CA1051430A

CA1051430A - Benzisoxazole derivatives

Info

Publication number: CA1051430A
Application number: CA230,174A
Authority: CA
Inventors: Junki Katsube; Shigeho Inaba; Hisao Yamamoto; Yoshiaki Takebayashi; Katsumi Tamoto; Tsuyoshi Kobayashi; Kikuo Sasajima
Original assignee: Sumitomo Chemical Co Ltd
Current assignee: Sumitomo Chemical Co Ltd
Priority date: 1974-07-01
Filing date: 1975-06-25
Publication date: 1979-03-27
Also published as: FR2276820A1; AT344162B; ES439014A1; AR207986A1; NO752245L; DK294175A; FI751890A; NO142910C; AU8264175A; ATA498675A; FI59586C; GB1502384A; NL7507835A; CH612189A5; FI59586B; HU173527B; SE7507365L; NO142910B; DE2529292A1

Abstract

Abstract of the Disclorure:
Novel benzisoxazole compounds of the formula:

wherein R1 and R2 are each hydrogen, C1-4 alkyl, C1-4 alkoxy, halogon or trifluoromethyl or, when taken together, they form C1-2 alkylenedioxy; Alk is C1-4 alkylene and A is a group of the formula:

or (wherein R3 and R4 are each C1-4 alkyl, phenyl or phenyl sub-stituted with C1-4 alkyl, C1-4 alkoxy or halogen, or when taken together with the adjacent nitrogen atom, they represent a hetorocyclic ring having 5 to 7 members wherein one nitrogen atom is included as the only hetero atom or having six members wherein one nitrogen atom and one oxygen atom are included as the only hetero atoms; and R5 is C1-4 alkyl, phenyl or phenyl substituted with C1-4 alkyl, C1-4 alkoxy or halogen and their non-toxic salts. The compounds can be produced by cyclization of the corresponding o-substituted nitrobenzenes of the formula:

wherein Z is or (wherein R6 is C1-4 alkyl) and R1, R2, Alk and A are each as defined above. The compounds have a variety of pharmacological activities such as CNS
depressing, muscle relaxing, vasodilating, bronchodilating, anti-asthmatic, spasmogenic, analgesic, anti-narcotic, anti-arrhythmic, local anesthetic and anti-platelet aggregation activities.

- ? -

Description

lOS~430 The present invention relates to novel benzisoxazole derivatives and their production and use.
The benzisoxazole skeleton itself has been known since the end of the l9th century, but only a few chemical studies have been done on benzisoxazole derivatives, and only a few reports have appeared on the synthesis of the related compounds.
The novel benzisoxazole derivatives provided by this invention are benzisoxazole compounds of the formula:
Alk-A
Rl ~ ~ / [I]

wherein Rl and R2 are each hydrogen, Cl 4 alkyl, Cl 4'alkoxy, halogen or trifluoromethyl or, when taken together, they form Cl_2 alkylenedioxy; Alk is Cl 4 alkyiene and A is a group of the formula;

/ 3 /~~~\
-N \ R4 or -N N-R5 (wherein R3 and R4 are each Cl_4 alkyl, phenyl or phenyl sub-stituted with Cl 4 alkyl, Cl_4 alkoxy or halogen, or when taken together with the adjacent nitrogen atom, they represent either a morpholino group or a saturated heterocyclic ring having 5 to 7 members wherein one nitrogen atom is included as the only hetero atom; and R5 is Cl 4 alkyl, phenyl or phenyl substituted with Cl 4 alkyl, Cl_4 alkoxy or halogen, and their non-toxic salts.
In the above formula, examples of "Cl_4 alkyl" are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, etc., a~ - 3 _ - . . ,: ,, . , , :

~05~430 and examples of "Cl 4 alkoxy" are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, etc, As "halogen", there may be exemplified chlorine, bromine, fluorine, etc.
Examples of "Cl 4 alkylene" include methylene, ethylene, pro-pylene, butylene, methyl-methylene, methylethylene and tri-methylene, and examples of "C1 2 alkylenedioxy" include methylenedioxy and ethylene dioxy.
As the 5-7 membered heterocyclic ring which may be represented by the symbol A, there are exemplified pyrrolidino, piperidino, morpholino, etc.
The structure of the benzisoxazole compounds tI]
is characterized by the aminoalkyl side chain at the 3-position of the benzisoxazole skeleton.
Among the benzisoxazole compounds [I] of the invention, the ~ompounds of the following formula are preferable:

~0~il430 Alk-N
Rl ¦ R4 0 [Ia]
N

wherein Rl and R2 are each hydrogen, C1_2 alkoxy or halo-gsn or, when taken together, they form Cl_2 alkylenedioxy, R3 and R4 are each Cl 4 alkyl or, when taken together with the adjacent nitrogen atom, they represent pyrrolidino, piperidino or morpholino and Alk is C2 3 alkylene.
Particularly preferred are the compounds of the formula:
, R3 Alk-N
Rl ¦ R4 ~'1~\
~N/ ' ' `

wherein Rl is Cl_2 alkoxy, R3 and R4 are each Cl_4 alkyl and Alk is C2_3 alkylene, for instance, in view o~ their notable anti-platelet aggregation activity.
Also particularly preferred are the compounds of the formula:

Alk-N N-R
Rl ¦ ~ 5 ~\ ' ' .
~ 0 - ~Ic]

1()5~430 wherein Rl and R2 are each hydrogen, Cl 2 alkoxy or halogen or, when taken together, they form Cl 2 alkylenedioxy, R5 is Cl 4 alkyl or phenyl, or phenyl substituted with Cl 4 alkyl, Cl 4 alkoxy or halogen and Alk is C2 3 alkylene, for instance, in view of their appreciable central nervous system (CNS) depressing activity.
Specific examples of the benzisoxazole compounds ~I]
are as follows: ~:
3- ~'-(4"-Phenylpiperazi no) ethy~ -5,6-dimethoxy-benz-

2,1-isoxazole;

3-(2'-Dimethylaminoethyl)-benz-2,1-isoxazole;
3-(2'-Dimethylaminoethyl)-5-methoxy-benz-2,1-isoxazole;
3-(2'-Diethylaminoethyl)-5,6-dimethoxy-benz-2,1-isoxazole;
3-(2'-Piperidinoethyl)-5,6-dimethoxy-benz-2,1-isoxazole;
3-~2'-Morpholinoethyl)-5,6-dimethoxy-benz-2,1-isoxazole;
3-(3'-Dimethylaminopropyl)-5,6-dimethoxy-benz-2,1-isoxazole;
3- ~2'-(4"-Phenylpiperazino)ethyl]-5,6-methylene-dioxy-benz-2,1-isoxazole;
3-(2'-Piperidinoethyl)-5,6-methylenedioxy-benz-2,1-isoxazole;
3-(2'-Diethylaminoethyl)-5,6-methylenedioxy-benz-2,1-isoxazole;
3-(2'-Morpholinoethyl)-5,6-methylenedioxy-benz-2,1-isoxazole;
3- ~2'-(4"-Pherylpiperazino)ethyl~-benz-2,1-izoxazole:

lOS~430 3-(2'-Morpholinoethyl)-benz-2,1-isoxazole;
3-(2'-Piperidinoethyl)-benz-2,1-isoxazole;
3-(2'-Pyrrolidinoethyl)-benz-2,1-isoxazole;
3-[2'-(4"-Methylpiperazino)ethyl]-benz-2,1-iso-xazole;
3-(2'-Morpholinoethyl)-5-methoxy-benz-2,1-iso-xazole;
3-(2'-Di-n-propylaminoethyl)-5-methoxy-benz-2,1-isoxazole;
3-(2'-Dimethylaminoethyl)-5-ethoxy-benz-2,1-10 isoxazole;' .
3-(2'-Dimethylaminoethyl)-6-fluoro-benz-2,1- , , isoxazole;
3-(2'-Morpholinoethyl)-6-fluoro-benz-2,1-isoxazole oxalate;
, 3-(2''-Dimethylaminoethyl)-6-methoxy-benz-2,1-i~oxazole;
3-(2'-Morpholinoethyl)-6-methoxy-benz-2,1-iso-xazole;
3-[2'-(4"-o-Methoxyphenylpiperazino)ethyll-5,6-dimethoxy-benz-2,1-isoxazole;
3-(1'-Diethylaminomethyl)-benz-2,1-isoxazole;
3-[2'-(4N-Phenylpiperazino)ethyl]-6-fluoro-benz-2,1-isoxzzole;
3-[2'-(4"-Methylpiperazino)ethyl-5,6-dimethoxy-benz-2,1-isoxazole;
3-t2~-(N-Methyl-N-phenethylamino)ethyll-benz-2 isoxazole;
3-t2l-(N-Methyl-N-phenylamino)ethyll-benz-2,1-isoxazole; . '' .~0 7 _ -1051~;~0 3-(2'-Morpholinoethyl)-6-chloro-benz-2,1-iso-xazole;
3-(2'-Dimethylaminoethyl)-5-methyl-benz-2,1-isoxazole; ~ - :
3^-(2'-Dimethylaminoethyl)-6-methyl-benz-2,1-isoxazoie;
3-(~'-Dimethylaminoethyl)-5-trifluoromethyl-benz-2,1,-isoxazole;
. 3-~2'-Dimethylaminoethyl)-6-trifluoromethyl-benz-2,1-isoxazole;
3-l2~-(4~-Benzylpiperazino)ethyl]-s~6-dimeth benz-2,1-isoxazole, etc.
The benzisoxazole compounds {I] can form acid addi-tion æalts, of which examples are hydrochloride, hydro-bromide, acetate, oxalate, citrats, tartrate, succinate, fumarate, lactate, etc.
The benzisoxazole compounds lI] ana their non-toxic salts exhibit a wide variety of pharmacological properties and are useful as medicines.
That is, these benzisoxazole compounds all possess ome or most of several pharmacological activities such as CNS depressing, muscie relaxing, vasodilating, anti-asth-; matic, spasmogenic, analgesic, anti-narcotic, anti-arrhy~:.
thmic, local.-anesthetic and anti-platelet aggregation:ac- .-tivities.
- For example, the compounds of Formula [I] wherein ~: A represents a piperazine moiety generally show CNS depress-; ing, muscle relaxing and neurolept~c activities. They also show vasodilating and anti-asthmatic activities. Therefore, these compounds may be useful as neuroleptics or anti-- ~ ~

asthmatic agents.
Further, for example, the compounds of Formula [I]
wherein Rl represents a lower alkoxy group and R3 and R4 are each a lower alkyl group show, in general, potent inhibitory activities of both ADP and collagen induced platelet aggregation in vitro. Since anti-platelet aggregation agents are considered to be one of desirable anti-thrombosis agents, they may be useful as such agents.
The benzisoxazole compounds [I] and their pharma-ceutically acceptable salts can be administered parenterally or orally (with dosage adjusted to individual requirements) in the form of conventional pharmaceutical preparations.
For instance, they can be administered in the form of conventional solid pharmaceutical preparations such as tablets or capsules, or in the form of conventional liquid pharmaceutical preparations such as suspensions, emuisions or s~lutions.
Besides, the benzisoxazole compounds [I] are also useful as intermediates for preparation of other compounds which are per se useful as medicines.
The benzisoxazole compounds [I] of the invention can be prepared from the corresponding o-substituted nitro-be~zenes of the formula-AlK-A
Rl R~ No2 lII]
wherein Z is ~ C0 or ~ CHCOR6 (wherein R6 is Cl 4 alkyl) and Rl, R2, Alk and A are each as deined above by subject-.

i(~5i430 ing the latter to cyclization.
The cyclization may be accomplished by variousprocedures. As a typical example of such procedures, the o-substituted nitrobenzene of Formula lII] wherein Z is ~CHCOR6 may be cyclized by treatment with a base or an acid to give the benzisoxazole compound [I].
As the base, the use of a strong base such as potassium hydroxide, sodium hydroxide, potassium t-butoxide, sodium ethoxide, sodium methoxide, lithium triphenylmethane, sodium triphenylmethane or sodium hydride is preferred. As the acid, there may be employed any one having a dehydrating activity such as conc. sulfuric acid or polyphosphoric acid.
The treatment is usually carried out in the presence of an inert solvent. Examples of the inert solvent are alcohols (e.g. t-butanol, ethanol, methanol), ethers ~e.g. ethyl ether, tetrahydrofuran, dioxane, dimethoxy-ethane), hydrocarbons (e.g. heptane, hexane, benzene, toluene), amides ~e.g. dimethylformamides, hexamethylene-phosphorotriamide), water, etc. The conditions, under which --the treatment is made, such as temperature and time may vary depending upon the starting o-substituted nitrobenzene lII]
and the base or the acid to be used therein. The treatment may be efected while warming or cooling depending upon the extent of the progress, but the temperature is usually from about -20 to 100C. The base may be used in a stoichio-metric amount or more, while the acid may be preferably employed in an excess amount so as to use the same as the medium.
Another typical example is trea~ment of the o-substituted nitrobenzene of Formula [II] wherein Z is lO~i430 CO in any appropriate reduction system, whereby reductivecyclization takes place to give the benzisoxazole compound [I].
The reduction system may be the one using a reducing agent such as the combination of a metal or its compound (e.g. tin, zinc, stannous chloride) with an acid ~e.g. hydrochloric acid, acetic acid), the combination of an alkali metal (e.g. sodium, lithium, potassium, amalgamated sodium) with an alcohol or liquid ammonia, a sulfide compound (e.g. sodium sulfide, ammonium sulfide) or the like.
Among them, one of the most preferred reducing -- agents is the combination of a metal or its compound with an aoid. The treatment with this particular reducing agent may be carrled out in the presence or absence of an inert solvent such as water, alcohols ~e.g. methanol, ethanol), hydrocarbons (e.g. benzene, toluene) or ethers (e.g. ethyl ether, tetrahydrofuran, dioxane). An excess amount of the acid may be also used as a solvent. The temperature for the treatment may be varied from room temperature to the refluxing temperature of the reduction system. Likewise, the treatment using any other reducing agent may be e$fected in a per se conventional manner established on each reducing ` agent.
~ he reduction system may be also catalytic re-duction, i.e. the one using a hydrogenation catalyst. In this case, conventional standard procedures are applicable, but it i9 recommendable to use mild conditions in order to avoid overreduction. Thus, a temperature around room temperature, an atmospheric pressure of hydrogen gas and a .

-1~5i430 relatively mild catalyst such as Pd-BaS04, Pd-BaC03 or a metallic catalyst poisoned with quinoline, dimethylsulfide, diethylsulfide or the like may be preferably used.
The benzisoxazole compounds [I] thus produced may be separated from the reaction mixture and purified by conventional proced~res.
The thus obtained benzisoxazole compounds [I] may be converted into their addition salts by usual methods, and reconversion from the addition salts to the original free bases may be also carried out by ordinary methods.
The following examples are given for the purpose of illustration only and it is not intended to limit the invention.
Example 1 To a mixture of 36 ml of t-butanol and 18 ml of ~oluene was added 1.8 g of metallic potassium, followed by heating to a solution. To this solution was added 12.6 g of 1-(2'-nitro-4',5'-dimethoxyphenyl)-1-[2'-(4"-phenyl-piperazino)ethyl]propan-2-one under cooling with water, followed by stirring for 4 hours at room temperature.
The reaction mixture was poured onto ice-water and extracted with chloroform. The chloroform layer was washed with water, dried and evaporated to dryness. The oily residue was dissolved in ethyl acetate and mixed with 10 g of silica gel. The whole mixture was stirred for 30 minutes and filtered to remove off the silica gel. The filtrate was concentrated to dryness, and the residue was crystallized by methanol-ether to give 7.0 g of 3-[2'-(4"-phenylpiperazino)-ethyl]-5,6-dimethoxy-benz-2,1-isoxazole having a melting point of 115 - 117C.

105~430 Example 2 To 20 ml of sulfuric acid was added 2 g of l-(2'-nitro-4',5'-dimethoxyphenyl)-l-[2'-(4"-phenylpiperazino)-ethyl]propan-2-one, followed by stirring for 4 hours at room temperature.
The reaction mixture was poured onto ice-water, neutralized with ~queous ammonia and extracted with chloroform. ~The chloroform layer was washed with water, dried, treated with charcoal and evaporated to dryness. The oily residue was crystallized by methanol-ether to give 3-~2'-(4'1-phenylpiperazino)ethyl]-5,6-dimethoxy-benz-2,1- -isoxazole. This product was identified with the compound obtained in Example l.
Example 3 To a solution of 9.03 g of stannous chloride dihydrate in 72 g of conc. hydrochloric acid was added a solution of 2.59 g of l-(2'-nitrophenyl)-3-dimethylamino-propan-l-one hydrochloride in 18 g of conc. hydrochloric acid, followed by stirring for 3 hours at room temperature.
The reaction mixture was diluted with water and stirred for several minutes, basified with aqueous sodium hydroxide under cooling and extracted with chloroform. The chloroform layer was washed with water, dried and con-~centrated to dryness. The oily residue was dissolved in ethanol and mixed with 4.5 g of oxalic acid in ethanol. The deposited precipitates were collected and recrystallized from ethanol to give 2.2 g of 3-(2'-dimethylaminoethyl)-benz-2,1-isoxazole oxalate having a melting point of 145 -146.5C.
Example 4 ~5i430 Using the procedure similar to that described in Example 3 but replacing 1-(2'-nitrophenyl)-3-dimethylamino-propan-l-one hydrochloride by l-(2'-nitro-5'-methoxyphenyl)-3-dimet~lylaminopropan-1-one hydrochloride, there was obtained 3-~2'-dimethylaminoethyl)-5-methoxy-benz-2,1-isoxazole oxalate having a melting point of 159 - 160C.
Example 5 A mixture of 0.8 g of 1-(2'-nitrophenyl)-3-di-methylaminopropan-l-one hydrochloride and 4.5 g of sodium sulfide in 45 ml of methanol was heated under reflux for 10 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was dissolved in chloroform, washed with water, dried and concentrated to dryness. The res;due was chromatographed on silica gel and treated with oxalic acid to give 3-(2'-dimethylaminoethyl)-benz-2,1-isoxazole oxalate. This product was identified with the compound obtained in Example 3.
Example 6 0.8 g of 1-(2'-nitrophenyl)-3-dimethylamino-propan-l-one hydrochloride in 12 ml of acetic acid was hydrogenated over 120 mg of 5 % palladium-barium sulfate.
After 2 equivalents of hydrogen was absorbed, the reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was dissolved in chloroform, washed with 2 % aqueous sodium hydroxide and then with water, dried and concentrated to dryness. The residue was chromato-graphed on silica gel and treated with oxalic acid to give 3-(2'-dimethylaminoethyl)-benz-2,1-isoxazole oxalate. This pro~uct was identified with the compound obtained in Example . .

lOSi4;30 The following compounds were produced ~y the manner similar to that in Examples 1 and 3.
3-(2'-Diethylaminoethyl)-5,6-dimethoxy-benz-2,1-isoxazole oxalate, m.p. 160 - 162C;
~ -(2'-Piperidinoethyl)-5,6-dimethoxy-benz-2,1-isoxazole oxalate, m.p. 199 - 200C;
3-(2'-Morpholinoethyl)-5,6-dimethoxy-benz-2,1-isoxazole oxalate, m.p. 183 - 185C;
3-(3'-Dimethylaminopropyl)-5,6-dimethoxy-benz-2,1-isoxazole oxalate, m.p. 14S - 147C;
3-[2'-(4 n -Phenylpiperazino)ethyl]-5,6-methylene-dioxy-benz-2,1-isoxazole, m.p. 126 - 127.5C;
3-(2'-Piperidinoethyl)-5,6-methylenedioxy-benz-2,1-isoxazole, m.p. 97.5 - 99.5C;
3-(2'-Diethylaminoethyl)-5,6-methylenedioxy-benz-2,1-isoxaæole oxalate, m.p. 168.5 - 169.5C;
3-(2'-Morpholinoethyl)-5,6-methylenedioxy-benz-2,1-isoxazole, m.p. 116.5 - 119C;
3-12'-(4''-Phenylpiperazino)ethyl]-benz-2,1-isoxazole oxalate, m.p. 194 - 196C;
3~ (? ~ -Morpholinoethyl)-benz-2,1-isoxazole oxalate, m.p. 174 - 175C; `
3-(2'-Piperidinoethyl)-benz-2,1-isoxazole oxalate, m.p. 154 - 155C;
3-(2'-Pyrrolidinoethyl)-benz-2,1-isoxazole oxa-late, m.p. 152 - 153C;
3-12'-(4"-Methylpiperazino)ethyl]-benz-2,1-iso-xazole oxalate, m.p. 229 - 232C;
3-(2'-Morpholinoethyl)-5-methoxy-benz-2,1-iso-xazole oxalate, m.p. 178 - 180C;

105~4;~0 3-(2'-Di-n-propylaminoethyl)-5-methoxy-benz-2,1- `~
isoxazole oxalate, m.p. 146 - 148C;
3-(2'-Dimethylaminoethyl)-5-ethoxy-benz-2,1-isoxazole oxalate, m.p. 153 - 155C;
3-(2'-Dimethylaminoethyl)-6-fluoro-benz-2,1-isoxazole oxalate, m.p. 150 - 151C;
3-(2'-Morpholinoethyl)-6-fluoro-benz-2,1-isoxazole oxalate, m.p. 176 - 177C;
3-(2'-Dimethylaminoethyl)-6-methoxy-benZ-2,1-isoxazole oxalate, m.p. 172 - 174C;
3-(2'-Morpholinoethyl)~6-methoxy-benz-2,1-iso-xazole oxalate, m.p. 147 - 148C.

.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing benzisoxazole compounds of the formula:

wherein R1 and R2 are each hydrogen, C1-4 alkyl, C1-4 alkoxy, halogen or trifluoromethyl or, when taken together, they form C1-2 alkylenedioxy; Alk is C1-4 alkylene and A is a group of the formula:

or (wherein R3 and R4 are each C1-4 alkyl, phenyl or phenyl sub-stituted with C1-4 alkyl, C1-4 alkoxy or halogen, or when taken together with the adjacent nitrogen atom, they represent either a morpholino group or a saturated heterocyclic ring having 5 to 7 members wherein one nitrogen atom is included as the only hetero atom; and R5 is C1-4 alkyl, phenyl or phenyl substituted with C1-4 alkyl, C1-4 alkoxy or halogen and their non-toxic salts, which comprises subjecting an o-substituted nitrobenzene of the formula:

wherein Z is or (wherein R6 is C1-4 alkyl) and R1, R2, Alk and A are each as defined above to cyclization.

2. The process according to Claim 1, wherein the o-substituted nitrobenzene wherein Z is is subjected to cyclization by treatment with a base or an acid.

3. The process according to Claim 2, wherein the base is potassium hydroxide, sodium hydroxide, potassium t-butoxide, sodium ethoxide, sodium methoxide, lithium triphenylmethane, sodium triphenylmethane or sodium hydride.

4. The process according to Claim 3, wherein the treatment is effected in an inert solvent.

5. The process according to Claim 2, wherein the acid is sulfuric acid or polyphosphoric acid.

6. The process according to Claim 1, wherein the o-subsituted nitrobenzene wherein Z is is subjected to cyclization by treatment in a reduction system.

7. The process according to Claim 6, wherein the reduction system is the one using a reducing agent.

8. The process according to claim 7, wherein the reducing agent is the combination of a metal or its compound with an acid.

9. The process according to claim 8, wherein the reducing agent is the combination of stannous chloride with hdyrochloric acid.

10. A compound of the formula:

wherein R1 and R2 are each hydrogen, C1-4 alkyl, C1-4 alkoxy, halogen or trifluoromethyl or, when taken together, they form C1-2 alkylenedioxy; Alk is C1-4 alkylene and A is a group of the formula:

or (wherein R3 and R4 are each C1-4 alkyl, phenyl or phenyl sub-stituted with C1-4 alkyl; C1-4 alkoxy or halogen or when taken together with the adjacent nitrogen atom, they represent either a morpholino group or a saturated heterocyclic ring having 5 to 7 members wherein one nitrogen atom is included as the only hetero atom; and R5 is C1-4 alkyl, phenyl or phenyl substituted with C1-4 alkyl, C1-4 alkoxy or halogen, and its non-toxic salt, whenever produced by the process according to claim 1 or an obvious chemical equivalent.

11. The process according to Claim 1, wherein A is .

12. The process according to Claim 1, wherein A is .

13. The process according to Claim 1, wherein R1 and R2 are each hydrogen, C1-2 alkoxy or halogen or, when taken together, they form C1-2 alkylenedioxy, A is a group of the formula:

(wherein R3 and R4 are each C1-4 alkyl or, when taken together with the adjacent nitrogen atom, they represent pyrrolidino, piperidino, or morpholino) and Alk is C2-3 alkylene.

14. The process according to Claim 1, wherein R1 is C1-2 alkoxy, R2 is hydrogen, A is a group of the formula:

(wherein R3 and R4 are each C1-4 alkyl) and Alk is C2-3 alkylene.

15. The process according to Claim 1, wherein R1 and R2 are each hydrogen, C1-2 alkoxy or halogen or, when taken together they form C1-2 alkylenedioxy, A is a group of the formula:

(wherein R5 is as defined in claim 1 and Alk is C2-3 alkylene.

16. The process according to Claim 1 for producing 3-(2'-dimethylaminoethyl)-5-methoxy-benz-2, 1-isoxazole which comprises subjecting 1-(2'nitro-5'methoxyphenyl)-3-dimethyl-aminopropan-1-one hydrochloride to reductive cyclization with a reducing agent and acid.

17. The process according to Claim 1 for producing 3-[2'-(4"phenylpiperazino)ethyl]-5,6-dimethoxy-benz-2,1-isoxazole which comprises subjecting 1-(2'nitro-4',5'-dimethoxyphenyl)-1-12'-(4"-phenylpiperazino)-ethyl] propan-2-one to cyclization with a strong acid.

18. A compound of the formula:

wherein R1 and R2 are each hydrogen, C1-2 alkoxy or halogen or, when taken together, they form C1-2 alkylenedioxy, R3 and R4 are each C1-4 alkyl or, when taken together with the adjacent nitrogen atom, they represent pyrrolidino, piperidino, or morpholino, and Alk is C2-3 alkylene, and its non-toxic salt, whenever produced by the process of claim 13 or an obvious chemical equivalent.

19. A compound of the formula:

wherein R1 is C1-2 alkoxy, R3 and R4 are each C1-4 alkyl and Alk is C2-3 alkylene, and its non-toxic salt, whenever produced by the process of claim 14 or an obvious chemical equivalent.

20. A compound of the formula:

wherein R1 and R2 are each hydrogen, C1-2 alkoxy or halogen or, when taken together, they form C1-2 alkylenedioxy, R5 is C1-4 alkyl, phenyl, or phenyl substituted with C1-4 alkyl, C1-4 alkoxy or halogen, and Alk is C2-3 alkylene, its non-toxic salt, whenever produced by the process of claim 15 or an obvious chemical equivalent.

21. 3-(2'-Dimethylaminoethyl)-5-methoxy-benz-2,1-isoxazole, and its non-toxic salt, whenever produced by the process of claim 16 or an obvious chemical equivalent.

22. 3-[2'-(4"-Phenylpiperazino)ethyl]-5,6-dimethoxy-benz-2,1-isoxazole, and its non-toxic salt, whenever produced by the process of claim 17 or an obvious chemical equlvalent.