysis is reported as grade 1.

Example 1 5-fluorouracil 262 (262) in dioxane 500-
A mixture of 459 (0.12 mol) and 459 (0.2 mol) pentasulfide was heated under reflux for 3 hours.The hot reaction mixture was filtered once and concentrated in vacuo.The residue was dissolved in 650-ml of water and heated with activated carbon 52 and heated for 1 filtration. After cooling, the crystallized solid was collected by filtration to obtain 25.49 (88%) of 5-fluoro-4-thiouracil, melting point 269-272°C.

5-Fluoro-4 in 0.15N NaOH350-
-Methyl iodide 59,49 (0,348 mol) was added dropwise to a solution of 25.4 r (0,174 mol) of -thiouracil.The mixture was stirred at room temperature for 2 hours, then cooled with ice and filtered for 1 hour.

The solid was crushed with methanol to produce the product 185y (
66%]. Melting point 205-207°C.

5-Fluoro-4-methylthiopyrimidin-2-one 2
1,19 (0,132 mol), phosphorus oxychloride 126
．． A mixture of 1' (0,824 mol) and N,N-dimethylaniline 2102 (0,224 mol) was heated under reflux for 2 hours. While cooling the mixture in an ice bath, ice was added and extracted with ether. The ether extract was converted into MgSO
, heat skelly B100mAX2 to dry and evaporate the residue.
Nito9 Skelly B supernatant was passed through to remove insoluble matter. Treat the liquid with activated carbon, filter it once, and concentrate it to ■20, El (88 cm).
I got it.

Example 2 Tetramethylene glutarimide 50,2 f (0,3 mol), 1,4-dibromobutane 1302 (0,6 mol) in 500 rnI toluene, and 2Co36.
A mixture of 7 f (0.7 mol) was heated under reflux for 20 hours, filtered and concentrated in vacuo. Distill the residue at 165-170℃
10.017 FIM, +8-[4-(1-bromo]butyl]-8-azaspiro[4,5]tecan-7°9-dione 64.ili' was obtained. This was dissolved in 900 ml of toluene with 90.4 r (1 ,05 mol] and 2C
O3145,52 (1.05 mol) was combined and heated under reflux for 18 hours. This was filtered once, concentrated in vacuo, and the residue was distilled (18
0-200℃70.01mM) l, VS2.7
I got a score of 9 (82%).

Example 3 8-[4-[4-(5-fluoro-2-pyrimidinyl)
-■4.479 (0,025 mol), V7.71 (0,
9 mol of K2CO3, 10,37f of K2CO3 (0.07 mol) and KI (contact amount) were mixed in 100 d of acetonitrile and heated under reflux for 18 hours. The mixture was filtered and concentrated in vacuo and the residue was chromatographed on 230ft silica gel eluting with 2% ethanol-chloroform. Removal of solvent yields 8-[4-(4-[5-fluoro-4-(methylthio)-2-pyrimidinyl-1-piperazinyl]butyl]-8-azaspiro(4,5)tecan-Z9-dione 9
．． Obtained Of (80%).

Compound s, s r (o, o
o s mol) and wet Nei nickel catalyst (1,5 tsp
) was heated under reflux for 3 hours.

This was filtered, the solvent was evaporated and the residue was heated with acetonitrile, filtered and concentrated in vacuo. The residue was heated with Skelly B on a steam bath, and the supernatant liquid was decanted from the insoluble matter and cooled to give compound 1,8 S' (59th) of I. Shaten 83-8
5℃.

C2□H3oF'N50. -0. Analysis value for I H2O: Calculated value: C,62,23: H17,5
1; N, 1728 Measured value: C, 62, 17;
H, 7,46; N, 16.88 Example 4 Hydrochloride Salt of MJ 14594 The hydrochloride salt of I was obtained by a modification of the above method. That is 8
-[:4-[4-[5-fluoro-4-(methylthio)
-2-pyrimidinyl-1-piperazinyl]butyl]-
8-Azaspiro[4,5]]tecan-z9-dione9.
(0.02 mol) of tri-isomer 10-1!M' was heated under reflux in 200 ml of ethanol for 6 hours, filtered and concentrated. 50 ml of water was added and the mixture was made alkaline with 50% NaOH and extracted with ether. The extract was dried with MgSO4 and the residue was dissolved in 20-20% ethanol and 2.15 ml of 7N ethanolic HCI was added to give 5.6t (64%) of MJ 14594 hydrochloride, melting point 224-22.
6℃0C2,:H3o FN502 # Analysis value for HC1: Calculated value: C, 57, 34; H17,
12; N, 15.92° Measured value: C157,4
2; H, 7, 15; N, i5.66°NMR (
DMSO-d,'): 150 (12, m); 2
．． 61 (4, s); 3.02 (4, m); 3.5
0 (4, m); 3.64 (2, t[6,9Hz])
; 4.54 (2, m); a51 (2, s); 1
1.70 (1, bs).

IR (KBr): 790, 1110, 1250, 1
350.1490, 1560, 1670, 1750, 2
600.2935 and 2950α-1゜ Procedural Amendment (Method) % Formula % 1. Indication of the case 1982 Patent/S+ No. 18502 2. Name of the invention 5-fluoropyrimidin-2-ylpiperazine for treatment of sheath psychosis Relationship with the person making the compound 3 amendment Patent applicant name Bristol-Myers Company Akasaka Taisei Building (telephone: 582-7161) Handwritten specification attached to Lu

Claims (1)

[Claims] 1. Compound 8. -[4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro(4,5)decane-Z9-dione or a pharmaceutically acceptable acid addition salt thereof. 2. A therapeutic agent for psychosis, which contains a compound represented by formula (I) or a pharmaceutically acceptable acid adduct thereof as an essential ingredient. 3. The therapeutic agent for psychosis according to claim 2, which is in a unit dosage form. 4. The psychosis treatment or agent according to claim 3, wherein the dosage is within the range of about 0.01 to about 401 ng of the compound having formula (1) or its pharmaceutically acceptable acid addition per kilogram of body weight. (a) If W is O in the above formula, then Y is H2N-(Ckb
) < - and the compounds ■ and ■ are reacted by a condensation method to lose water, or the compounds ■ and ■ are reacted to produce a tertiary amine by alkylation of a secondary amine. (cl W is N-(CH2)4-X, Y is H, and compounds B and m can be reacted under suitable conditions to produce a tertiary amine by alkylation of a secondary amine. A compound having the formula (1) is produced by contacting the compound with the formula (1) by reacting under suitable conditions (X in (b) and (c) above is an appropriate substituent), and (2) ff: A process for producing a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, which comprises producing a compound having formula I by a known method. 6. The process according to claim 5, using the above (a) and refluxing the compounds (1) and (2) in a dry inert reaction medium. from about 60 to about 1 in the presence of an acid binder in a suitable organic liquid.
6. A method according to claim 5, wherein the method is heated to a temperature range of 50<0>C. A compound having the formula ■: is brought into contact with a compound having the formula X: under conditions to produce a compound having the formula A method for producing a compound represented by the above formula I, which comprises producing a compound having the following formula: