JPH02240072A - Salt of pgenylpyrazine,preparation thereof, neuraxial agonist containing same,and preparation af said agonist - Google Patents

Abstract

NEW MATERIAL: A salt of a phenylpiperazine compd. of formula I (wherein R is H, halogen, trifluoromethyl, hydroxy, 1-6C alkyl, 1-6C alkoxy, amino, 1-6C alkanoylamino, or 1-6C alkanoyloxy) and an acidic compd. of formula II [wherein X is H, hydroxy, or amino or combines with the H atom bonded to the C atom to form an oxo grodp; and R¹ is H, phenyl, indolyl-(3)-methyl, imidazolyl-(4)-methyl, or a 1-10C alkyl group optionally substd. by one or two hydroxy, carboxyl, phosphono (-POH₃), 1-6C alkoxy groups, etc.].

EXAMPLE: The salt of 2-methoxyphenylpiperazine and glutamic acid.

USE: Useful as a medicine acting on central nervous system as a prophylactic for anxiety and aggression without exhibiting a side effect.

PROCESS: A phenylpiperazine compd. of formula I of which R is the same as described above is reacted with an acidic compd. of formula II to give the salt of these two compds.

COPYRIGHT: (C)1990,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a salt of 7-enylvirazine, a process for producing the same, a central nervous system active agent containing the salt, and a process for producing the active agent.

[Prior Art] Phenylbiperazine having a substituent in the phenyl group is known. For example, these include US Pat. No. 3,211,735
This is a starting material for phenylbiverazine containing one 7-enoxyoxyalkyl group on the second nitrogen atom based on the description in the specification.

U.S. Pat. No. 4,139,621 describes three substituents in the phenyl ring of the following formula: phenylbiperazine with the group was described.

[Structure of the Invention] By the way, it has been found that the salt of Shikiko's 7-enylbiverazine and the acidic compound of Formula (1) acts on the central nervous system (ZNS) and has, for example, an anxiolytic or anti-aggressive effect.

Accordingly, the subject matter of the present invention is a compound of the formula: [wherein R1 is fluorine, chlorine, methyl, nitro, hydroxy, methoxy, cyano, amino, methylamino or dimethylamino and R2 is a hydrogen atom, tetrahydropyranyl, Cl-C4-alkyl [wherein R is a hydrogen atom, a halogen atom, a trifluoromethyl group, and a droxy group, 01-C
B-alkyl group, Cl-C6-alkoxy group, amino group C1-C6-alkanoylamino group or C1-Cs-alkanoyloxy group] and a phenylvirazine represented by the formula: R 1 -C H - C 0 2 H
I[XE In the formula, (3) monomethyl group, imidazolyl group (4
) one methyl group, C1-C1o-alkyl group, or one or two hydroxy groups, carboxy group, phosphono group (-
P OsH2), C1-C6-alkoxy group, mercapto group, 01-CB-alkylthio group, 7enyl group,
represents a C1-01 lowalkyl group substituted by a hydroxyphenyl group, a 02-C6-alkanoylamino group or a 01-CB-alkoxycarbonyl group, in which case the hydroxy groups present may also be esterified with phosphoric acid ], a method for producing the same, and a medicine containing the compound as an active substance.

Effect of the invention 1 The compounds according to the invention have particularly good compatibility and a favorable therapeutic range, and have particularly few side effects.

The following characteristics of the invention are described: When the radical R of formula (1) contains an alkyl group or an alkoxy group or an alkanoyl group, these groups may be linear or branched. The advantageous ones are 1~
It is an alkyl group having 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms. In the case of C1-cB-alkanoyl radicals, this preferably consists of 2 to 4 carbon atoms. Halogen atoms preferably represent F, CQ and Br. Advantageously, the radical R is present in the ortho or para position of the 7-enyl ring, especially in the ortho position. Advantageously, R is an alkoxy group, especially a methoxy group.

, when the group Rl of formula (2) represents an 01-CIO-alkyl group, the group may be linear or branched.

Particularly suitable are alkyl radicals having 1 to 7, preferably 1 to 4 carbon atoms.

If this alkyl group is substituted by an alkoxy group, an alkylthio group, an alkanoylamino group or an alkoxycarbonyl group, these groups may likewise be straight-chain or branched; Suitable alkyl groups or alkoxy groups are those having 1 to 4 carbon atoms. In the case of alkanoylamino groups, preference is given to O2-C4-alkanoylamino groups, in particular acetylamino groups. If the 01-01 low alkyl group is substituted by a hydroxyphenyl group, this is the case, for example, with the amino acid tyrosine.

When R1 represents an 01-CIO-alkyl group, a 7-enylmethyl group (penzyl) or a phenylethyl group is particularly suitable. Rl may also be an 01-CIO-alkyl group containing one or two hydroxy groups, in which case such hydroxy groups may also be esterified with orthophosphoric acid. Therefore, in such a case, the group at l or 2 positions: -0-PO(OH)2
This applies to alkyl groups containing

Suitable compounds of formula (1) are acidic compounds, ie compounds containing at least one carboxy group and optionally a phosphono group as acidic group. Examples of such acidic compounds of the formula (■) are aspartic acid, acetylaspartic acid, glutamic acid, acetylglutamic acid, glutaric acid α-ketoglutaric acid, succinic acid, malic acid, phosphoserine, acetylphosphoserine, tartaric acid, N-acetylglycine, N-penzoyl-alanine.

When X in formula (2) represents a protected amino group, it corresponds to an amino group protected by a conventional and known protecting group. Suitable in this case are the customary sleeping groups, which are easily degradable by hydrolysis or hydrogenolysis and are used, for example, in the synthesis of pevitides. Suitable in this case are, for example, the protecting groups described in the following publications: J. F. W.
“Protective Groups” by NcOmie
in OrganicChmeistry', Pla
num Press. Now York, 1973.4
Pages 3-143 and 183-215; Jesse P
．． Greenstein and former 1ton Winit
Written by Z”Cbmeistry of AminoAcid
s', New York+ 196L John
Witty and SonsIncz Volume 2,
For example, from page 883; J. Written by Gante “MeLh
Oden der Pepidcbmie l'',K
ontakte(Merck). 1972 (2) 29
;E. E. “Schu” by Btjllesbach
tz-gruppen in der Peptid-
Synthese”, Part 2, KontakLe(Me
rck), 1980 (7) 23.

Suitable protecting groups of this kind are, for example, the following groups: a benzyl group or an a-phenylethyl group, in which case the benzene nucleus optionally also contains one or more (for example 4 {up to 1) halogen atoms, Branched saturated or unsaturated alkyl groups having, for example, 1 to 6 carbon atoms, which may contain nitro groups, 01-C4-alkoxy groups, C1-C4-alkyl groups, e.g. butyl, methylene, in which the methylene group is substituted with l or 2 alkyl groups each having 1 to 4 carbon atoms (e.g. dimethylmethylene); benzyloxycarbonyl or pendylthiocarbonyl groups, in which case these groups may optionally contain more than is (up to 4) substituents within the benzyl group, for example Cl-C
4-alkoxy group, trifluoromethyl group, nitro group;
C! optionally substituted, for example by a halogen atom (chlorine, fluorine)! ~C6-alkanoyl group, in which up to 3 substituents bonded to the carbon atom can be present, for example formyl, probionyl, trifluoroacetyl: optionally in the aryl group, for example cl-c. 5
- an arylsulfonyl group substituted with an alkyl group, in which case the aryl group is particularly relevant, such as p-toluenesulfonyl group; 7thalyl group; trityl group; nitro group; urethane protecting group, such as straight 01-C6-alkoxycarbonyl radicals having linear or branched alkyl radicals, in which the alkyl radicals are optionally substituted by e.g. cyano radicals, halogen atoms (up to 3 halogen atoms, e.g. chlorine, fluorine). Optionally substituted; biphenyl group, fluorenyl (9)! , a 7-enyl group, the group being in l or 2 positions, e.g.
optionally substituted by a Cl-C4-alkyl group; a P-dihydroxyborylphenyl group; optionally substituted by a Cl-C4-alkyl group; Alkoxy homologues of the carbonyl group, such as the adamantyloxycarbonyl group; sulfenyl compounds, especially 7-enylsulfenyl compounds optionally substituted with a phenyl ring, in which case the substituents are particularly suitable, such as the nitro group ( 2-
nitrophenylsulf7enyl group, 2.4-'; nitrophenylsulf7enyl group).

The process for preparing the salts according to the invention can advantageously be carried out in an inert solvent. Such solvents include, for example, water, c
It is also possible to use mixtures thereof, such as 1-C9-alkanols, saturated cyclic ethers, amides and 01-C-alkylamides of C1-C6-alkanoic acids, such as dimethylformamide, dimethylacetamide.

The reaction is carried out at a temperature of 0 to 120°C, preferably 20 to 80°C.

Advantageously, stoichiometric amounts of acid are reacted with the active biverazine compound. If the acidic compound ■ has, for example, two acidic groups capable of forming a salt with the basic NH group of the compound I, then 2 moles of the compound can be reacted with the acidic compound ■ to obtain a new salt. can be done. Salt-forming groups (-CO21{, -PO
The same can be said when containing 3H2-OPO(OH)2).

If the acidic compound (2) contains more than one acidic group and is reacted, for example with one mole of compound I, the excess acidic groups of the compound (1) can be neutralized by another customary basic cation. this. Neutralization such as NaOH, KO
Preference is given to using H or their equivalents.

The compounds according to the invention were tested in the combat test [Tedeschie
tal. Author “J. Pharmacol. Exp.
Therap-" 125+28 (1959)] and the four-plate test [Aron et al., "Neu
rhopharmakology”10 (1971)
459-469] shows good anxiolytic effects in experimental models.

For example, in the above experimental method, ITlig/mouse body weight l
A clear anxiolytic effect is achieved in 50% of the animals at the ke dose.

In the animal studies described above, the lowest effective dose is e.g. Oral 0. 4 rag/k9 Intravenous 0. 1 ra97kg It is.

The general effective dose range (same animal studies as above) is:
For example, oral 0.4-4 tag/ktp, especially 2 rn/kg
Intravenous 0. 1-1 mglkg, especially 0.
5 19/J! 9 applies.

The direction of action of the compounds according to the invention is comparable to the known pharmaceutical active substance diazepam, but with the following differences: a better therapeutic range for sedation and ataxia.

Indications for the compounds according to the invention include anxiety, nervous and excited states, vegetative neurological disorders and psychosomatic disorders.

Pharmaceutical formulations generally contain from 1 to 8 doses of the active ingredient according to the invention.
, advantageously containing 2 to 4 mg.

Administration can be carried out, for example, in the form of tablets, capsules, pills, dragees, suppositories, ointments, gels, creams, powders, micropowders, disoles, or in liquid form. Liquid application forms include, for example, oily or alcoholic or aqueous solutions as well as suspensions and emulsions. An advantageous application is
Tablets containing 2-4+n active substances or 10-10 active substances
The solution contains 20% by weight.

The unit dose of the active ingredient according to the invention may be, for example: a) 1 to 8119, advantageously . 2~41m9
, b) Parenteral drug forms (e.g. intravenous, intramuscular) 0.25 to 2
++g, advantageously from 0.5 to 119 (each dose based on the free base).

For example, 1 to 2 tablets containing 2 to 41 m9 of the active substance 3 times a day or, for example, in the case of intravenous injection, 1 ampoule of volume 1 to 3 s + ff containing 0.5 to 19 of the active substance. Preferably, it is administered once or twice a day. For oral administration, the minimum daily dose should not exceed 6 mg and the maximum daily dose for oral administration should not exceed 24 mg.

When treating dogs and cats, the oral unit dose is generally about 0.5-4 1119/kg body weight and the parenteral dose is about 0.2-2 11 g/kg body weight.

Acute toxicity in mice of compounds according to the invention (L
D 5 0 lIl9/k9, by Miller and Tainter, “Proc. Soc.
．． Biot. a. Med. ”57 (1944)
261-based method), for example for oral application 40
0 rsy/kg or more.

The agents can be used alone or in admixture with the administration of other pharmacologically active substances in medicine, veterinary medicine and agriculture.

1. The anti-aggressive effects of the combat test compounds were determined by R. E. Tedeschi and co-authors “J. Pharmacol. Exp.
．． Therap. 125. 28 (1959). In this method, adult male mice were placed in pairs in cages with a lattice bottom of approximately 13 x 13 cm and a cage was inserted through the bottom. After stimulation with electrical current for 3 minutes, both mice adopt a certain characteristic fighting posture (both mice face each other and stare at each other, and in some cases even actually interlock).

This typical fighting behavior of mice can be released by anti-aggressive substances.

ED was then determined by propit analysis from a large number of mouse pairs.
5 0 Confirm. ED50 is 50% of the mouse tested.
This is the dose that does not produce a typical fighting posture in % of cases.

The table below shows the anti-aggressive action of the compounds according to the invention with ED
Display in 50.

2.4 Plate Test (Measurement of Anxiolytic Effect) Species: Mouse Method: Animals are placed in an enclosure with a floorboard consisting of 4 metal plates (8X11 cm) and allowed to explore freely for 15 seconds. During this, the animal always crosses from one plate to the other and receives a weak electric shock (0.35 mA). The number of crossings is counted in a 1 minute test. IO animals are studied per dose. Test compounds are generally administered 30 minutes before the test.

The results are shown in the table.

Note: When exposed to this situation, animals quickly learn to stop their exploratory behavior. Anxiolytics block this behavioral inhibition and increase the number of crossings.

References: Acron C. , Simon P. , Larou
sseC. and Bois-sier J. R. ，
1971"Evaluation of a r.ap
idtechnique for detecting
minor tranquizer. Neurop
hermacology. 'Ij4: 459-46
9 Pharmacological effects of compounds according to the present invention! Substance Example No. Chiffre Combat Test Oral mg/k9 Effect as ED50 4 Plate Test Oral mg/kg Effect (%) l D 20264 0.3 112.0 D 20265 0.8 115.6 [Example 1 Example l 2 -Salt of methoxyphenynoleviperazine and gnoretamic acid: NH2H0.2C-(C:H2)2-CH-COOH-glutamic acid 2-Methoxy7enylbiperazine 69 is dissolved in methanol 50+ma. And methanol/water (2
l) A suspension of 4.69 g of glutamic acid in 90 mQ is added and the mixture is boiled for 30 minutes, a solution forming, filtered off and concentrated. Add A7T to the resulting viscous oil. Glutamate precipitates out. The crystals are filtered off with suction, washed twice with acetone and then three times with diethyl ether and dried.

Melting point: 159-162°C Yield: 76% of theory Dissolved in methanol 501 and added methanol/water (2:l) 9
A suspension of 4.6 g of DL-aspartic acid in 0+m(2) is added and the mixture is boiled for 30 minutes, the solution is concentrated and acetone is added to the resulting viscous oil and stirred. Gradual crystallization takes place.The crystals are filtered off with suction, washed twice with acetone and then three times with diethyl ether and dried.

Melting point: 213 DEG -215 DEG C. Yield: 68% of theory Analogously to Examples 1 and 2, the following salts are obtained using the acids listed in column 2 of the table.

R acid 2-Co 2-Cl2 3-(J 3-C! 3-CF3 3-CF3 2-OH 2-OH 2-NH2 2-OH 2-OCH3 2-OCH, L-glutamic acid DL-aspartic acid L-glutamic acid D, L-aspartic acid L-glutamic acid D. L-aspartic acid L-glutamic acid D, L-aspartic acid L-gnoretamic acid D, L-aspartic acid N-acetylglycine L-monotartrate Yield 9 (%) Melting point °C In the cases of Examples 9, 10..ll and l2, the salts each contain 2 mol of acid per 1 mol of 7-enylpiperazine I. In all other cases the salt contains 2 mol of acid per 1 mol of phenylpiperazine I. contains 1 mole of acid.

Examples of Galen Formulation Example 1: Ampoule with 10+u of active substance The active substance 109 of Example 1 is dissolved under stirring in 1.8 Q of water for injection purposes. The solution is filled 2a with water for injection purposes and after mixing is filtered through a membrane filter with a mesh width of 0.2 μm and a glass front filter. The filtrate is filled under aseptic conditions into sterile ampoules up to 21 mm.

One ampoule contains active substance 10119.

Example 2: Capsule implementation fl2 with active substance 2019 with modified starch (starch 1500) 200 g of active substance
8509 and highly dispersed silicon dioxide (aerosol 200
) 109 and magnesium stearate log. The mixture is filled into hard gelatin cells of particle size 1 to 107 s+g.

Claims (1)

[Claims] 1. Formulas: ▲ Numerical formulas, chemical formulas, tables, etc.▼ I [In the formula, R is a hydrogen atom, a halogen atom, a trifluoromethyl group, a hydroxy group, a C_1-C_6-alkyl group,
C_1-C_6-alkoxy group, amino group, C_1-C
Represents a _6-alkanoylamino group or a C_1-C_6-alkanoyloxy group] and the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼II [In the formula, X is a hydrogen atom, a hydroxyl group, an amino group , a protected amino group, or an oxo group together with a hydrogen atom bonded to a carbon atom, and R^1 is a hydrogen atom, a phenyl group, an indolyl-(3)-methyl group, an imidazolyl-(
4) -Methyl group, C_1-C_1_0-alkyl group, or one or two hydroxy groups, carboxy group, phosphono group (-PO_3H_2), C_1-C_6-alkoxy group, mercapto group, C_1-C_6-alkylthio group,
Phenyl group, hydroxyphenyl group, C_2-C_6-
C_1-C_1_0- substituted by an alkanoylamino group or a C_1-C_6-alkoxycarbonyl group
salts with acidic compounds representing an alkyl group, in which case the hydroxy groups present may also be esterified with phosphoric acid. 2. Formulas: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I [In the formula, R is a hydrogen atom, a halogen atom, a trifluoromethyl group, a hydroxy group, a C_1-C_6-alkyl group,
C_1-C_6-alkoxy group, amino group, C_1-C
Represents a _6-alkanoylamino group or a C_1-C_6-alkanoyloxy group] and the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼II [In the formula, X is a hydrogen atom, a hydroxyl group, an amino group , a protected amino group, or an oxo group together with a hydrogen atom bonded to a carbon atom, and R^1 is a hydrogen atom, a phenyl group, an indolyl-(3)-methyl group, an imidazolyl-(
4) -Methyl group, C_1-C_1_0-alkyl group, or one or two hydroxy groups, carboxy group, phosphono group (-PO_3H_2), C_1-C_6-alkoxy group, mercapto group, C_1-C_6-alkylthio group,
Phenyl group, hydroxyphenyl group, C_2-C_6-
C_1-C_1_0- substituted by an alkanoylamino group or a C_1-C_6-alkoxycarbonyl group
a phenylpyrazine of the formula I in which the group R represents an alkyl group, in which case the hydroxy group present may also be esterified with phosphoric acid. , the base R^1
and an acidic compound of formula II in which X is as defined above. 3. Central nervous system active agents containing a salt of phenylpyrazine of the formula I and an acidic compound of the formula II and the customary carrier substances and/or diluents or auxiliaries. 4. A method for producing a central nervous system agent, wherein formula I
of phenylpyrazine with an acidic compound of formula II, together with customary pharmaceutical carrier substances and/or diluents, to form a pharmaceutical preparation or to a therapeutically applicable form. Process for producing central nervous system active agents.