JPH0319233B2 - - Google Patents

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 diseases that affect living things, 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, one is CH and the other is N, and R ¹ and R ² are substituents consisting of hydrogen and halogen among other moieties, regardless of their relationship) ). U et al., J.Med.Chem. 15/5, 477-479 (1972)
In US Pat. No. 3,717,634 published on February 20, 1973, a psychotropic compound having the above structure was disclosed. In addition, three types of 5-substituted pyrimidinyl derivatives have been announced. In these formulas, W is N and Y is C-
It corresponds to the compounds _NO2 , _C - _NHSO2C4H9 and C- _OH . 5-halogenopyrimidines are not specifically disclosed or claimed. The following documents are related but not very relevant. U.S. Patent No. 2, published September 23, 1975
No. 3,907,801 is part of the W et al. patent No. 3,717,634 mentioned above. U.S. Patent No. 3907801 discloses a substance mainly composed of pyridinyl compounds (for example, W and Y are both
CH). U.S. Patent No. 2, published August 24, 1976
Similar to the above, No. 3976776 also partially claims the use of these compounds for tranquilizing the mind. U.S. Patent No. Kasten et al., published January 8, 1980.
No. 4182763 discloses specific compounds of the above series for the treatment of anxiety,
Formula (2): The company has announced the use of buspirone and has filed a patent claim. U.S. Pat. No. 3,398,151, published August 20, 1968, discloses and claims related compounds in which the pyrimidine ring is substituted with a substituted (eg, halogen) or unsubstituted phenyl group. U et al., J.Medicinal Chem. 12/4, 876-881
(1969) reported on these phenyl congeners. However, neither the examples nor any of the tables list fluoro-substituted phenyl derivatives. In the end, patent application No. 06/1981, filed on December 28, 1981,
Attention is drawn to issue 334688. This application describes 1-[4-(4,4-dialkyl-26-
has announced and claimed a patent for the piperidinedione-1-yl)butyl]piperazine system. The pyrimidine ring of this compound system may be unsubstituted or may have one fluoro, chloro, hydroxyl, or trifluoromethyl substituent. The present invention includes compound 8-
[4-[4-(5-fluoro-pyrimidine-2-
These include the discovery that yl)-1-piperazinyl]butyl]-8-azaspiro[4,5]-decane-7,9-dione has long-acting psychotherapeutic 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 slight and short-lasting. 8-[4-[4-(5-fluoro-pyrimidine-
2-yl]-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione (.hereinafter also referred to as MJ 14594) and its pharmaceutically acceptable salts have a good duration of action. It has useful psychotherapeutic activity. This compound has the following structural formula (): Several methods (A,
A single method encompassing B and C) can be used. 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. In the above formula, W is O, NH, or N-
(CH ₂ ) ₄ −X is sufficient. Y is _H2N- ( _CH2 ) _4- ,X-
(CH ₂ ) ₄ −,

[Formula] or H may be used. W and Y The relationship is as follows:

TABLE X represents a suitable substituent such as chloride, bromide, iodide, sulfate, phosphate, tosylate or mesylate. In fact, intermediate compound b is the only type that can be easily isolated.
Easily converted to b′. The two compounds are equivalent for use as intermediates. The condensation process of Method A is carried out by refluxing the reactants in a dry inert reaction medium such as 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 60-150°C in the presence of an acid binder in a suitable organic liquid. Benzene, dimethylformamide, ethanol, acetonitrile, toluene, and n -butyl alcohol are preferred examples of organic reaction liquid media.
The preferred acid binder is potassium carbonate, but other inorganic and tertiary organic bases, other alkali and alkaline earth metal carbonates, bicarbonates, or hydrides, and tertiary amines can also be used. These 3
All methods are described in the above patents and publications of U et al., all of which are incorporated herein by reference. An example of a variant that produces the same compound in a slightly different way is N-substituted [4-(4-piperazinyl)-
Butyl]azaspirodecanedione () can be reacted with a suitable pyrimidine system to give a compound with the formula: This variant is derived from the preferred process described below. Intermediate spiroglutaric anhydrides or imides having the formula are either commercially available as found in the above references or as described herein. Pyrimidinylpiperazine intermediates () are described in the above-mentioned patents or literature. Although these methods are not specifically described herein but can be used to prepare the 5-fluoropyrimidinylpiperazine intermediate required as an intermediate of the present invention, for further illustration, a practical example is provided for the representative synthesis of c. shows. Intermediates a and b are readily obtained from c by standard methods described by U et al. This synthetic method begins with 5-pluorouracil and proceeds through known reactions to the desired piperazine intermediate. There is also a method via carbethoxypiperazine, which is somewhat superior as it provides a higher yield of c without by-products. In practice, it has been found that it is preferable to prepare 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. MJ14594 is approximately three times more effective than buspirone in the conditioned avoidance response test using the method described in the patent and literature of U et al. This test method is administered orally to fasted mice and generally reflects tranquilizing activity without necessarily distinguishing tranquilizers from psychotherapeutic compounds. What is even more interesting is that when 35 mg/Kg of MJ14594 was orally administered, it was found to be approximately three times more effective over a long period of time than when 100 mg/Kg of buspirone was orally administered. A more definitive test of psychotherapeutic efficacy is the apomorphine stereotypy behavioral test in nonfasting mice. This test determines the ability of the central active compound to prevent stereotypic behavior caused by apomorphine. This preliminary clinical trial provides a useful indication of effective psychosis treatment efficacy (Jjansen et al.
Arzneimittel-Farsch., 17 , 841 (1966)).
MJ14594 was approximately as potent as buspirone in this reversal of the apomorphin stereotopy test, but in this test the activity lasted for 6 hours versus 1-2 hours for buspirone. Antipsychotic drugs are believed to modulate psychotic symptomatology by acting as postsynaptic dopamine receptor inhibitors. Since the stereotopic reversal test is a reflection of dopamine suppressive activity, a comparison of the duration of action of the two drugs shows that the suppressive component (psychotic treatment effect) 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. Radioreceptor binding assays are used to test various neuronal
It measures the inhibition of the binding of physically active molecules, and is particularly used to measure tranquilizing activity. Although MJ14594 has only 10-20% of the binding affinity of buspirone for dopaminergic receptors, its properties appear more like an inhibitor.
The binding affinity of buspirone at the [H ³ ]spiperone-tagged receptor is decreased in the presence of 5 μM guanine triphosphate (GTP), but MJ
14594's is essentially unchanged. GTP-induced changes in this binding 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: Burt, Kries and Snyder, Molecular Pharmacolgy. 12 ;
800 (1976); Burt, Cleese and Snyder, Science , 196 , 326 (1977); Cleese, Burt, and Snyder, Science , 192 , 481 (1976);
Life of Cleese, Protzser and Snyder
Science, 23 , 495 (1978); Creese and Snyder, European Journal of Pharmacology ,
50, 459 (1978); Creese, Asgin and Snyder, Nature , 278 , 577 (1979). MJ 14594's mouse Vogel model anxiolytic behavioral example test shows that this compound is inactive at dosages below 5 mg/Kg, whereas buspirone at a dose of 1.0 mg/Kg is active in this anxiolytic review test. .
The murine Vogel model is a modification of the Vogel fight test, a reliable fight test for testing anxiolytics (Fogel, Beyer and Kloday).
Psychopharmacologia (Berl) 21, 1-7
(1971)). Further data are available from comparative trials with other CNS examination methods. Although MJ14594 does not show catalepsy at doses up to 70 mg/Kg (higher doses cause toxicity), buspirone does not reverse the catalepsy caused by trifluoperazine. A recently developed monkey model (Kobashik, Domino J. Clin. Psychopharmacol ., 2 , 305-307
(1982)), MJ14954 appeared to be ineffective against the development of clinical side effects such as extrapyramidal symptoms when tested against standard psychiatric drugs. Therefore, MJ14594 appears to have significantly more therapeutic properties than most conventional psychosis treatments.
MJ14594 exhibits a feline central electroencephalogram pattern similar to but with better efficacy than buspirone. Taken together, the in vivo efficacy, long duration of action, and depressant-like binding of MJ14594 clearly demonstrate that the pharmacological activity of this psychotherapeutic compound is distinct from buspirone and other related compounds. According to the pharmacological properties established by the above-mentioned tests, the present compound having formula () has good efficacy as a psychosis treatment agent. Thus, another form of the invention comprises systemically administering to a mammal in need of psychiatric treatment an effective dosage of about 0.01 to 40 mg per kilogram of body weight of a compound having formula () or a pharmaceutically acceptable acid addition salt thereof. The present invention relates to a method for treating mental illness in the above-mentioned mammal. As used herein, systemic administration refers to oral, rectal and parenteral (ie intramuscular, intravenous and subcutaneous) administration methods. Oral administration of the compounds of this invention, which is generally the preferred method, requires larger amounts of active agent to produce the same effect as the smaller amounts given parenterally. In clinical practice, the compounds of the present invention may be administered at concentrations that produce effective psychosis treatment effects without causing harmful or troublesome side effects. In general therapy, the compounds of the present 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 mg of active ingredient per unit dose are preferably tablets,
They are conveniently prepared as oral 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 polyvinyl pyrrolidone), fillers (lactose, sugar, cornstarch, calcium phosphate,
sorbitol or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silica), disintegrants (e.g. starch)
and lubricants (e.g. sodium lauryl sulfate)
etc. may 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 contains the active compound in a vehicle consisting of water or a polyhydric aliphatic alcohol such as glycerin, propylene glycol, and polyethylene glycol or mixtures thereof. 0.1 to 10% by weight
You can get it by combing it. Polyethylene glycol is soluble in both water and organic liquids.
It consists of a non-volatile, usually liquid polyethylene glycol mixture with a molecular weight of . 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 unspecified temperatures are in degrees Celsius (°C). Nuclear magnetic resonance (NMR) spectral characteristics were compared to tetramethylsilane (TMS) as a comparison standard.
Chemical shift (δ) expressed in ppm. The comparative areas reported for various shifts in proton NMR spectral data correspond to the number of specific functional hydrogen atoms in the molecule. The nature of the multiplicity shift is reported as broad singlet (bs), singlet (s), multiplet (m) or doublet (d). The symbol used is
DMSO−d ₆ (deuterodimethylsulfoxide),
CDCl ₃ (deuterochloroform), otherwise normal. The infrared (IR) spectral description consists only of absorption wavenumbers (cm ^- ) with functional group identification values. IR measurements were performed using potassium bromide (KBr) as a diluent. Elemental analysis is reported as weight percent. Example 1 Intermediate synthesis 2-chloro-5-fluoro-4-methylthiopyrimidin-2-one () 5-fluoro-4-thiouracil 5-fluorouracil 26 in 500 ml dioxane
(0.12 mol) and 45 g (0.2 mol) of phosphorus pentasulfide were heated under reflux for 3 hours. The hot reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in 650 ml of water and heated with 5 g of activated carbon. After cooling, the crystallized solid was collected by super-collection to obtain 5-fluoro-4-thiouracil.
I gained 25.4g (88%). Melting point 269-272℃. 5-Fluoro-4-methylthiopyrimidine-2
-one 59.4 g (0.348 mol) of methyl iodide were added dropwise to a solution of 25.4 g (0.174 mol) of 5-fluoro-4-thiouracil in 350 ml of 0.15N NaOH. The mixture was stirred at room temperature for 2 hours, then cooled with ice and filtered. Grind the obtained solid with methanol to obtain 18.5g of product.
(66%). Melting point 205-207℃. 5-Fluoro-4-methylthiopyrimidine-2
-one 21.1g (0.132mol), phosphorus oxychloride 126.4
(0.824 mol) and 27.0 g (0.224 mol) of N,N-dimethylaniline was heated under reflux for 2 hours. While cooling the mixture in an ice bath, ice was added and extracted with ether. ether extract
Heat skelly the dried and evaporated residue with MgSO ₄ B100
The Skelly B supernatant was poured into 2×2 ml to remove insoluble materials. The liquid is treated with activated carbon, filtered and concentrated.
I gained 20.8g (88%). Example 2 8-[4-(Piperazinyl)butyl]-8-azaspiro[4.5]decane-7,9-dione[] 50.2 g (0.3 mol) of tetramethylene glutarimide, 1,4-dibromobutane in 500 ml of toluene
A mixture of 130 g (0.6 mol) and 6.7 g (0.7 mol) of anhydrous K ₂ CO ₃ was heated under reflux for 20 hours and concentrated in vacuo. Distill the residue (165-170℃/0.01mM)8
64.1 g of -[4-(1-bromo)butyl]-8-azaspiro[4.5]decane-7,9-dione was obtained. Add this to 900 ml of toluene and 90.4 g (1.05 g) of piperazine.
mol) and 145.5 g (1.05 mol) of K ₂ CO ₃ and heated under reflux for 18 hours. This was filtered, concentrated in vacuo, and the residue was distilled (180-200℃/0.01mM) to obtain V52.7.
g (82%). Example 3 8-[4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazine]butyl]-8-azaspiro[4.5]decane-7,9-dione hydrate (.MJ14594-3) 4.47 g (0.025 mol), 7.7 g (0.025 mol),
10.37 g (0.07 mol) of K ₂ CO ₃ and KI (contact amount) were mixed in 100 ml of acetonitrile and heated under reflux for 18 hours. The mixture was filtered and concentrated in vacuo, and the residue was chromatographed on 230 g silica gel, eluting with 2% ethanol-chloroform. After removing the solvent, 8-
[4-[4-[5-fluoro-4-(methylthio)-
2-pyrimidinyl]-1-piperazinyl]butyl
9.0 g (80%) of -8-azaspiro[4.5]decane-7,9-dione was obtained. 3.5 g (0.008 mol) of the compound in 70 ml of ethanol and wet Raney Nickel catalyst (1.5 tsp) were heated under reflux for 3 hours. This was filtered, the solvent was evaporated and the residue heated with acetonitrile, filtered and concentrated in vacuo. This residue was heated with Skelly B on a steam bath, the supernatant liquid was decanted from the insoluble matter, and the compound was cooled, yielding 1.8 g (59%).
I got it. Melting point 83-85℃. Analytical values _{for C21H30FN5O2 ・ 0.1H2O} : Calculated value _: C, 62.23; H, 7.51; N, 17.28 Measured value: C, 62.17; H, 7.46; N, 16.88. Example 4 Hydrochloride of MJ14594 The hydrochloride 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]decane-
9.0 g (0.02 mol) of 7,9-dione and 10-15 g of Reine nickel were heated under reflux in 200 ml of ethanol for 6 hours and overconcentrated. Add 50ml of water to make the mixture 50%
The mixture was made alkaline with NaOH and extracted with ether.
Dry the extract with MgSO ₄ and add 20 ml of ethanol to the residue.
Add 2.15ml of 7N ethanolic HCl
5.6 g (64%) of MJ14594 hydrochloride was obtained. Melting point 224−
226℃. Analytical values _{for C21H30FN5O2.HCl} : Calculated _values : C, 57.34; H, 7.12; _N , 15.92. Measured values: C, 57.42; H, 7.15; N, 15.66. NMR (DMSO-d ₆ ): 1.50 (12, m); 2.61 (4,
s); 3.02 (4, m); 3.50 (4, m); 3.64
(2, t [6.9Hz]); 4.54 (2, m); 8.51 (2,
s); 11.70 (1, bs). IR (KBr): 790, 1110, 1250, 1350, 1490,
1560, 1670, 1750, 2600, 2935 and 2950
cm ^-1 .

Claims (1)

[Claims] 1 Compound 8-[4-[4-(5-fluoro-2-
pyrimidinyl)-1-piperazinyl]butyl]-8
-Azaspiro[4.5]decane-7,9-dione or a pharmaceutically acceptable acid addition salt thereof.