JPS61118351A - Antihypertensive dialkylaminoethylaniline derivative - 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 [Background of the Invention] [Field of the Invention] The present invention relates to the treatment of hypertension, congestive heart failure, arrhythmia, migraine,
and dialkyl and cycloalkylaminoethylaniline derivatives and pharmaceutically acceptable acid addition salts thereof useful in the treatment of cardiovascular diseases such as vascular and mesovascular diseases, and intraocular diseases such as glaucoma. The present invention further relates to pharmaceutically acceptable compositions containing an effective amount of at least one instant compound in combination with suitable excipients, which compositions are useful for treating hypertension, congestive heart failure, arrhythmias, dysrhythmia, and hyperplasia in mammals. It is useful in the treatment of cardiovascular diseases such as headaches and mesovascular diseases, and intraocular diseases such as glaucoma. The present invention also relates to methods of making the compounds of the invention, and to compounds useful in making the compounds of the invention by this method.

Prior Art Certain alkyl and dialkylaminoethylanilines are known. For example, US Pat. No. 4,287,211
No. 4404222, No. 3803230, and No. 36
No. 89524 and German Patent No. 2612354
Please refer to the issue. A new class of dialkyl and dichloroalkylami/ethylaniline derivatives has now been prepared.

[Summary of the invention]

A first aspect of the present invention is a compound of the formula: [wherein - is alkyl having 2 to 4 carbon atoms, and - is alkyl having 3 or 4 carbon atoms, or R
yo and R2 together form [in the formula, n is 0.1 or 2, R5 and 2 are each independently lower alkyl or hydrogen], - is hydrogen or hydroquine, and 2 is hydrogen , lower alkyl, amino, or lower alkylamine, or a pharmaceutically acceptable acid addition salt thereof.

Another aspect of the invention is a composition useful for the treatment of cardiovascular diseases such as hypertension, congestive heart failure, arrhythmias, migraines, and vasoconstrictive diseases, and intraocular diseases such as glaucoma in mammals. The composition comprises an effective amount of at least one compound selected from the compounds represented by formula (I) above or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable excipient. It is something.

Yet another aspect of the invention provides a method for treating hypertension, congestive heart failure, arrhythmia, migraine headaches in mammals, comprising administering an effective amount of at least one compound selected from the compounds represented by formula (I) above. , and methods of treating cardiovascular diseases such as mesovascular disease, and intraocular diseases such as glaucoma.

Yet another aspect of the invention is a method of making a compound of formula (I).

Yet another aspect of the present invention is a compound of formula (■) useful as an intermediate for the preparation of a compound of formula (I): [wherein A is hydrogen or benzyloxy, R1 and R2 are as defined above] It is a compound represented by

[Detailed description and preferred embodiments]

The broadest aspect of the invention relates to the formula: [wherein 1 is alkyl of 2 to 4 carbon atoms, and -
is alkyl having 3 or 4 carbon atoms, or 0 and R2 taken together with N, where n is 0.
1, or 2, and λ5 and R6 are each independently lower alkyl or hydrogen, and is hydrogen or hydroxy, and is hydrogen, lower alkyl, amine, or lower alkylamino. or pharmaceutically acceptable acid addition salts thereof.

Among the group of compounds of formula (I), one preferred subgroup is R
This is a group of compounds in which R4 is hydrogen, especially R4 is amino. Preferred compounds are those in which R1 and R2 are each n-propyl.

Another preferred subgroup of the group of compounds of formula (I) is K-Ko and Trap. together with N, [where n is 1
and R5 and R6 are methyl]. Particularly preferred compounds are R
This is a compound where 3 is hydrogen and 艮 is amino.

As used in this specification and the claims appended hereto, the following terms have the meanings ascribed to them, unless indicated otherwise.

The term "lower alkyl" includes straight or branched chain monovalent substituents consisting only of carbon and hydrogen, containing no unsaturation, and having from 1 to 4 carbon atoms. Examples of lower alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, S-butyl and [-butyl.

The term "hydroxy" refers to -OH.

The term "alkylamino" refers to an amine group monosubstituted by a lower alkyl group as defined above.

The term "pharmaceutically acceptable acid addition salts" refers to salts that have the desired pharmacological activity and are not biologically or otherwise harmful.
Indicates a salt of the above compound. These salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acids, or acetic, propionic, glycolic, pyruvic, malonic, conolilic, malic, maleic, fumaric acids. acid,
It is produced by organic acids such as tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid.

The term "ophthalmologically acceptable" means suitable for ophthalmic use. That is, an ophthalmologically acceptable carrier is one that does not cause irritation when administered directly to the eye.

The term "direct administration" means administration directly to the eye of a subject and excludes systemic administration. Direct administration includes, but is not limited to, topical administration of aqueous solutions and ointments, administration of controlled release dosage forms, and epiconjunctival injection.

As used herein, the term "treatment" includes any treatment for a disease in a mammal, particularly a human, who (1) may be predisposed to contracting the disease;
prevent the appearance of the disease in subjects who have not yet been diagnosed with it; (11) arrest the disease, i.e., suppress its progression; In other words, it includes inducing remission of the disease.

Compounds of formula (I) in which R1 and R2 together with N are not the same,
May be isomers. The wavy line is used to indicate that either the nce isomer, the trans isomer, or a mixture can be used.

Isomers can be separated by various methods, such as selective crystallization and column chromatography.

Alternatively, the free base (eg 3,5-dimethylpiperidine) can be resolved and then incorporated into the compounds of the invention. (The invention encompasses all geometrical isomers of any asymmetric compound of formula (I), as well as mixtures thereof.) ADMINISTRATION AND FORMULATION Another aspect of the invention is , a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable non-toxic carrier. It relates to pharmaceutical compositions useful for the treatment of cardiovascular diseases such as sexual diseases, especially hypertension in mammalian subjects. In subjects who are predisposed to the disease but have not yet been diagnosed with it,
The amount is sufficient to prevent the appearance of the disease. The concentration of the drug in the formulation is approximately 5% by weight (%W) based on the total amount of the formulation.
) to about 95% W drug and excipients about 5% W to 95
It can be changed to %W. Preferably the drug is about 10% W to about 70% W
%W.

Pharmaceutical carriers useful in the manufacture of this pharmaceutical composition can be solid or liquid. Therefore, this composition
It can take the form of tablets, pills, capsules, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. The carrier can be selected from a variety of oils including petroleum, animal, vegetable or synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water, saline, aqueous dextrose and glycols are preferred liquid carriers;
It is a preferred carrier, especially for injectable solutions. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour,
Contains white powder, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dry skim milk, glycerol, propylene glycol, water, ethanol, etc. Other suitable pharmaceutical carriers and formulations using them include E, W
, by Martin [Remington's Pharmaceutical Sciences (Remington's Phar
mechanical 5sciences) J 1st
It is described in the 5th edition (1975).

Another aspect of the invention is a mammalian subject (particularly a human)
A method of treating cardiovascular diseases such as hypertension, congestive heart failure, arrhythmia, migraine, and vascular disease in patients, the method comprising: a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof; to a mammal in need thereof.

In carrying out the above method according to the invention, a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition containing it may be administered alone or in combination with another compound or compounds according to the invention or another agent. in combination with the administration via any method conventional and acceptable in the art. For example, these compounds or compositions can be administered orally, systemically (e.g. transdermally, nasally, or semi-openly).
, or parenterally (e.g., intramuscularly, subcutaneously, and intravenously), including tablets, solutions, suspensions, aerosols, etc., as discussed in more detail above. It can be administered in either solid or liquid dosage forms.

Preferably, compounds of formula (I) in which R3 is hydrogen are administered orally. Parenteral administration is preferred for compounds of formula (I) where R3 is hydroxy.

The formulation can be administered in a single unit dosage form for continuous treatment, and single unit dosage forms can be administered ad libitum when symptomatic relief is particularly needed.

Although all factors can be determined by routine experiments by those skilled in the art, the present invention takes into account the severity of the condition to be treated, the age of the subject, etc., and in view of the above-mentioned facts. Effective doses can vary within wide limits. Generally, therapeutically effective amounts range from about 0.01 to about 10 s+y/KF body weight/day, preferably from about 5 to about 50 q/4 body weight/day, for example for antihypertensive uses. In other words, for an adult patient with an average weight of 701f, a therapeutically effective amount according to the present invention will in a preferred embodiment range from about 0.7 to about 700 #v per patient per day, and preferably from about 35 #v per patient per day. This makes up 350 my days.

The spontaneously hypertensive rat (SHR) assay is an accepted test for measuring antihypertensive activity. For example, J
, Rover et al., Archives Internationals Dough Pharmacodynamics (Arch, Int, P
harmacodyn, ), 2Q Volume Q, page 182 (
(1972). The compounds of the invention exhibit antihypertensive activity in the SHR assay.

Ophthalmic formulations are sterile products for topical administration to the eye or for instillation into the space between the eyeball and eyelids (culpa).

Ophthalmic preparations that can be used according to the present invention include solutions, suspensions,
Includes ointments, and controlled-release formulations. Treatments for eye diseases available in the present invention include topically applied eye drops, solutions,
including suspensions or ointments or their subconjunctival injection.

The composition of the present invention comprises a compound of formula (1) (as defined herein) or a salt thereof in admixture with an ophthalmologically acceptable excipient.

An excipient is ophthalmologically acceptable if it is non-irritating to the eye and non-toxic at effective levels.

Ophthalmic compositions can be aqueous or non-aqueous and can be in the form of solutions, suspensions, gels, ointments, sustained release polymers, or other dosage forms. The amount of active ingredient will vary depending on its formulation and disease state, but will generally contain 0.001 to 10% w/v of active ingredient per individual dose, preferably o
, oos~7% by weight/volume.

Ophthalmic pharmaceutical compositions typically contain from 0.001% to 10% by weight of active ingredient, along with suitable buffers, stabilizers and preservatives.
It is provided as a sterile aqueous solution (ie, eye drops) containing % o, oos to 1% by volume. The total concentration of solutes should, if possible, be such that the resulting solution is isotonic with the tear fluid (although this is not absolutely necessary) and has a similar pH (pH range 6-8). Should. Typical preservatives/fungicides are phenylmercuric acetate, thimerosal, chlorobutanol, and benzalkonium chloride. Typical buffer systems and salts are based on, for example, citric acid, boric acid or phosphoric acid; suitable stabilizers include glycerin and polysorbate 80. Aqueous solutions are prepared by simply dissolving the components in an appropriate amount of water and adjusting the pH to about 6.8-8.
0, add water to make final volume adjustment, and sterilize the formulation using methods known to those skilled in the art.

The dosage level of the resulting composition will of course depend on the concentration of the drops,
It will depend on the condition of the subject and the magnitude of that individual's response to treatment. However, a typical dosage range is approximately 20% of a 0.1% solution of the active ingredient 1 to 3 times per day.
~10 drops would be administered.

Most ophthalmic solutions and suspensions contain an aqueous rather than an oil-based vehicle. Eye ointments usually contain a white petrolatum-mineral oil base, often with anhydrous lanolin, and some have a polyethylene-gelled mineral oil base.

Solutions are the most commonly used type of formulation for topical ophthalmic therapy. These can be easily added dropwise and induce few harmful reactions. The medium must not interfere with vision and must not interfere with corneal epithelial regeneration.

Suspensions have the advantage of longer and more widespread action, but have the disadvantage that the presence of some particles large enough to cause irritation is difficult to avoid.

Eye ointment is a sterile preparation for application to the conjunctival sac or lid margin. This includes longer contact times and effects,
The advantages include minimal irritation upon first application, slower migration into the tube, greater storage stability, and less contamination problems. The disadvantages of this formulation are that it creates a coating over the eye, causing blurred vision, and that this may prevent new corneal epithelial cells from firmly attaching to the normal base. . Ointments, depending on their ability to pass through the outer capsule of the eyeball, can be applied to the outer and rim of the eyelids, conjunctiva,
Acts on the cornea and iris.

Eye ointments containing active ingredients can be used on the outside and margins of the eyelids, conjunctiva, and cornea. Most eye ointments are made from a base of white or yellow petrolatum and mineral oil, often with the addition of anhydrous lanolin.

Whichever carrier is selected, it must be non-irritating to the eye, capable of dispersing the drug into the secretions that bathe the eye, and retain the activity of the drug for a reasonable period of time under appropriate storage conditions. Must be retained.

The compounds of the invention can also be administered by other non-systemic methods. Ophthalmic packs can be used to provide prolonged contact of the solution with the eye. For example, cotton inserts impregnated with an ophthalmologically suitable solution of a compound of the invention can be inserted into the superior or inferior fornix. Controlled release ophthalmic discs of drugs produce stronger and longer-lasting effects than solutions. No. 41, which discloses a controlled release device for administering compounds to the eye, which may be useful in the practice of the present invention.
No. 90642, which is incorporated by reference and incorporated by reference.

The compounds of the invention can also be administered by iontophoresis. In this method, an electrode is attached to the cornea in the calf.
It keeps the solution in contact.

Diffusion of the drug is effected by a potential difference. Remington's Pharmaceutical Sciences (Remin)
gton's Pharmaceutical 5ci
ences) 15th edition, pp. 1489-1504 (197
5).

[Production method according to the present invention]

Compounds of formula (I) are produced by the following reaction steps.

Reaction formula (V) (■) (■) (■a) (■C) (■d) [In the formula, K, R2, k3, and R4 have the same meanings as above in the broadest scope of the present invention. and “rs is tosyl(p-)luenesulfonyl], A is benzyloxy (BzO) or hydrogen, BzCz is benzyl chloride, and ≮ is lower alkyl]. If desired, steps (1) 3 and (7) are not necessary and are omitted. In such cases, steps (6a,
b, c, or d) is the final step.

For compounds in which R3 is hydroxy, in particular - Aldrich Ch.
4-Hydroxy-3 available from
- Nidophenyl acetic acid (If) is first converted to the methyl ester and then reacted using Williamson's ether synthesis method with an equimolar amount of benzyl chloride, also available from Aldrich Chemical Company, among others. Hydroxy protected methyl 4-benzyloxy-3-trophenylacetate (
III, A = Bz O) Obtain. This reaction is usually carried out using potassium carbonate in refluxing acetonitrile or ethanol.

(Step 1) Next IC, preservation ffl nitrophenyl acetate (■, A
=BzO) is reduced at room temperature using borane-methyl sulfide in tetrahydrochloride (THF) solution.

After acidification with HC/ in methanol, the solution was evaporated and the product 4-benzyloxy-3-nitrophenylethanol (■, A = BzO) was dissolved in carbonic acid with the addition of diethyl ether (E t 20 ). ) Extract from IJum water. Similarly, 4-benzyloxy-
Compounds where A=H can be prepared by the same method using 3-nitrophenylacetic acid (I[, A=H) in place of methyl 3-nitrophenylacetate. 3-Nitrophenylacetic acid is commercially available from Aldlich Chemical Company, among others. (Step 2) Next, 4-benzyloxy-3-nitrophenylethanol (■, A=BzO) was added to a 1 molar excess of p in pyridine.
-) with luenesulfonyl chloride at 0°C to produce 4-benzyloxy-3-nitrophenylethyl tosylate (V%A=BzO). This toshira)
(V, A=BzO) is extracted using ethyl acetate.

Similarly, in place of 4-benzyloxy-3-nitrophenylethanol, IC 3-nitrophenylethanol (
(2) Compounds where A=H can be prepared by the same method using A=H). (Step 3) This tosylate (■, A=BzO) was treated with dimethylformamide (D
MF) at 65° C. to form 2-benzyloxy-5-dialkyl or cycloalkylaminoethylnitrobenzene (■, A=BzO). Similarly, 4-benzyloxy-3-nitrophenyl
Compounds where A=H can be prepared by the same method using 3-nitrophenylethyl tosylate (v, A=H) instead of ethyl tosylate.

Dialkyl and cycloalkylamines are available from commercial sources, such as Aldrich Chemical Company.

or can be manufactured by methods known in the art. (Step 4) Next, 2-benzyloxy-5-dialkyl or cycloalkylaminoethylnitrobenzene (■, A=Bz
O) is reduced with hydrazine and Raney nickel in refluxing ethanol under ambient pressure with equimolar amounts of hydrogen using common methods known for other compounds not related to the present invention. benzyloxy-5-dialkyl or cycloalkylaminoethylaniline derivative (■, A=BzO). For example, Andrew Streitweiser, Jr., and Clayton H.
・Introduction to Organic Chemistry by Heathcock
to Organic Chemistry) J
, Chapter 32, page 961 (1976).

Similarly, instead of 2-benzyloxy-5-dialkyl or cycloalkylamine ethylnitrobenzene, 3
- by method using dialkyl or cycloalkylaminoethylnitrobenzene (VI, A:H)
A compound that is H can be produced. (Step 5) This reaction step is completed by reacting the aniline derivative with an equimolar amount of a suitable reactive formyl derivative, carboxylic acid derivative, incyanate, or alkyl isocyanate.

Formamide derivative (■a, A-=H or B z O
) is desired, this new aniline derivative (■, A=H
or BzO) at 0° C. in a suitable aprotic base with a suitable reactive formyl derivative (e.g. formic acetic anhydride, which can be produced in situ from the commercially available sodium formate and acetyl chloride). react with equimolar amounts of (Step 6a) Compounds in which R4 is lower alkyl (■
b, A=H or BzO), the aniline derivative (■, A=H or BzO) is combined with an equimolar amount of a suitable reactive carboxylic acid derivative, especially an acyl, in a suitable aprotic base. React with halide at 25°C. Carboxylic acid chlorides are commercially available or can be prepared from commercially available carboxylic acids by methods known in the art. (Step 6b) Ureidobenzene derivative (■c, A
=Htf; is BzO), the aniline derivative (■, A=)I or BzO) is mixed with an equimolar amount of a suitable cyanate salt, e.g. potassium cyanate, in an acidic solvent at 25 React at ℃. (Step 5c) In order to produce an alkylureidobenzene derivative (■d, A=H or BzO), an aniline derivative (■, A
=H or BzO) at 25° C. with equimolar amounts of the appropriate alkyl isocyanate using common methods known in the art for compounds not related to the invention. For example, Introduction to Organic Chemistry
ic Chemistry) J, :x, Treitweiser and Heathcock, Chapter 27.

See page 801. Alkylin cyanate compounds are commercially available or can be prepared by reacting the appropriate alkyl halide with a reactive cyanate salt. (Step fid) For compounds where R3 is hydrogen, step 5a, b, C or d directly produces the compound of formula (I).

If R3 is hydroxy, the benzyloxy protecting group needs to be removed. This is done, for example, using palladium/carbon in methanol at ambient temperature and 2 atm.
Catalytic hydrogenolysis of the penultimate compound (■2-d) [Catalytic hydrogenation]
In Organic Synthesis, Procedures and Commentary (Catalytic Hydrogenation in Organic Synthesis:
Method and Commentary) (Cacalytic Hydro
genacion inOrganic 5ynthe
sis: Procedures and Comms
9M, Freifelder, (Wiley, 1978).

The compound of the present invention (I
) is obtained.

In summary, compounds of formula (I) are prepared by the following method: Compounds of formula (I) in which R3 is H are prepared by reacting a compound of formula (Vl) (where A=H) with a suitable reactivity. Produced by reaction with formyl derivatives, carboxylic acid derivatives, isocyanates, or alkyl isocyanates to produce the corresponding formanilide, alkanylanilide, ureidobenzene, or alkylurea derivatives.

These reactions are carried out under atmospheric pressure and at temperatures between the freezing and boiling points of the solvent used, preferably from about -5°C to about 11°C.
It can be carried out at 0°C, most preferably at about 25°C.

Compounds of formula (I) in which R3 is OH can be obtained by carrying out the same method using compounds of formula (■) where A=BzO;
Subsequent removal of the protected benzyloxy group, for example, by catalytic hydrogenolysis with H2 using palladium/carbon at about 60 DEG C. and about 2 atmospheres.

Pharmaceutically acceptable acid addition salts of compounds of formula (I) are those of formula (I).
Prepared by reacting the free base of I) with a suitable acid. Free bases of formula (I) are prepared by reacting acid addition salts of compounds of formula (I) with a suitable base.

The following specific description has been prepared to enable those skilled in the art to more clearly understand and implement the invention.

This should not be construed as limiting the scope of the invention;
The invention is merely illustrative and representative.

Production Example 1 (Production of compound of formula (III) in which A is benzyloxy) (Step 1) Unpalatable-hydroxy-3-nitrophenylacetic acid (II)
The carboxy group of is protected by forming a methyl ester using M(I in methanol, a method known in the art. The 4-hydroxy-3
- Methyl nitrophenylacetate 10.5F and benzyl chloride 10y are reacted with potassium carbonate 5y in ethanol. Extract the product with ether.

Preparation Example 2 (Preparation of a compound of formula QV in which A is hydrogen or benzyloxy) (Step 2) A) 3-nide o
7 engineering = /L/4 op of acetic acid, 1 in 200 d of THF
A solution of 0M borane-methyl sulfide 26- is added and the mixture is stirred at 25° C. for 3 hours. The solution is then acidified with HC in methanol and then evaporated.

Product 3-nitrophenylethanol (■, A=H)
diethyl ether (E t 20 ) and carbonic acid)
Distribute between IJ and water, E [20 layers with sulfuric acid] IJ
Dry with um. Evaporation of E t 20 gave 3-nitrophenylethanol (IV, A=H) 34.8F as an oil.

B) Similarly, proceed as in section A above except using methyl 4-benzyloxy-3-nitrophenylacetate instead of 3-nitrophenylacetic acid. Compound (■, A =
BzO) is produced.

Production Example 3 (Production of compound of formula (V)) (Step 3) A)
3-nitrophenylethanol (■, A=H) 34.
61 is added to p-toluenesulfonyl chloride 41F in pyridine 200 at 0°C and left for 24 hours. Water is added and the mixture is extracted with ethyl acetate. The ethyl acetate extract was washed with 5% HC/, water, and brine, and Na2S
Dry with O4 and evaporate to obtain a residue. Recrystallization of this residue from E t 20 gives 3-nitrophenylethyl tosylate (v1A=H) 34 y.

B) Similarly, proceed as in section A above except using 4-benzyloxy-3-nitrophenylethanol instead of 3-nitrophenylethanol. A tosylate compound (V, A=BzO) is produced.

Production Example 4 (Production of compound of formula (5)) (Step 4) A)D
3-nitrophenylethyl-2- in MFIQQ-
A mixture of tosylate 18.85' and di-n-propylamine 25- is stirred at 65°C for 12 hours. The solution is diluted with water and acidified with H(I). The mixture is then diluted with E
Wash with t20, basify with NH4OH and extract with ethyl acetate. Evaporation of the solvent (after drying with Na2SO4) yields 3-(2-N).

N −') -n-propylaminoethyl)nitrobenzene (■, A=H) 10.15E is produced.

B) Similarly, the following compound (■, A=
H): 3-(2+ N,N-ethyl-n-propylaminoethyl)nitrobenzene, 3-(2-N,N-ethyl-i-propylaminoethyl)nitrobenzene, 3-(2-N, N-ethyl-n-butylaminoethyl)
Nitrobenzene, 3-(2+ N, N-ethyl-5-butylaminoethyl) nitrobenzene, 3-(2-N, N-ethyl-t-butylaminoethyl)
Nitrobenzene, 3-(2-N,N-n-propy/1z-n-butylaminoethyl)nitrobenzene, 3-(2-N,N-n-propyl-s-butylaminoethyl)nitrobenzene, 3-(2 -N,N-n-propyl-m-butylaminoethyl)nitrobenzene, 3-(2-N,N-diisopropylaminoethyl)nitrobenzene, 3-(2-N,N-i-propyl-n-butylaminoethyl) ) nitrobenzene, 3-(2-N,N-i-propyl-3-butylamide/
ethyl)nitrobenzene, 3-(2+N,N-di-n-butylaminoethyl)nitrobenzene, 3-(2-(1-piperidyl)ethylconitrobenzene, 3-(2-(3,5-dimethyl-1-piperidyl) ) Ethylconitrobenzene, 3 (2-(1-pyrrolidyl)ethylconitrobenzene, 3 (2-(3,4-dimethyl-1-pyrrolidyl)ethylconitrobenzene, Oyohi 3-(2-(1-azacycloheptyl) Ethylconitrobenzene.

C) Same as IC, except that 4-benzyloxyl 3-nitrophenylethyl tosylate is used instead of 3-nitrophenylethyl tosylate. = BzO): 2-benzyloxy-5-(2-N,N-di-n-furopylaminoethyl)nitrobenzene, 2-benzyloxy-5-(2-N,N-ethyl-n- propylaminoethyl)nitrobenzene, 2-benzyloxy-5-(2
, N, N-ethyl-1-7'pyraminoethyl) nitrobenzene, 2-benzyloxy-5+ (2-N, N
-ethyl-n-butylaminoethyl)nitrobenzene,
2-benzyloxy-5-(2-N,N-ethyl-s-
butylaminoethyl)nitrobenzene, 2-benzyloxy-5-(2-N,N-ethyl-t-butylaminoethyl)nitrobenzene, 2-benzyloxy-5-(2
-N, N-n-pyro-n-butylaminoethyl)
Nitrobenzene, 2-benzyloxy-5-(2-N,N-n-propyl-3-butylaminoethyln, 2-benzyloxy-,5-(2-N,N-n-propyl-L-butylamino) ethyl)nitrobenzene, 2-benzyloxy-5-(2-N,N-diisopropylaminoethyl)nitrobenzene, 2-benzyloxy-5-(2-N,N-i-propyl-n-butylaminoethyl 2-benzyl Oxy-5-(2-N,N-i
-propyl-S-butylaminoethyl)nitrobenzene, 2-benzyloxy-5-(2-N,N-di-
n-butylaminoethyl)nitrobenzene, 2-benzyloxy-5(2-(1-piperidyl)ethylconitrobenzene, 2-benzyloxy-5(2-(3.5-dimethyl-1-piperidyl)ethylconitrobenzene, 2-
Benzyloxy-5 (2-(1-pyrrolidyl)
Ethylconitrobenzene, 2-benzyloxy-5 (2-(3,4-dimethyl-
1-pyrrolidyl)ethylconitrobenzene, and 2-benzyloxy-5(2-(1-azacycloheptyl)ethylconitrobenzene.

Production Example 5 (Novel intermediate of the present invention, production of compound of formula (■)) (Step 5) A) 3-(2-N,N-) in 200% ethanol
di-n-propylaminoethyl)nitrobenzene (Vl
) 10. Add 1.01 l of Raney nickel to the IP and heat the solution to reflux. Hydrazine hydrate in ethanol 10-
Gradually add the solution. After purification and evaporation, 6.81 of 3(2-N,N-di-n-propylaminoethyl)aniline (■, A=H) were obtained as an oil from this mixture.

B) Similarly, the procedure was carried out as in the above A section except that the compound produced in Production Example 4 (B) above was used instead of 3-(2 + N, N-di-n-propylaminoethyl)nitrobenzene. , prepares the following compound: 3-(2-
N,N-ethyl-n-propylaminoethyl)aniline, 3-(2-N,N-ethyl-i-propylaminoethyl)aniline, 3-(2 + N,N-ethyl-n-butylaminoethyl) Aniline, 3-(2-N,N-ethyl-S-butylaminoethyl)aniline, 3-(2-N,N-ethyl-(-butylaminoethyl)aniline, 3-(2-N,N-n) -Propy/L/-
n-butylaminoethyl)aniline, 3-(2-N,N-n-propy)Lt-S-butylaminoethyl)aniline, 3-(2-N,N-n-propyl-t-buty/Iz7minoethyl ) Aniline, 3-(2-N,N-diisopropylaminoethyl)aniline, 3-(2-N,N-i-propyl-〇-butylaminoethyl)aniline, 3-(2-N,N-i- Propyl-3-butylaminoethyl)aniline, 3-(2+N,N-di-n-butylaminoethyl)aniline, 3-(2-(1-piperidyl)ethylcoaniline, 3(2-(3. 5-dimethyl-1-piperidyl)ethylcoaniline, 3 (2-(1-pyrrolidyl)ethylcoaniline,
3-(2-(3.4-dimethyl-1-pyrrolidyl)ethylcoaniline, and 3-(2-(1-7fcycloheptyl)ethylcoaniline).

C) Similarly, the same procedure as in Sections A and B above except that the compound produced in Production Example 4(C) above is used instead of 3-(2-N,N-di-n~propylaminoethyl)nitrobenzene. <Execute the following compound (■, A = Bz
O): 2-benzyloxy-5-(2-N,N-ethyl-n-
propylaminoethyl)aniline, 2-benzyloxy-5-(2-N,N-ethyl-i-propylaminoethyl)aniline, 2-benzyloxy-5-(2-N,N
-ethyl-n-butylaminoethyl)aniline, 2-benzyloxy-5-(2-N,N-ethyl-3-
butylaminoethyl)aniline, 2-benzyloxy-5-(2-N,N-ethyl-(-
butylaminoethyl)aniline, 2-benzyloxy-5-(2-N,N-〇-propyl-n-butylaminoethyl)aniline, 2-benzyloxy'/-5-(2-N,N-n-pro.

Pyl-5-butylaminoethyl)aniline, 2-benzyloxy-5-(2-N,N-n-propyl-(-butylaminoethyl)aniline, 2-benzyloxy-5
-(2-N,N-diisopropylaminoethyl)aniline, 2-benzyloxy-5-(2-N,N-1-propyl-n-butylaminoethyl)aniline, 2-benzyloxy-5-(2- N, N-i-propyl-3-butylaminoethyl)aniline, 2-benzyloxy-5-(2
'-N,N-di-n-butylaminoethyl)aniline, 2-benzyloxy-5(2-(1-piperidyl)ethylcoaniline, 2-benzyloxy-5(2(3,5-dimethyl-i −
piperidyl)ethyl,]auniline2-benzyloxy-5(2-(1-pyrrolidinoethyl)aniline, 2-benzyloxy-5(2-(3,4-dimethyl-1
-pyrrolidyl)ethylcoaniline, and 2-benzyloxy-5(2-(1-azacycloheptyl)ethylcoaniline.

Example 1 (Production of compound of formula (■@)) (Step 5a) A
3.41 ml of sodium persulfate is added to 3.64 ml of acetyl chloride in THF 20 rnt at 0° C. and left for 24 hours to form formic acid anhydrous. To this solution are added 10 parts of 3-(2-N,N-di-n-propylaminoethyl)aniline in 50 parts of pyridine. The solution was left at 0° C. for 12 hours, then added with water and extracted with CH2C12.

The solvent is evaporated and the residue is purified by silica gel chromatography to yield 3-(2-N,N-di-n-propylaminoethyl)formanilide (3, A-H).

B) Similarly, in place of 3-(2-N,N-di-n-propylaminoethyl)aniline, the procedure was carried out as in Section A above, except that the compound produced in Production Example 5 (Hyundai) was used. Prepare the following compounds (vla, A=H): 3-(2-N,N-ethyl-1-propylaminoethyl)formanilide, 3-(2-N,N-ethyl-n-butylaminoethyl) )
Formanilide, 3-(2-N,N-ethyl-5-butylaminoethyl)
Formanilide, 3-(2-N,N~ethyl-t-butylaminoethyl)
Formanilide, 3-(2-N,N-n-propyl-n-butylaminoethyl)formanilide, 3-(2-N,N-n-propyl-5-butylaminoethyl)formanilide, 3-( 2-N,N-n-propyl-t-butylaminoethyl)formanilide, 3-(2-N,N-diisopropylaminoethyl)formanilide, 3-(2-N,N-i-propyl-n- Buchi/1,7
3-(2-N,N-i-propyl-8-butylaminoethyl)formanilide, 3-(2-N,N-di-n-butylaminoethyl)formanilide, 3(2-N,N-di-n-butylaminoethyl)formanilide, -(1-piperidyl)ethyl]formanily
3 (2-(3,5-dimethyl-1-piperidyl)ethyl)formanilide, 3 (2-(1-pyrrolidyl)ethyl)formanilide
3 (2-(3,4-dimethyl-1-pyrrolidyl)ethyl)formanilide, and 3-C2-(1-azacycloheptyl)ethyl]formanilide.

C) Similarly, the procedure was carried out as in Sections A and B above except that the compound prepared in Production Example 5(C) was used instead of 3-(2+ N, N-di-n-propylaminoethyl)aniline. to produce the following compound (■λ, A=BzO): 2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)formanilide, 2-benzyloxy-5-, (2-N,N-ethyl-n-propylaminoethyl)formanilide, 2--'endyloxy-5-
(2-N,N-ethyl-1-propylaminoethyl)formanilide, 2-benzyloxy-5-(2-N,N
-ethyl-〇-butylaminoethyl) formanilide,
2-benzyloxy-5-(2-N,N-ethyl-5-
butylaminoethyl)formanilide, 2-benzyloxy-5-(2-N,N-ethyl-(-butylaminoethyl)formanilide, 2-benzyloxy-5-(2
-N,N-n-propyl-n-butylaminoethyl)
Formanilide, 2-benzyloxy-5-(2-N,
N-n-propyl-5-butylaminoethyl)formanilide, 2-benzyloxy-5-(2-N,N-
n-Propyl-(-butylaminoethyl)formanilide, 2-benzyloxy-5-(2-N,N-diisopropylaminoethyl)formanilide, 2-benzyloxy-,5-(2-N,N-i -propyl-n-butylaminoethyl)formanilide, 2-benzyloxy-5-, (2-N,N-i-propyl-8-butylaminoethyl)formanilide, 2-benzyloxy-5
-(2+ N,N-di-n-butylaminoethyl)formanilide, 2-benzyloxy-5(2-(1-piperidituriethyl)formanilide, 2-benzyloxy-5-(2-(3 ,5-dimethyl-
1-piperidyl)ethyl]formanilide, 2-benzyloxy-5(2-(1-pyrrolidinoethyl)formanilide, 2-benzyloxy-5-(2-(3,4-dimethyl-
1-pyrrolidyl)ethyl]formanilide, and 2-benzyloxy-5(2-(1-azacycloheptyl)ethyl)formanilide.

Example 2 (Production of compound of formula (■b) → (Step 6b) A
) 3.52 of 3-(2-N,N-di-n-propylaminoethyl)aniline in 20-pyridine is treated with 1 rnl of acetyl chloride at 0°C. Add this solution to water and add CH
Extract with 2C12. The solvent was evaporated and the product 3-(2
-N,N-zyl n-propylaminoethyl)acetanilide (■b, A=H) is purified by silica gel chromatography (HBr salt. m, p.

212-213°C).

B) Similarly, use the above A seedlings, except using propanoyl chloride or butamyl chloride instead of acetyl chloride.
N-di-n-propylaminoethyl)propionanilide, 3-(2-N,N-di-n-propylaminoethyl)butylanilide.

Similarly to Q, the procedure was carried out as in Section A above except that the compound produced in Production Example 5 (B) was used instead of 3-(2-N,N-di-n-propylaminoethyl)aniline. The following compounds (■b, A-H) are prepared: 3-(2+ N,N-ethyl-n-propylaminoethyl)acetanilide, 3-(2-N,N-ethyl-1-propylaminoethyl) Acetanilide, 3 (2+ N, N-ethyl-n-butylaminoethyl)acetanilide, 3-(2-N, N-ethyl-5-butylaminoethyl)
Acetanilide, 3-(2+ N, N-ethyl-(-butylaminoethyl)acetanilide, 3-(2-N, N-n-propyl-n-butylamide/
ethyl)acetanilide, m, p, 188-189℃
, 3-(2-N, N-n-propyl-5-butylaminoethyl)acetanilide, 3-(2-N, N-n-propyl-(-butylaminoethyl)acetanilide, 3-(2-N, N-diisopropylaminoethyl)acetanilide, 3-(2-N,N-i-propyl-n-butylaminoethyl)acetanilide, 3-(2-N,N-i-propyl-5-butylaminoethyl)acetanilide, 3-(2-N,N-di-n-butylaminoethyl)acetanilide, 3-(2-(1-piperidyl)ethyl)acetanilide
3 (2-(3,5-dimethyl-1-piperidyl)ethyldiacetanilide), 3 (2-(1-pyrrolidyl)ethyl)acetanilide
3(2-(3,4-dimethyl-1-pyrrolidyl)ethyldiacetanilide), and 3-(2-(1-azacycloheptyl)ethyldiacetanilide).

D) Similarly, using the compound prepared in Preparation Example 5(C) instead of 3-(2+ N, N-di-n-propylaminoethyl)aniline and propanoyl chloride or butanoyl chloride instead of acetyl chloride. Outside A and B above
and 0 to prepare the corresponding propionanilide and butylanilide derivatives (Vlb, A=H).

E) Similarly, the procedure was carried out as in Section A above except that the compound produced in Production Example 5(C) was used instead of 3-(2-N,N-di-n-propylaminoethyl)aniline. The following compound (Vlb, A = B, 0) is prepared: 2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)acetanilide, 2-benzyloxy-5-(2- N,N-di-n-propylaminoethyl)acetanilide, 2-benzyloxy-5-(2-N
, N-ethyl-n-propylaminoethyl)acetanilide, 2-benzyloxy-5-(2-N,N-ethyl-1-propylaminoethyl)acetanilide, 2-benzyloxy-5-(2-N,N -ethyl-n-butylaminoethyl)acetanilide, 2-benzyloxy-
5(2-N,N-ethyl-5-butylaminoethyl)acetanilide, 2-benzyloxy-5-(2-N,N
-ethyl-1-butylaminoethyl)acetanilide,
2-Benzyloxy-5-(2-N,N-n-propyl-n-butylaminoethyl)acetanilide, 2-benzyloxy-5-(2-N,N-n-propyl-
5-Butylaminoethyl)acetanilide, 2-benzyloxy-5-(2-N,N-n-propyl-t-butylaminoethyl)acetanilide, 2-benzyloxy-5-(2-N,N-diisopropylamino) ethyl)
Acetanilide, 2-benzyloxy-5-(2-N,
N-i-propyl-n-butylaminoethyl)acetanilide, 2-benzyloxy-5-(2-N, N-i
-propyl-3-butylaminoethyl)acetanilide, 2-benzyloxy-5-(2-N,N-di-n-butylaminoethyl)acetanilide, 2-benzyloxy-5(2-(1-piperidyl)ethyl) Diacetanilide, 2-benzyloxy-5(2-(3,5-dimethyl-1
-piperidyl)ethyldiacetanilide, 2-benzyloxy-5(2-(1-pyrrolidyl)ethyldiacetanilide, 2-benzyloxy-5-(2-(3,4-dimethyl-
1-pyrrolidyl)ethyldiacetanilide, and 2-benzyloxy-5-(2-(1-azacycloheptyl)ethyldiacetanilide.

F) Similarly, carry out steps B and E above to prepare the corresponding 2-benzyloxy-propionanilide and butylanilide derivatives (Vllb%A=BzO).

Example 3 (Production of compound of formula (■C)) (Step 5c) A
)2: 3-(2-N, N in 1 water/acetic acid 10-
A solution of 2.2 y of -di-n-propylaminoethyl)aniline is treated with 1.51 y of potassium cyanate in 5 d of water. The mixture was then made basic with NH40H and CH2
Cl. Extract with The CH2Cl□ is evaporated and the residue is dissolved in methanol. Then add 48% aqueous HBr or H(I) until the solution becomes acidic.Product 3
-(2-N,N-di-n-propylaminoethyl)ureidobenzene.HBr (■C1A=t-i) is E
By t20 it precipitates out of this solution. The yield is 3. OF
Met. m, P, 186-189℃6B) Similarly, 3-(2-N,N-di-n-propylaminoethyl)
The following compound (Wilc, A = H) is produced as in Section A above except that the compound produced in Production Example 5β) above is used instead of aniline: 3-(2-N,N- Ethyl-n-propylaminoethyl)ureidobenzene.HBr, 3-(2-N,N-ethyl-i-propylaminoethyl)ureidobenzene.HBr.

3-(2-N,N-ethyl-〇-butylaminoethyl)
Ureidobenzene/HBr, 3-(2-N,N-ethyl-5-butylaminoethyl)
Ureidobenzene・HBr, 3-(2-N,N-ethyl-t-butylaminoethyl)
Ureidobenzene.HBr, 3-(2-N, N-n-propyl-n-butylaminoethyl)ureidobenzene.H (I%tr1.P, 19
4-196°C, 3-(2-N,N-n-propy)Lt-5-butylaminoethyl)ureidobenzene・HBr, 3-(2-N
, N-n-propyl-(-butylaminoethyl)ureidobenzene.HBr, 3-(2+ N,N-diinpropylaminoethyl)ureidobenzene.HBr.

3-(2~N,N-i-propyl-n-butylaminoethyl)ureidobenzene HBr, 3-(2~N,N
-1-propyl-3-butylaminoethyl)ureidobenzene-HBr.

3-(2+ N, N-di-n-butylaminoethyl) Kleidohenze 7-H (I, Ifl, p, 200-20
0.5°C, 3-(2-(1-piperidyl)ethyl cocleidobenzene.HBr).

3 (2-(3,5-dimethyl-1-piperidyl)ethyl)cladobenze 7-M(I, m, p, 189
~191°C, 3-(2-(1-pyrrolidyl)ethylcocleidobenzene.HBr, 3-(2-(3,4-dimethyl-1-pyrrolidyl)ethylcocleidobenzene.HBr, and 3-(2- (1
-azacycloheptyl)ethyl cocladobenzene H
Br.

q Similarly, the same procedures as in Sections A and 8 above were carried out except that the compound prepared in Production Example 5(C) was used instead of 3-(2-N,N-di-n-propylaminoethyl)aniline. to produce the following compound (■c, A = BzO): 2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)ureidobenzene.HBr12-benzyloxy-5 -(2-N,N-ethyl-〇-propylaminoethyl)ureidobenzene・HBr, 2-benzi,ruoxy-5-(2-N,N-ethyl-i
-propylaminoethyl)ureidobenzene.HBr.

2-benzyloxy-5-(2-N,N-ethyl-n-
butylaminoethyl)ureidobenzene-HBr.

2-benzyloxy-5-(2-N,N-ethyl-3-
butylaminoethyl) ureidobenzene/HBr.

2-benzyloxy-5-(2-N,N-ethyl-t-
Butylaminoethyl 2-benzyloxy-5-(2-N,N-n-propyl-n-butylaminoethyl)ureidobenzene/HBr
.

2-benzyloxy-5-(2-N,N-n-propyl-s-butylaminoethyln.HBr, 2-benzyloxy-5-(2-N,N-n
-Propyl-[-butylaminoethyl)ureidobenzene.HBr, 2-benzyloxy-5-(2 + N,N-diisopropylaminoethyl)ureidobenzene.HBr.

2-benzyloxy-5-(2-N, N-i-propyl-n-butylaminoethyl)fried benzene HB
r.

2-benzyloxy-5-(2-N, N-i-propyl-s-butylaminoethyl)fried benzene HB
r, 2-benzyloxy-5-(2-N,N-di-n-butylaminoethyl)fried benzene.HBr.

2-benzyloxy-5-(2-(1-hiheIJ sit
b) Ethyl cocladobenzene HBr, 2-benzyloxy-5-(2-(3,5-dimethyl-
1-piperidyl)ethyl cocleidobenzene.HBr.

2-benzyloxy-5-(2-(1-pyro!J dino b
) Ethyl cocladobenzene HBr, 2-benzyloxy-5-(2-(3,4-dimethyl-
1-pyrrolidyl)ethyl cocleidobenzene HBr,
and 2-benzyloxy-5-(2-(1-azacycloheptyl)ethyl]ureidobenzene.HB r .

Example 4 (Production of compound of formula (■d)) (Step 6d) A) 3-(2-N) in 10 rnl of 2:1 water/acetic acid.

N-di-n-propylaminoethyl)aniline 2゜2g
A solution of is treated with 1.1 g of methyl isocyanate in 5.5 g of water. The mixture was made basic with NH4OH and CH2
Extract with Cl2. Evaporating the solvent gives 1-[3-(2
-N,N-di-n-propylaminoethyl)phenylcou-3-methylurea (■d, A=H) (HCl salt, m,
p, 151-152°C) is obtained.

B) Similarly, the following compound (■d, A=H) was prepared as described in Section A above except that ethyl isocyanate or propyl incyanate was used instead of methyl inocyanate.
Prepare: 1-(3-(2-N,N-di-n-propylaminoethyl)phenyl]-3-ethylurea, 1-(3-(2-
N,N-di-n-propylaminoethyl)phenyl]-
3-propylurea, 1- (3-(2-N, N-n-
Propy/1z-n-butylaminoethyl)phenyl]-
3-1-Propylurea, m, P, >230°C.

C) Similarly, the procedure was carried out as in Section A above except that the compound produced in Production Example 5 (B) above was used instead of 3-(2-N,N-di-n-propylaminoethyl)aniline. ,
The following compound (■d, A=H) is prepared: 1-(3-(2-N,N-ethyl7L/-n-propylaminoethyl)phenylcou 3-methylurea, 1-(
3-(2-N,N-ethyl-1-propylaminoethyl)phenylcou 3-methylurea, 1-(3-(2-
N,N-z'thiJLt-n-butylaminoethyl)phenylcou 3-methylurea,1-(3-(2-N,N-
Ethyl-5-butylaminoethyl)phenylcou-3-methylurea, 1-C3-(2-N,N-ethyl-[-
butylaminoethyl) phenylcou 3-methylurea,
1-(3-(2-N,N-n-propy/L/-n-butylaminoethyl)phenylcou 3-methylurea, m
, P, 143-145°C, 1-(3-(2-N,N-n-propy/Iz-5-butylaminoethyl)phenylcou-3-methylurea, 1-[3-(2-N,N- n-propy/L/-L-butylaminoethyl) phenyl 3-methylurea 1-(3-(2-N, N-diisopropylaminoethyl) phenyl 3-methyl urea, 1-(3-(2-N)
, N-1-propy/L/-n-butylaminoethyl)phenyl]-3-methylurea, 1-(3-(2-N,N-1-propyl-5-butylaminoethyl)phenyl-3-methylurea Otsu 1- (3-(2-N,N-di-n-butylaminoethyl)phenylcou 3-methylurea, 1-(3-[2-
(1-piperidyl)ethyl]phenyl)-3-methylurea, 1-(3-[2-(3,5-dimethyl-1-piperidyl)ethyl]phenyl)-3-methylurea, 1-(3-
[2-(1-pyrrolidyl)ethyl]phenyl)-3-methylurea, 1-[3-(2-(3,4-dimethyl-1-pyrrolidyl)ethyl]phenyl)-3-methylurea, and 1-(3 -(2-(1-azacycloheptyl)ethyl)
phenyl)-3-methylurea.

D) Similarly, the same procedure as in Section A above was carried out except that the compound produced in Production Example 5(C) was used instead of 3-(2-N,N-di-n-propylaminoethyl)aniline. The following compound (■dSA=BzO) is prepared: 1-[2-benzyloxy-5-(2-N,N-di-n
-propylaminoethyl)phenyl]-3-methylurea, 1-[2-benzyloxy-5-(2-N,N-ethyl-n-propylaminoethyl)phenyl]-3-methylurea, ni[2-benzyloxy -5-(2-N,N-ethyl-1-propylaminoethyl)phenyl]-3-methylurea 1-[2-benzyloxy-5-(2-N,N-ethyl-n-butylaminoethyl)phenyl ]-3-methylurea, 1-[2-benzyloxy-5-(2-N,N-,ethyl-s-butylaminoethyl)phenyl]-3-methylurea, 1-[2-benzyloxy-5-( 2-N,N-ethyl-[-butylaminoethyl)phenyl]-3-methylurea, 1-[2-benzyloxy-5-(2-N,N-1'l
-7”Ohill-n-butylaminoethyl)phenyl]
-3-methylurea, 1-[2-benzyloxy-5-(2-N,N-n-propyl-5-butylami/ethyl)phenyl]-3-methylurea, l-[2-benzyloxy-5-( 2-N,N-n-propyl-[-butylamino/ethyl)phenyl]-3-methylurea, 1-[2-benzyloxy-5-(2-N,N-diisopropylaminoethyl)phenyl)-3-methylurea , 1-[2-benzyloxy-5-(2-N,N-'-
7”ahill-n-butylaminoethyl)phenyl]-3
-methylurea, 1-[2-benzyloxy-5-(2-N,N-1-propyl-5-butylaminoethyl)phenyl]-3-methylurea, 1-[2-benzyloxy-5-(2- N, N-')-
n-butylami/ethyl)phenyl)-3-methylurea, 1-(2-benzyloxy-5-[2-(1-piperidyl)ethyl]phenyl)-3-methylurea, 1-(2-benzyloxy-5- (2-(3,5-dimethyl-1-piperidyl)ethyl]phenyl)-3-methylurea, 1-(2-benzyloxy-5-(2-(1-pyrrolidyl)ethyl]phenyl)-3-methylurea, 1-(2-benzyloxy-5-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]phenyl)-3-methylurea, and 1-(2-benzyloxy-5-(2-(1- Azacycloheptyl)ethyl]phenyl)-3-methylurea.

E) Similarly, the procedure was carried out as in Section B above except that the compound produced in Production Example 5 (C1) was used instead of 3-(2-N,N-di-ropylaminoethyl)aniline. 3-ethyl urea and 3-propylurea compounds (dSA=BzO) are produced.

Example 5 (Preparation of a compound of formula (I) in which R3 is hydroxy) (Step 7) A) 2-benzyloxy- in 150 rnl of methanol
A solution of 3°3g of 5-(2-N,N-di-n-propylaminoethyl)ureidobenzene (■c, A=BzO) was heated at 2 atm and 60°C with 10% Pd-C0.5g. Hydrogenate for 6 hours under Evaporation through a sieve gives an oil, which is dissolved in methanol and acidified with hydrogen bromide. When Et20 is added, HBr salt, 2-
Hydroxy-5-(2-N,N-di-n-propylaminoethyl)ureidobenzene.HBr precipitates.

m, P, 148-149°C (I-HBr).

Similarly, the hydrochloride salt is prepared as described above except that hydrogen chloride is used in place of hydrogen bromide.

B) Similarly, 2-benzyloxy-5-(2-N,N-
Proceed as in Section A above except using the compound prepared in Example 1(C) in place of di-n-propylaminoethyl)ureidobenzene to produce the following compound: 2-Hydroxy-5- (2-N,N-di-n-propylaminoethyl)formanilide.HBr.

m, p, 116-119°C, 2-hydroxy-5-(2-N, N-ethyl JLt-n-
Propylaminoethyl) formanilide/HBr.

2-Hydroxy-5-(2-N,N-ethyl-i-propylaminoethyl)formanilide lHBr.

2-Hydroxy-5-(2-N,N-ethyl-〇-butylaminoethyl)formanilide.HBr.

2-Hydroxy-5-(2-N,N-ethyl-S-butylaminoethyl)formanilide.HBr.

2-Hydroxy-5-(2-N,N-ethyl-(-butylaminoethyl)formanilide.HBr.

2-hydroxy-5-(2-N, N-n-propyl-n
-butylaminoethyl)formanilide.HBr.

2-hydroxy-5-(2-N, N-n-propyl-5
-butylaminoethyl)formanilide.HBr.

2-Hydroxy-5-(2-N, N-n-proyl-[
-butylaminoethyl)formanilide.HBr.

2-Hydroxy-5-(2-N,N-diisopropylaminoethyl)formanilide.HBr.

2-hydroxy-5-(2-N,N-1-propyl-n
-butylaminoethyl)formanilide.HBr.

2-hydroxy-5-(2-N,N-1-propyl-5
-butylaminoethyl)formanilide.HBr.

2-Hydroxy-5-(2-N,N-di-n-butylaminoethyl)formanilide.HBr.

2-Hydroxy-5-(2-(1-piperidyl)ethyl]formanilide eHBr.

2-hydroxy-5-[2-(3,5-dimethyl-1-
Piperidyl)ethyl]formanilide/HBr.

2-Hydroxy-5-[2-(1-pyrrolidyl)ethyl]formanilide.HBr.

2-hydroxy-5-(2-(3,4-dimethyl-1-
pyrrolidyl)ethyl]formanilide.HBr, and 2-hydroxy-5-[2-(1-azacycloheptyl)ethyl]formanilide.HBraC).
Example 2 (
Proceed as in Section A above except for using the compound produced in step D) to produce the following compound: 2-hydroxy-5-(2-N,N-di-n-propylaminoethyl)acetanilide. HC/.

'n, P, 158-160°C, 2-hydroxy-5-(2-N,N-ethyl-n-propylaminoethyl)acetanilide.HBr.

2-Hydroxy-5-(2-N,N-ethyl-1-propylaminoethyl)acetanilide.HBr.

2-Hydroxy-5-(2-N,N-ethyl-n-butylaminoethyl)acetanilide.HBr.

2-Hydroxy-5-(2-N,N-x thyl-8-butylaminoethyl)acetanilide.HBr12-Hydroxy-5-(2-N,N-ethyl-[-butylaminoethyl)acetanilide.HBr.

2-hydroxy-5-(2-N, N-n-propyl-n
-butylaminoethyl)acetanilide.HBr.

2-Hydroxy-5-(2-N, N-n-p-a-pil S
-butylaminoethyl)acetanilide.HBr.

2-hydroxy-5-(2-N, N-n-propyl-t
-butylaminoethyl)acetanilide.HBr.

2-Hydroxy-5-(2-N,N-diimpropylaminoethyl)acetanilide.HBr.

2-hydroxy-5-(2-N,N-1-propyl-n
-butylaminoethyl)acetanilide Br1 2-hydroxy-5-(2-N,N-1-propyl-3
-butylaminoethyl)acetanilide.HBr.

2-Hydroxy-5-(2-N,N-di-n-butylaminoethyl)acetanilide.HBr.

2-Hydroxy-5-(2-(1-piperidyl)ethyl)acetanilide.HBr, 2-Hydroxy-5-(2-(3,5-dimethyl-1-piperidyl)ethyl)acetanilide.HBr.

2-Hydroxy-5-[2-(1-pyrrolidyl)ethyl]acetanilide lHBr.

2-hydroxy-5-[2-(3,4-dimethyl-1-
pyrrolidyl)ethyl]acetanilide HBr, and 2-hydroxy-5-(2-(1-azacycloheptyl)ethyl)acetanilide 1HBr.

D) Similarly, 2-benzyloxy-5-(2-N,N-
The procedure was as in Section A above except that the compound prepared in Example 2 (F) was used in place of di-n-propylaminoethyl)ureidobenzene. =H) is produced.

E) Similarly, 2-benzyloxy-5-(2-N,N-
Proceed as in Section A above except that the compound prepared in Example 3(C) is used in place of di-n-propylaminoethyl)ureidobenzene to produce the following compound: 2-Hydroxy-5- (2-N,N-ethyl-n-propylaminoethyl)ureidobenzene.HBr.

2-Hydroxy-5-(2-N,N-ethyl-1-propylaminoethyl)ureidobenzene.HBr.

2-Hydroxy-5-(2-N, N-xthia L/-n-
butylaminoethyl) ureidobenzene/HBr.

2-Hydroxy-5-(2-N,N-ethyl-3-butylaminoethyl)ureidobenzene・HBr12-Hydroxy-5-(2-N,N-ethyl-butylaminoethyl)ureidobenzene・HBr .

2-hydroxy-5-(2-N, N-n-propyl-n
-butylaminoethyl)ureidobenzene, HBr, m
, p, 130-135°C, 2-hydroxy-5-(2-
N,N-n-propyl-5-butylaminoethyl)ureidobenzene, HBr.

2-Hydroxy-5-(2-N,N-n-propyl-
1-Butylaminoethyl)ureidobenzene/HBr.

2-Hydroxy-5-(2-N,N-diisopropylaminoethyl)ureidobenzene-HBr.

2-hydroxy-5-(2-N,N-1-propyl-n
-butylaminoethyl)ureidobenzene, HBr.

2-hydroxy-5-(2-N,N-1-propyl-3
-butylaminoethyl)ureidobenzene.HBr.

2-Hydroxy-5-(2-N,N-di-n-butylaminoethyl)ureidobenzene.HBr.

2-Hydroxy-5-[2-(1-piperidyl)ethyl]ureidobenzene.HBr.

2-hydroxy-5-(2-(3,5-dimethyl-1-
piperidyl)ethyl]ureidobenzene/HBr.

2-Hydroxy-5-(2-(1-pyrrolidyl)ethyl)ureidobenzene.HBr.

2-hydroxy-5-(2-(3,4-dimethyl-1-
pyrrolidyl)ethyl]ureidobenzene.HBr, and 2-hydroxy-5-[2-(1-azacycloheptyl)ethyl]ureidobenzene.HBr.

F) Similarly, 2-benzyloxy-5-(2-N,N-
Proceed as in Section A above except using the compound prepared in Example 4(D) in place of di-n-propylaminoethyl)ureidobenzene to produce the following compound: 1-[2-hydroxy -5-(2-N, N-ji-n-7
' o Hylaminoethyl]phenyl 3-3-methylurea/HBr.

1-[2-human axy-5-(2-N,N-engineering
-propylaminoethyl)phenyl,]-]3-methylurea HBr.

1-[2-hydroxy-5-(2-N,N-ethyl-i
-Flopylaminoethyl)phenyl)-3-methylurea.HBr.

1-[2-hydroxy-5-(2-N,N-ethyl-n
-butylaminoethyl)phenyl)-3-methylurea.HBr.

l-[2- and droxy-5-(2-N, N-ethyl 71/
-s-]f-ruaminoethyl)phenyl]-3-methylurea, HBr.

1-[2-hydroxy-5-(2-N,N-ethyl-t
-butylaminoethyl)phenyl)-3-methylurea.HBr.

1-[2-Hydroxy-5-(2-N,N-n-propyl-n-butylaminoethyl)phenylcou 3-methylurea.HBr.

l-[2-hydroxy-5-(2-N, N-n-p-a
H;'ruS-butylaminoethyl)phenylcou 3-
Methylurea/HBr.

1-[2-hydroxy-5-(2-N,N-n-]o
humanLt-t-butylaminoethyl)phenyl].

-3-methylurea/HBr.

1-[2-human axy-5-(2-N,N-diimpropylaminoethyl)phenylcou 3-methylurea H
Br.

1-[2-Hydroxy-5-(2-N,N-i-propyl-n-butylaminoethyl)phenylcou 3-methylurea.HBr.

1-[2-Hydroxy-5-(2-N,N-i-propyl-5-butylaminoethyl)phenylcou 3-methylurea.HBr.

1-[2-Hydroxy-5-(2-N,N-di-n-butylaminoethyl)phenyl J-3-1+Luurea H
Br.

1-(2-hydroxy-5-[-1(l-piperidyl)
Ethyl]phenyl 13-methylurea, HBr.

l-[2-Hydroxy-5-(2-(3,5-dimethyl-1-piperidyl)ethyl]phenyl)-3-methylurea HBr, '1-(2-hydroxy-5-(2-(1- pyrrolidyl)
Ethyl]phenyl)-3-methylurea.HBr.

1-(2-hydroxy-5-(2-(3,4-dimethyl-1-pyrrolidyl)ethyl]phenyl)23-methylurea.HBr, and 1-(2-hydroxy-5-[2-(1- azacycloheptyl)ethyl]phenyl 13-methyG) Similarly, 2-
Example 4 (
3-Ethyl urea and 3-propylurea derivatives to be used as core material are produced as described in section A above except that the compound produced in step E) is used: Example 6 (Production of salt from free base) 1- (3-(2
8.0 g of -N,N-di-n-propylaminoethyl)phenylcou-3-methylurea are dissolved in methanol and acidified with methanolic HC/. Precipitate with E[20
Washing with water yields 7.0 g of 1-[3-(2-N,N-di-n-propylaminoethyl)phenylcou-3-methylurea hydrochloride. M, P, 151-152℃
5 In a similar manner, all compounds of formula (I) in basic form prepared according to the method described above can be treated with a suitable acid, such as HBr,
Sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, chriflic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, sulfonic acid, ethanesulfonic acid, p-1 luenesulfonic acid, etc. can be converted into their pharmaceutically acceptable acid addition salts by treatment.

Example 7 (Preparation of free base from salt) Water (50 m
1-C3-(2-N, N-n-propyl-n-
A solution of 3.5 g of butylaminoethyl)phenyl]ureidobenzene hydrochloride is adjusted to NH40t (Pi(12) in solution and extracted with methylene chloride.The methylene chloride is then evaporated and the 1-[3- (2-N,
3 g of N-n-propyl-n-butylaminoethyl)phenyl J')laid benzene are obtained. m, p, 75~
77℃.

A similar procedure can be taken to convert all acid addition salts of compounds of formula (I) prepared according to the above process into their free base form.

Example 8 (Formulation) The following example shows the active compounds of formula (I), e.g. 3-
(2-N,N-G-HARP9 PILFUMI/ENGFJLt) describes the production of a representative pharmaceutical formulation containing ureidobenzene.

1, V, Formulation Active compound 0.14g Propylene glycol 20g Polyethylene glycol 40020g Tween 80 1 go, 9
% saline solution Add appropriate amount of active compound to lO〇-, propylene glycol, polyethylene glycol 40%
0 and Tween 80. Then 100Tn
T's! , V, 0.9 of the sufficient amount of l to make the solution! % saline solution is added with stirring, filtered through a 0.2 micron membrane filter, and filled and packaged under aseptic conditions.

Tablet Weight percentage Active compound SO, O Magnesium stearate 0.75 Starch
0.75 lactose
29.0 pvp (polyvinylpyrrolidone) 0.75 The above components were combined and granulated using methanol as a solvent. This preparation is then dried and made into tablets (containing the active compound SO+19) on a suitable tablet press.

Ophthalmic Solution Active Compounds 0.10g Benzalkonium Chloride 0.01g EDTA
0.10g sodium phosphate buffer Add appropriate amount of 2% boric acid solution to pH 7.4 Add appropriate amount of active compound to 100-2% boric acid solution, benzalkonium chloride, sodium phosphate buffer and ethylenediaminetetraacetic acid (EDTA). This solution is then filtered through a 0.2 micron membrane filter and filled and packaged under aseptic conditions.

Eye ointment active compounds 1g benzalkonium chloride 0.1g EDTA
1. Og White Crow
50 g Vaseline
Melt 950 g wax on a water bath. Then add Vaseline and heat until it liquefies. The mixture is then cooled and stirred until solidified. The remaining ingredients are then added as a fine powder and the mixture is filled and packaged under aseptic conditions.

Example 9 Spontaneous Hypertensive Rat Assay Twenty-four adult preconditioned male spontaneous hypertensive rats are divided into six groups (4 animals per group) with approximately equal mean systolic blood pressure. These six groups are then used simultaneously in a two-day compound screening procedure.

Test compounds are randomly assigned to each group. Five groups will receive a potential antihypertensive agent and one control group will receive vehicle only (water and Tween).

Approximately 17 hours before the first day of drug administration, food is removed from the rat's cage. On the morning of the 18th day, one group of four rats was given a solution/suspension in water using a homogenizer.
3-(2-N, N
-di-n-propylaminoethyl)ureidobenzene (
I) or other test compound 12.5■/kg or 2
51 Ni/kg is administered orally (by gavage) at a concentration such that a solution of 0.1 d/10 g of body weight is administered.

41/2 hours after dosing, put the food back in the basket and 21/2 hours after dosing. Allow the rat to feed for an hour and then remove food again.

On the morning of the second day, rats are dosed orally as described above.

Immediately after administration, the rats are placed in a restrainer and placed in a heated room (30±1.0°C) for 4 hours.

At the end of the second day of testing, normal feeding resumes.

Systolic blood pressure (ie, the pressure at the appearance of the first pulse) is recorded using a photoelectric transducer. The tail movements of three rats (in the side split group) are occluded simultaneously with a pump-inflatable tail cuff that automatically inflates to 3001 PHg and then de-inflates. Blood pressure curves and tail pulses are monitored simultaneously with an MFE recorder.

Four consecutive trajectories (at 30 second intervals) are recorded for each rat in a given horizontal group at 1.2.3 and 4 hours after compound administration. The next horizontal group is automatically measured in the same way.

The mean systolic blood pressure (SBP) of each rat at each observation time
) is calculated. The SBP of animals in each dose group is compared to the SBP of animals in the control group (vehicle only) at each observation time using a one-way analysis of variance test. Compounds exhibiting P<0.05 at any observation time were considered to exhibit significant antihypertensive activity. Compounds that significantly lowered blood pressure by 20 mHg or more from control values over all four observation times were considered worthy of further investigation.

In these examples, heart rate was calculated and a two-tailed test was used to test for significant changes from control heart rate. Blood pressure is
1.2.3 of dosing on both days 1 and 2
and read after 4 hours.

As shown in the table below, the compounds of the invention showed positive antihypertensive activity in this test.

N-fu'okri I/N-bu bhira l, HC)lL
3 HBr 25 36 25 1
7 33N-7tyushi N-7tr HN
) L2 HBr 25 53 32 24
32n -14-t and n-1-f-t HN
H2H(I 25 23 26 2
1 15n-jfntn-bu b hirare HNFIC
J(aHcl 25 20 18
15 13 Example 10 (Eye Irritation Test) Each test compound is administered simultaneously to one eye with an ophthalmic solution containing the test compound as the active ingredient and to the other eye with a vehicle-only ophthalmic solution. By testing individually in one animal. The irritation, if any, induced by the test compound is compared to the non-irritating effect of the vehicle ophthalmic solution applied to the other eye. Stimulation is measured by the number of hibernation blinks l within the same period of time. The test will be carried out on rabbits.

An ophthalmic solution containing the compound of the present invention as an active ingredient is
Prepared at a concentration of 1% to 0.5%. One drop of the test ophthalmic solution containing the active ingredient is administered directly into the conjunctival capsule of the rabbit's left eye. At the same time, one drop of the medium is administered into the mucosal sac of the rabbit's right eye.

Irritation in each eye is measured by counting the number of blinks within 1 minute after administration. Results are expressed as standard error on mean number of blinks/eye. The average blink frequency of 7 minutes is averaged for vehicle treatment and compared to eyes treated with active compound. Compounds can be tested in mongrel dogs and rhesus monkeys as well.

The compounds according to the invention do not exhibit eye irritation and their effects are comparable to those of ophthalmic solutions in the medium to which no active compound is added.

Example 11 (Lowering Intraocular Pressure) This example illustrates the effect of compounds of the invention on intraocular pressure (IOP).

Two groups of normal Alpino White New Sealant rabbits were used in this study. Control group = 4 animals Test group: 8 animals (experimental design) At time O, both eyes of each animal in the control and test groups were examined. Measure intraocular pressure.

Immediately after the intraocular reading was taken, all animals were treated with saline (control group) or test compound (test group). The control group received 50 μl of vehicle in each eye;
Meanwhile, 50 μl of the medium is administered to the left eye of the test animal, and 50 μl of a 1% solution of the test compound is administered to the right eye.

Intraocular pressure is measured 30 minutes, 1.2, and 4 hours after administration.

(Experimental Method) The effect of the test compound on intraocular pressure (IOP) in rabbits is measured using a Digilab model 30D pneumatotrometer. Initial IOP readings are obtained in all animals after administration of 50 μl of 0.5% Optine (proparacaine hydrochloride). One group of 4 rabbits serves as a control and both eyes are treated with 50 μl of saline. Another eight rabbits receive 50 μl of test compound in the right eye and 50 μl of drug vehicle in the contralateral left eye. 30 minutes of administration, 1
IOP readings are taken after 1 hour, 2 hours, and 4 hours. Observe the rabbit for signs of eye irritation.

This method allows comparison of the active compound treated eye with the contralateral vehicle treated eye and also with the saline treated eye. For statistical analysis, comparisons are made between the IOP values for the active compound treated eye, the contralateral vehicle treated eye and the saline treated eye. As shown in the table below, compounds of formula (I) are active in this assay.

Claims (1)

[Claims] 1. Formulas: ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R_1 is alkyl having 2 to 4 carbon atoms, and R_2 is 3 carbon atoms or 4 alkyl or
Or R_1 and R_2 together with N ▲ formula,
There are chemical formulas, tables, etc. ▼ [In the formula, n is 0, 1 or 2, and R_5 and R_
6 is lower alkyl or hydrogen respectively], R_3 is hydrogen or hydroxy, R_4 is hydrogen, amino, lower alkyl, or lower alkylamino] or a pharmaceutically acceptable acid addition salt thereof . 2. The compound according to claim 1, wherein R_3 is hydrogen. 3. The compound according to claim 2, wherein R_4 is amino. 4. The compound according to claim 3, wherein R_1 and R_2 are each n-propyl, ie, a 3-(2-N,N-di-n-propylaminoethyl)ureidobenzene compound. 5. Hydrochloride of the compound according to claim 4. 6. Compounds in which R_1 is n-propyl and R_2 is n-butyl, i.e. 3-(2-N,N-n-propyl-n
-butylaminoethyl)ureidobenzene compound according to claim 3. 7. Hydrochloride of the compound according to claim 6. 8. When R_1 and R_2 are combined with N, ▲formula,
There are chemical formulas, tables, etc. ▼ [In the formula, n is 0, 1, or 2, and R_5 and R
6 is each lower alkyl or hydrogen. 9, compounds in which R_5 and R_6 are hydrogen, i.e. 3-
The compound according to claim 8, which is a [2-(1-piperidyl)ethyl]ureidobenzene compound. 10, a compound in which R_5 and R_6 are each methyl,
That is, 3-[2-(3,5-dimethyl-1-piperidyl)
9. The compound according to claim 8, which is an ethyl]ureidobenzene compound. 11. The compound according to claim 2, wherein R_4 is methyl. 12. The compound according to claim 1, wherein R_3 is hydroxy. 13. The compound according to claim 12, wherein R_4 is amino. 14, compounds in which R_1 and R_2 are each n-propyl, i.e. 2-hydroxy-5-(2-N,N-di-n
-propylaminoethyl)ureidobenzene compound according to claim 13. 15, R_1 and R_2 together with N ▲ formula,
There are chemical formulas, tables, etc. ▼ [In the formula, n is 0, 1, or 2, and R_5 and R
14. The compound according to claim 13, wherein each of _6 is lower alkyl or hydrogen. 16, compounds in which R_5 and R_6 are hydrogen, i.e. 2
-Hydroxy-5-[2-(1-piperidyl)ethyl]
Claim 15, which is a ureidobenzene compound
Compounds described in Section. 17, compounds in which R_5 and R_6 are methyl, i.e. 2-hydroxy-5-[2-(3,5-dimethyl-1-
piperidyl)ethyl]ureidobenzene compound,
A compound according to claim 15. 18. Formulas for pharmaceutically acceptable non-toxic carriers and therapeutically effective amounts: ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) [wherein R_1 is alkyl having 2 to 4 carbon atoms, and R
_2 is alkyl having 3 or 4 carbon atoms, or R_1 and R_2 together are ▲a mathematical formula, a chemical formula, a table, etc.▼ [wherein n is 0, 1, or 2, and R_5 and R
_6 is lower alkyl or hydrogen respectively], R_3 is hydrogen or hydroxy, R_4 is hydrogen, amino, lower alkyl, or lower alkylamino] or a pharmaceutically acceptable acid addition salt thereof A pharmaceutical composition comprising: 19. Formula for therapeutically effective amount in mammals in need of treatment: ▲Mathical formula, chemical formula, table, etc.▼(I) [wherein R_1 is alkyl having 2 to 4 carbon atoms, and R
_2 is alkyl having 3 or 4 carbon atoms, or R_1 and R_2 together with N are ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [where n is 0, 1, or 2] , R_5 and R
_6 is lower alkyl or hydrogen respectively], R_3 is hydrogen or hydroxy, R_4 is hydrogen, amino-lower alkyl, or lower alkylamino] or a pharmaceutically acceptable acid addition salt thereof. A method of treating hypertension, congestive heart failure, migraine, or vasospastic disease in a mammal, the method comprising administering. 20. The method according to claim 19, wherein the compound in which R_3 is hydrogen is orally administered. 21. The method according to claim 20, wherein 3-(2-N,N-di-n-propylaminoethyl)ureidobenzene is orally administered. 22. The method according to claim 19, wherein the compound in which R_3 is hydroxy is administered intravenously or intraperitoneally. 23. Compound represented by formula (VII): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VII) [In the formula, R_1 is alkyl having 2 to 4 carbon atoms, and R
_2 is alkyl having 3 or 4 carbon atoms, or R_1 and R_2 together with N are ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [where n is 0, 1, or 2] , R_5 and R
each of _6 is lower alkyl or hydrogen], and A is hydrogen or benzyloxy]. 24. A method of treating intraocular hyperbaric disease in a mammal, the method comprising:
Formula for therapeutically effective amount (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 is alkyl having 2 to 4 carbon atoms, and R
_2 is alkyl of 3 or 4 carbon atoms, or R_1 and R_2 together with N form the formula ▲
There are chemical formulas, tables, etc. ▼ [In the formula, n is 0, 1, or 2, and R_5 and R
and R_3 is hydrogen or hydroxy, and R_4 is hydrogen, lower alkyl, amino, or lower alkylamino. or a pharmaceutically acceptable compound thereof A method comprising administering an acid addition salt directly to the eye of a mammal in need of treatment. 25. The method according to claim 24 for the treatment of glaucoma. 26. The method according to claim 24, wherein the compound is 3-(2-N,N-di-n-propylaminoethyl)ureidobenzene or a pharmaceutically acceptable salt thereof. 27, the compound is 3-(2-N,N-n-propyl-n-
25. The method according to claim 24, wherein the ureidobenzene is (butylaminoethyl)ureidobenzene. 28, the compound is 3-[2-(1-piperidyl)ethyl]
25. The method of claim 24, wherein the ureidobenzene is ureidobenzene. 29. The method according to claim 24, wherein the compound is 3-[2-(3,5-dimethyl-1-piperidyl)ethyl]ureidobenzene. 30. The method according to claim 24, wherein the compound is 2-hydroxy-5-(2-N,N-di-n-propylaminoethyl)ureidobenzene. 31. The method according to claim 24, wherein the compound is 2-hydroxy-5-[2-(1-piperidyl)ethyl]ureidobenzene. 32, the compound is 2-hydroxy-5-[2-(3,5-
25. The method according to claim 24, wherein the dimethyl-1-piperidyl)ethyl]ureidobenzene is used. 33. A pharmaceutical composition for treating intraocular hyperbaric disease, comprising an ophthalmologically acceptable non-toxic carrier and a therapeutically effective amount of a compound of formula (I). 34. The composition according to claim 33, wherein the compound is 3-(2-N,N-di-n-propylaminoethyl)ureidobenzene or a pharmaceutically acceptable salt thereof. 35, the compound is 3-(2-N,N-n-propyl-n-
34. The composition of claim 33, which is butylaminoethyl)ureidobenzene. 36, the compound is 3-[2-(1-piperidyl)ethyl]
34. The composition of claim 33 which is ureidobenzene. 37. The composition according to claim 33, wherein the compound is 3-[2-(3,5-dimethyl-1-piperidyl)ethyl]ureidobenzene. 38. The composition according to claim 33, wherein the compound is 2-hydroxy-5-(2-N,N-di-n-propylaminoethyl)ureidobenzene. 39. The composition according to claim 33, wherein the compound is 2-hydroxy-5-[2-(1-piperidyl)ethyl]ureidobenzene. 40, the compound is 2-hydroxy-5-[2-(3,5-
34. The composition of claim 33, which is dimethyl-1-piperidyl)ethyl]ureidobenzene. 41. Use of a compound of formula (I) for the manufacture of a pharmaceutical composition for the treatment of intraocular hyperbaric disease in a mammal. 42, Formulas: ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 is alkyl having 2 to 4 carbon atoms, and R
_2 is alkyl having 3 or 4 carbon atoms, or R_1 and R_2 together are ▲a mathematical formula, a chemical formula, a table, etc.▼ [wherein n is 0, 1, or 2, and R_5 and R
and R_3 is hydrogen or hydroxy, and R_4 is hydrogen, lower alkyl, amino, or lower alkylamino. or a pharmaceutically acceptable compound thereof A method for producing acid addition salts, formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_1 and R_2 have the same meanings as above, and A
is hydrogen or benzyloxy] with a suitable formyl derivative, carboxylic acid derivative, isocyanate or alkyl isocyanate, optionally followed by (a) removal of the benzyl protecting group so that R_3 is forming a compound of formula (I) that is hydroxy; or (b) converting a compound of formula (I) to an acid addition salt thereof; or (c) converting an acid addition salt to the corresponding compound of formula (I). A method consisting of doing.