JPH10101658A - Amidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an amidine derivative that has a strong nitrogen monoxide formation preventive action, and is useful as a preventive or therapeutic agent for enzyme-interstitial diseases, such as adult aspiratory distress syndrome, myocarditis, shocks, cerebral infarction, and chronic anticular rheumatism. SOLUTION: This amidine derivative of formula I (R<2> is an amino, heterocyclic amino, etc.; X is CO, 0, etc.; (m) and (n) are each 0-3; (q) is 2 or 3) or its salt, for example, 2-[4-(2-(-benzylamino)ethyl) phenyl]amino-2-thiazoline dihydrochloride, is obtained, for example, by a reaction of a compound of formula II or its salt with a compound of formula III or its salt in a solvent, such as alcohol or tetrahydrofuran. The compound of formula I can be administered preferably twice to four times a day with a unit dose of 0.01-10mg/kg.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an amidine derivative. More specifically, the present invention relates to an amidine derivative having pharmacological activity, a pharmaceutically acceptable salt thereof, a method for producing the same, a pharmaceutical composition containing the same, and a use thereof.

[0002]

OBJECTS OF THE INVENTION It is an object of the present invention to provide said novel and useful amidine derivatives having a strong inhibitory effect on nitric oxide production and their pharmaceutically acceptable salts. Another object of the present invention is to provide a method for producing the amidine derivative and a salt thereof. Another object of the present invention is to provide a pharmaceutical composition comprising the amidine derivative and a pharmaceutically acceptable salt thereof. Still another object of this invention is adult respiratory distress syndrome in humans and animals, myocarditis, synovitis, shock (eg, septic shock, etc.), insulin-dependent diabetes, ulcerative colitis, cerebral infarction, cerebral ischemia , Migraine, rheumatoid arthritis, osteoarthritis (osteoarthritis),
Nitric oxide synthase (N) such as osteoporosis, systemic lupus erythematosus, rejection after organ transplantation, asthma, pain, and ulcer
(OS) It is to provide a use of the amidine derivative and a pharmaceutically acceptable salt thereof as a medicament for preventing or treating a mediated disease.

[0003]

The amidine derivative which is the object of the present invention is novel and can be represented by the following general formula (I):

Embedded image Wherein R ¹ is amino, di-lower alkylamino, heterocyclic amino, heterocyclic lower alkylamino, ar-lower alkylamino, 2-lower alkylisothioureido, acylamino, hydrazino, arylamino, diaminomethyleneamino, [( Amino) (2-thienyl) methylene] amino, optionally substituted aryl, lower alkoxy,
Optionally protected carboxy or (optionally protected carboxy) (optionally protected amino)
X is CO, O or (CH ₂ ) _a (a is 0
Or 1), m and n are each 0 to 3, and q is 2 or 3. The target compound (I) of the present invention can be produced by the following method.

[0004] Method 1

Embedded image

Method 2

Embedded image Wherein R ¹ , X, m, n and q are each as defined above, R ² is lower alkylthio or halogen, and Z is halogen.

The desired compound (I) produced by the above method 1 or 2 can be further converted to another desired compound by the method described in the following Examples or a conventional method.
The starting compound can be produced by the method of Production Examples described later or by a conventional method. Suitable pharmaceutically acceptable salts of the target compound (I) are conventional non-toxic salts, and include salts with bases or acid addition salts such as alkali metal salts (eg, sodium salt, potassium salt and the like). , Alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.),
Salts of inorganic bases such as ammonium salts; organic amine salts (eg, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, etc.); Salts of organic bases; inorganic acid addition salts (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.); organic carboxylic or sulfonic acid addition salts (eg, formate, acetate, trifluoroacetate, maleic acid) Acid salt, tartrate, citrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); salts with basic or acidic amino acids (eg, arginine, aspartic acid, glutamic acid, etc.) Is mentioned.

[0007] Preferred and specific examples of the various definitions that the present invention includes within its scope in the above and following description of the specification are described in detail below. The term "lower" is used to designate a group having 1 to 6, preferably 1 to 4, carbon atoms, unless otherwise specified. Suitable lower alkyl moieties in the expressions "lower alkylthio", "di-lower alkylamino", "heterocyclic lower alkylamino", "ar lower alkylamino" and "2-lower alkylisothioureido" include 1-6 Straight or branched having 3 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, tertiary pentyl, hexyl, etc. Among them preferred examples are C ₁ -C ₄ alkyl. Suitable "lower alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like. Suitable "aryl" and suitable aryl moieties in the expressions "ar-lower alkylamino" and "arylamino" include phenyl, naphthyl and the like.
Suitable "optionally substituted aryl" refers to aryl optionally substituted with a suitable substituent such as lower alkyl (for example, methyl, ethyl and the like), substituted lower alkyl (for example, pyrrolidinylmethyl and the like). means. Suitable “optionally protected carboxy” includes carboxy, esterified carboxy (eg, methoxycarbonyl, ethoxycarbonyl, and the like). Suitable acyl groups in the expression "acylamino" include carbamoyl, sulfonic, carboxylic, carbonic and carbamoyl derived from their thioacids.
Examples include thiocarbamoyl, sulfamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl, and aliphatic acyl substituted with an aromatic or heterocyclic group.

Examples of the aliphatic acyl include saturated or unsaturated, acyclic or cyclic, such as lower alkanoyl (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like), lower alkane Sulfonyl (eg, mesyl, ethanesulfonyl, propanesulfonyl, etc.), lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), lower alkenoyl (eg, Acryloyl,
Methacryloyl, etc. crotonoyl), C ₃ -C ₇ - cycloalkanecarbonyl (e.g. cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc. cycloheptane carbonyl), lower Arukokisariru (e.g. methoxalyl, etc. ethoxalyl), lower alkanoylamino carbonyl (e.g. pyruvoyl Etc.). Examples of the aromatic acyl include aroyl (for example, benzoyl, nitrobenzoyl, toluoyl, xyloyl, and the like), arenesulfonyl (for example, benzenesulfonyl, tosyl, and the like). As the heterocyclic acyl, a heterocyclic carbonyl (for example, furoyl, thenoyl, nicotinoyl, 1-oxonicotinoyl, isonicotinoyl, thiazolylcarbonyl,
Thiadiazolylcarbonyl, tetrazolylcarbonyl,
Morpholinocarbonyl) and the like. Examples of the aliphatic acyl substituted with an aromatic group include phenyl lower alkanoyl (eg, phenylacetyl, phenylpropionyl, phenylhexanoyl), phenyl lower alkoxycarbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.), phenoxy lower alkanoyl ( For example, phenoxyacetyl, phenoxypropionyl and the like). Examples of the aliphatic acyl substituted with a heterocyclic group include thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, and thiadiazolylpropionyl.

These acyl groups may be further substituted with one or more suitable substituents, such as hydroxy, amino, guanidino, carboxy,
Lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), lower alkenyl (eg, vinyl, allyl, etc.), halogen (eg, chloro, bromo, iodo, fluoro), lower alkoxy (eg, methoxy, ethoxy, Propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), lower alkoxycarbonyl, lower alkoxy (for example, methoxycarbonylmethoxy),
Lower alkylthio (eg, methylthio, ethylthio,
Propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc.), heterocyclic lower alkylthio (eg, furylmethylthio, thiazolylmethylthio, etc.), heterocyclic lower alkylsulfinyl (eg, furylmethylsulfinyl, thiazolylmethylsulfinyl, etc.), nitro, Acyl, protected amino, aryl (eg, phenyl, etc.), aroyl (eg, benzoyl, etc.), aryloxy (eg, benzyloxy, tolyloxy, etc.) wherein the amino protecting moiety can be the same as described herein. ), Protected hydroxy, such as lower alkanoyl (eg, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy,
Acyloxy such as isovaleryloxy, pivaloyloxy, hexanoyloxy, etc., lower alkylamino (eg, methylamino, dimethylamino, ethylamino, etc.), the aforementioned amino-protecting groups, etc., are preferred. Preferred acyls having such substituents are Are lower alkoxy lower alkanoyl (eg, methoxyacetyl, ethoxyacetyl, etc.), lower alkanoyloxy lower alkanoyl (eg, acetoxyacetyl, acetoxypropionyl, etc.), N-lower alkylcarbamoyl (eg, N-methylcarbamoyl, N-ethylcarbamoyl, N- Propylcarbamoyl, N-isopropylcarbamoyl, etc.), aroylthiocarbamoyl (eg, benzoylthiocarbamoyl, etc.), heterocyclic lower alkylthio lower alka Yl (for example, furylmethylthioacetyl), N-lower alkylthiocarbamoyl (for example, N-methylthiocarbamoyl), halo-lower alkanoyl (for example, trifluoroacetyl), hydroxy-lower alkanoyl (for example, hydroxyacetyl), amino-lower alkanoyl (for example, amino) Acetyl), alkylamino lower alkanoyl (eg, dimethylaminoacetyl), lower alkylthio lower alkanoyl (eg, methylthioacetyl), lower alkoxycarbonyl lower alkoxy lower alkanoyl (eg, methoxycarbonylmethoxyacetyl), N-lower alkoxycarbonylamino lower Alkanoyl (such as Nt-butoxycarbonylaminoacetyl), lower alkyl (C ₃ -C ₇₎ cycloalkanecarbonyl (e.g., methyl cyclopropanecarbonyl), N- aminocarbamoylmethyl, N- guanidino carbamoyl, N- lower alkylsulfamoyl (e.g. N- methylsulfamoyl, etc.).

Suitable heterocyclic moieties in the expressions "heterocyclic amino" and "heterocyclic lower alkylamino" include at least one of an oxygen atom, a sulfur atom, a nitrogen atom and the like.
Saturated or unsaturated monocyclic or polycyclic groups containing one heteroatom. Particularly preferred heterocyclic groups are 5- or 6-membered aromatic heteromonocyclic groups (eg, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, thiazolinyl, imidazolinyl, dihydrothiazinyl, etc.) 5- or 6-membered aliphatic heterocyclic monocyclic groups (for example, morpholinyl, pyrrolidinyl, imidazolidyl, pyrazolidinyl, piperidyl, piperazinyl, etc.), unsaturated condensed heterocyclic groups containing 1 to 3 nitrogen atoms (for example, benzimidazolyl, dihydroiso Quinolinyl), unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (for example, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl and the like). . The heterocyclic moiety thus defined may have one or more suitable substituents such as amino, oxo, chloro and the like, lower alkyl as defined above. Suitable "halogens" include chloro, bromo, fluoro and iodo. Suitable "(optionally protected carboxy) (optionally protected amino) methyl" includes (carboxy) (amino) methyl, (lower alkoxycarbonyl) (lower alkanoylamino)
Methyl and the like. Particularly preferred examples of R ¹ are as follows. R ¹ is amino, di-lower alkylamino, thiazolinylamino, dihydro-1,3-thiazinylamino, lower alkylthiazolylamino, imidazolinylamino, aminotriazolylamino, pyrimidinylamino, benzothiazolylamino , Dihydroisoquinolinylamino, pyridyl lower alkylamino, phenyl lower alkylamino, benzoylamino, N′-phenylureido, thioureide, N′-benzoylthioureido, 2-lower alkylisothioureido, lower alkanoylamino, hydrazino, Phenylamino, diaminomethyleneamino, [(amino) (2-thienyl) methylene] amino, pyrrolidinyl lower alkylphenyl,
Lower alkoxy, carboxy, methoxycarbonyl,
(Lower alkoxycarbonyl) (lower alkanoylamino) methyl and (carboxy) (amino) methyl.

The process for producing the target compound (I) of the present invention will be described in detail below. Method 1 The target compound (I) or a salt thereof can be produced by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof. This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, for example, an alcohol [eg, methanol, ethanol, propanol, 2-methoxyethanol, etc.], tetrahydrofuran, dioxane, dimethyl sulfoxide, N, N-dimethylformamide or a mixture thereof. Implemented in Although the reaction temperature is not particularly limited, it is usually carried out at ambient temperature or under heating or heating. The reaction may be carried out in the presence of an inorganic or organic acid such as hydrochloric acid.

Method 2 The desired compound (I) or a salt thereof can be produced by reacting the compound (II) or a salt thereof with the compound (IV) or a salt thereof. The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, for example, methyl acetate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, acetone, N, N-dimethylformamide, N, N
It is carried out in N-dimethylacetamide, dioxane, water, alcohol [for example, methanol, ethanol and the like], acetic acid, formic acid and the like, or a mixture thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

Suitable salts of the target compound and the starting compound in the methods (1) and (2) include the compound (I)
Can be mentioned. The compound obtained by each of the above methods can be isolated and purified by a conventional method such as powdering, recrystallization, column chromatography, and reprecipitation. The compound obtained by the above method can be further converted to another compound within the scope of the target compound (I). Compound (I) and other compounds may include one or more stereoisomers such as optical isomers and geometric isomers based on an asymmetric carbon atom and a double bond. Are all included in the scope of the present invention. The target compound (I) and a pharmaceutically acceptable salt thereof are a solvate [eg, an inclusion compound (eg, a hydrate)].
In some cases. The target compound (I) and a pharmaceutically acceptable salt thereof have a strong inhibitory effect on the production of nitric oxide (NO). Therefore, the target compound (I) and a pharmaceutically acceptable salt thereof are expected to have nitric oxide synthase (NOS) inhibitory activity or NOS production inhibitory activity. Thus, they include adult respiratory distress syndrome, myocarditis, synovitis, shock (such as septic shock), insulin-dependent diabetes; ulcerative colitis, cerebral infarction, cerebral ischemia, migraine, rheumatoid arthritis, It is useful for preventing and / or treating osteoarthritis (osteoarthritis), osteoporosis, systemic lupus erythematosus, rejection after organ transplantation, asthma, pain or ulcer. In order to show the usefulness of the target compound (I), pharmacological test data of representative compounds of the compound (I) are shown below.

Test compound (a) 2- [4- [2- (benzylamino) ethyl] phenyl] amino-2-thiazoline test Binding assay using nitric oxide synthase (NOS) Test method Crude NOS sample Was obtained from the brains of male SD rats. Whole brain (including cerebellum) was homogenized in 5 volumes (W / V) of 50 mM Tris buffer (pH 7.0 at 4 ° C.), and
Centrifuge at 00 × g for 20 minutes, discard the pellet, and discard the supernatant with 1/4 volume (V / V) of Dowex AG50WX-
Endogenous arginine was removed by passing through 8 resin (Na ⁺ form). Collect the supernatant, adjust the pH to 7.0 at 22 ° C,
This cytosol (cytosol) sample was frozen and stored at -80 ° C until needed. In binding assays,
Each drug was combined with brain cytosol (200 μg protein / tube) with 10 μM CaCl ₂ and 10 nM ³ [H] N.
a (Amersham, UK) containing a final volume of 0.15
Incubated in ml of 50 mM Tris buffer.
Incubation was performed at 27 ° C. for 90 minutes, 0.3
The filtration was terminated by vacuum filtration using a pretreated GF / B glass fiber filter, and the filter was subsequently washed four times with 4 ml of 4 ° C. distilled water. Non-specific binding was defined using 100 μM Na. Data were expressed as% inhibition of specific binding.

Test results

[Table 1] For therapeutic administration, the desired compounds (I) of the present invention and pharmaceutically acceptable salts thereof may be formulated with organic or inorganic, solid or liquid excipients suitable for oral, parenteral administration or external use. It is used in the form of a pharmaceutical preparation as a mixture with a conventional pharmaceutically acceptable carrier. The pharmaceutical preparations may be in the form of solids such as granules, capsules, tablets, dragees, suppositories or liquids for injection, oral ingestion, eye drops, etc., suspensions,
It can be formulated in a liquid form such as an emulsion. If desired, auxiliary substances such as stabilizers, wetting or emulsifying agents, buffers and the like, or any other customary additives, can be included in the formulation. The active ingredient is usually administered in a unit dose of 0.001 mg / k
g to 500 mg / kg, preferably 0.01 mg / kg
It can be administered 1 to 4 times a day at 10 to 10 mg / kg. However, the above dosages and dosages may vary depending on the age of the patient,
It can be increased or decreased depending on the weight and condition or the administration method.

[0016]

The following production examples and examples are provided for the purpose of illustrating the present invention in detail. Production Example 1 4-nitrophenethyl bromide (5.0 g), morpholine (2.27 g) and trimethylamine (5.50 g)
In acetonitrile (50 ml) at 60 ° C. for 1 hour.
Heated for 8 hours. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of water (100ml) and tetrahydrofuran (30ml). The mixture was adjusted to pH 10 with 30% potassium carbonate solution, then ethyl acetate (100 ml)
Extracted. The extract was dried over magnesium sulfate. The solvent is removed under reduced pressure to give 1- (2-morpholinoethyl)
-4-Nitrobenzene (4.15 g) was obtained. IR (film): 3350, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 2.42 (4H, t, J = 4.7Hz), 2.56 (2H,
t, J = 7.1Hz), 2.89 (2H, t, J = 7.1Hz), 3.56 (4H, t, J = 4.7H
z), 7.50-7.57 (2H, m), 8.11-8.18 (2H, m)

Production Example 2 1- (2-morpholinoethyl) -4-nitrobenzene (4.0 g) and palladium on activated carbon (wet product) (40 g)
0 mg) in methanol (20 ml) was stirred at room temperature under a stream of nitrogen for 9 hours. Insolubles were removed by filtration. A 4N solution of hydrogen chloride in dioxane (15 ml) was added. The solvent was removed under reduced pressure to give 1-amino-4- (2-
Morpholinoethyl) benzene dihydrochloride (4.35 g) was obtained. mp: 278-280 ° C IR (Nujol): 3350, 1610 cm ^-1 NMR (DMSO-d ₆ , δ): 3.08-3.19 (4H, m), 3.24-3.35 (2
H, m), 3.43-3.49 (2H, m), 3.79-3.94 (4H, m), 7.31-7.4
1 (4H, m), 10.45 (1H, br s)

Production Example 3 The following compound was obtained in the same manner as in Production Example 1. 1- [2- (4-acetylpiperazin-1-yl) ethyl] -4-nitrobenzene mp: 74-75 ° C IR (Nujol): 3350, 1630 cm ^-1 NMR (DMSO-d ₆ , δ): 1.99 ( 3H, s), 2.30-2.46 (4H, m),
2.59 (2H, t, J = 7.4Hz), 2.90 (2H, t, J = 7.4Hz), 3.38-3.44
(4H, m), 7.54 (2H, d, J = 8.7Hz), 8.15 (2H, d, J = 8.7Hz)

Production Example 4 The following compound was obtained in the same manner as in Production Example 2. 1- [2- (4-acetylpiperazin-1-yl) ethyl] -4-aminobenzene dihydrochloride mp: 99-100 ° C. (decomposition) IR (nujol): 3350, 1620 cm ⁻¹ NMR (DMSO-d ₆ , δ): 2.05 (3H, s), 2.80-3.25 (5H, m),
3.25-3.43 (2H, m), 3.43-3.75 (2H, m), 3.90-4.20 (1H,
m), 4.20-5.05 (3H, m), 7.39 (4H, m), 10.42 (1H, br), 1
1.74 (1H, br)

EXAMPLE 1 A suspension of lithium aluminum hydride (70 mg) in tetrahydrofuran (10 ml) was stirred at ambient temperature with 2- [4- (benzylaminocarbonylmethyl).
[Phenyl] amino-2-thiazoline (600 mg) was added in small portions. After stirring for 2 hours, the mixture was heated at reflux for 6 hours. To the suspension was added saturated potassium sodium tartrate and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluted with chloroform-methanol (20: 1), the obtained base was converted into a dihydrochloride by a conventional method, and the salt was recrystallized from methanol-ethyl acetate-tetrahydrofuran. To give 2- [4- [2- (benzylamino) ethyl] phenyl] amino-2-thiazoline dihydrochloride (2
50 mg). mp: 218-220 ° C IR (Nujol): 3400, 3200, 1635 cm ^-1 NMR (DMSO-d ₆ , δ): 3.09 (4H, s), 3.58 (2H, t, J = 7.5H)
z), 3.94 (2H, d, J = 7.5Hz), 4.16 (2H, s), 7.29-7.44 (7
H, m), 7.60-7.62 (2H, m), 9.74 (2H, br s)

Example 2 2- (4-aminophenyl) ethylamine (0.68
g), a solution of 2-methylthio-2-thiazoline (1.3 g) and concentrated hydrochloric acid (0.88 ml) in 2-methoxyethanol (10 ml) was heated with stirring at 130 ° C. for 8 hours. After removal of the solvent, the residue was crystallized from acetone-ethyl acetate to give 2- [4- [2-[(2-thiazolin-2-yl) amino] ethyl] phenyl] amino-
2-Thiazoline dihydrochloride (0.75 g) was obtained. NMR (DMSO-d ₆ , δ): 2.85 (2H, t, J = 7Hz), 3.39-3.61 (6
H, m), 3.86 (2H, t, J = 7.5Hz), 3.93 (2H, t, J = 7.5Hz), 7.
28 (2H, d, J = 7.8Hz), 7.35 (2H, d, J = 8.5Hz), 10.33 (2H,
br s)

Example 3 A suspension of 2- [4- (2-ethoxycarbonylethyl) phenyl] amino-2-thiazoline (2.68 g) and hydrazine hydrate (2.01 g) in ethanol (50 ml). Was heated to reflux for 23 hours. The solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol = 20: 1. The corresponding fractions were collected and the solvent was removed under reduced pressure. The residue was crystallized from ethyl acetate. Recrystallization from an ethyl acetate-methanol mixture gave 2- [4- (2-hydrazinocarbonylethyl) phenyl] amino-2-thiazoline (1.3 g). mp: 148-150 ° C IR (Nujol): 3200, 1660, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 2.27 (2H, t, J = 7.7Hz), 2.73 (2H,
t, J = 7.7Hz), 3.26 (2H, t, J = 7.4Hz), 3.90 (2H, br), 4.14
(2H, d, J = 3.5Hz), 7.04 (2H, d, J = 8.4Hz), 7.33 (2H, br
s), 8.94 (2H, br s)

Example 4 2- [4- (2-benzoylaminoethyl) phenyl]
A mixture of amino-2-thiazoline (600 mg) in a 6N hydrochloric acid solution (15 ml) was heated to reflux for 25 hours. Wash the mixture with ethyl acetate and then pH with potassium hydroxide.
Adjusted to 13.5. Ethyl acetate (30 ml)
And extracted with a mixture of and tetrahydrofuran (30 ml). The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in methanol (5ml). A 4N solution of hydrogen chloride in dioxane (5 ml) was added.
The solvent was removed under reduced pressure. Recrystallization from a methanol-tetrahydrofuran mixture gave 2- [4- (2-aminoethyl) phenyl] amino-2-thiazoline dihydrochloride (3
30 mg). mp: 225-226 ° C IR (Nujol): 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 2.90-3.15 (4H, m), 3.58 (2H, t, J =
7.6Hz), 3.95 (2H, t, J = 7.6Hz), 7.29-7.41 (4H, m), 8.1
1 (3H, brs) Elemental analysis Calculated for C ₁₁ H ₁₅ N ₃ S · 2HCl: C 44.90, H
5.82, N 14.28 Found: C 44.91, H 5.80, N 13.90

Example 5 2- [4- (2-aminoethyl) phenyl] amino-2
A solution of -thiazoline dihydrochloride (600 mg), dimethyl N-cyanodithioiminocarbonate (298 mg) and triethylamine (412 mg) in methanol (10 ml) was stirred at room temperature for 3.5 hours. Hydrazine hydrate (1.02 g) was added. The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of water (50ml) and tetrahydrofuran (30ml). The mixture was adjusted to pH 10 with a 30% potassium carbonate solution and then extracted with ethyl acetate (50 ml). The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with chloroform: methanol = 20: 1. The relevant fractions were collected. The solvent was removed under reduced pressure and the residue was crystallized from a methanol-diisopropyl ether mixture to give 2- [4- [2- (5-amino-4H-
1,2,4-triazol-3-yl) aminoethyl]
[Phenyl] amino-2-thiazoline (100 mg) was obtained. NMR (DMSO-d ₆ , δ): 2.69 (2H, t, J = 7.4Hz), 3.13-3.20
(2H, m), 3.26 (2H, t, J = 7.3Hz), 3.91 (2H, br s), 5.25
(1H, br), 5.50 (1H, br), 6.55 (1H, s), 7.06 (2H, d, J =
(8.3Hz), 7.37 (2H, br s), 8.61 (1H, br s)

Example 6 2- [4- (2-aminoethyl) phenyl] amino-2
-Thiazoline dihydrochloride (500 mg), 2-chlorobenzothiazole (288 mg) and triethylamine (550 mg) in 2-methoxyethanol (10 ml)
The medium mixture was heated at 120 ° C. for 8 hours. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of water (50ml) and tetrahydrofuran (10ml). Mix 30
The solution was adjusted to pH 10 with a 10% potassium carbonate solution, and then extracted with ethyl acetate (60 ml). The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol = 30: 1. The relevant fractions were collected. The solvent was removed under reduced pressure. Recrystallization from a mixture of methanol-tetrahydrofuran-diisopropyl ether gave 2- [4- [2- (benzothiazol-2-yl).
Aminoethyl] phenyl] amino-2-thiazoline (2
70 mg). mp: 197-198 ° C IR (Nujol): 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 2.83 (2H, t, J = 7.3Hz), 3.26 (2H,
t, J = 7.4Hz), 3.50-3.59 (2H, m), 3.93 (2H, br), 6.96-7.
04 (1H, m), 7.10-7.24 (4H, m), 7.25-7.62 (3H, m), 7.6
5 (1H, d, J = 7.7Hz), 8.06 (1H, t, J = 5.8Hz) Elemental Analysis C ₁₈ H ₁₈ N ₄ Calculated as S _2: C 60.99, H 5.1
2, N 15.81 Found: C 60.73, H 5.12, N 15.55

Example 7 2- [4- (2-benzoylaminoethyl) phenyl]
A solution of amino-2-thiazoline (19.36 g) in a 6N hydrochloric acid solution (300 ml) was heated at 100 ° C. for 15 hours. The mixture was washed with ethyl acetate (200 ml) and then adjusted to pH 13.5 with potassium hydroxide. The mixture was mixed with ethyl acetate (300 ml) and tetrahydrofuran (100
ml). The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure to give 2- [4-
(2-Aminoethyl) phenyl] amino-2-thiazoline (9.76 g) was obtained. mp: 101-102 ° C IR (Nujol): 3320, 3140, 1610 cm ^-1 NMR (DMSO-d ₆ , δ): 2.48-2.58 (2H, m), 2.72 (2H, t, J =
6.9Hz), 3.22-3.29 (2H, m), 3.90 (2H, t, J = 7.1Hz), 7.04
(2H, d, J = 8.5Hz), 7.32-7.35 (2H, m)

Example 8 A solution of 2- [2- [2- (acetylamino) ethyl] phenyl] amino-2-thiazoline dihydrochloride (800 mg) in a 6N hydrochloric acid solution (20 ml) was heated at 100 ° C. for 10 hours. did. The solvent was removed under reduced pressure. The residue was dissolved in methanol (10 ml), 4N hydrogen chloride dioxane solution (5 ml) was added, and the solvent was removed under reduced pressure to give 2- [2- (2-aminoethyl) phenyl] amino-2-. Thiazoline (690 mg) was obtained as a foam. NMR (DMSO-d ₆ , δ): 2.90-3.15 (4H, m), 3.61 (2H, t, J =
7.3Hz), 3.90-4.05 (2H, m), 7.31-7.46 (4H, m), 8.35 (3
H, br s), 9.95 (1H, br s), 12.50 (1H, br s)

Example 9 2- [4- (2-aminoethyl) phenyl] amino-2
Dimethyl sulfoxide of thiazoline (700 mg) and 2-methylisothiourea sulfate (440 mg) (5 m
l) The medium mixture was heated at 120 ° C for 6 hours. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of water (20ml) and tetrahydrofuran (10ml). The mixture was adjusted to pH 13 with potassium hydroxide and ethyl acetate (10
ml). The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was treated with methanol (10
ml), and a 4N hydrogen chloride dioxane solution (5 m
l) was added. The solvent was removed under reduced pressure. The residue was crystallized from ethyl acetate to give 2- [4- [2- (diaminomethyleneamino) ethyl] phenyl] amino-2-thiazoline dihydrochloride (410 mg). NMR (DMSO-d ₆ , δ): 2.82 (2H, t, J = 7.3Hz), 3.39-3.63
(4H, m), 3.91-4.05 (2H, m), 7.23-7.44 (8H, m), 7.82 (1
(H, t, J = 5.9Hz), 9.60-10.80 (1H, br)

Example 10 Benzoyl chloride (1.52 g) was refluxed with sodium isothiocyanate (952 mg) in acetone (100 ml).
l) Added slowly to the solution. The mixture was refluxed for 5 minutes, then 2- [4- (2-aminoethyl) phenyl] amino-2-thiazoline (2.0 g) was added to the mixture. The mixture was refluxed for 1 hour. The solvent was removed under reduced pressure, and the residue was treated with water (200 ml) and tetrahydrofuran (100 ml).
l). The mixture was adjusted to pH 10 with 30% potassium carbonate solution and then ethyl acetate (15%).
0 ml). The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with chloroform: methanol = 50: 1 to give 2- [4- [2- (N ′).
-Benzoylthioureido) ethyl] phenyl] amino-2-thiazoline (1.24 g) was obtained. mp: 162-163 ° C IR (Nujol): 3200, 1635 cm ^-1 NMR (DMSO-d ₆ , δ): 2.88 (2H, t, J = 7.2Hz), 3.27 (2H,
t, J = 7.3Hz), 3.76-3.95 (4H, m), 7.15 (2H, d, J = 8.5Hz),
7.38-7.67 (5H, m), 7.90 (2H, d, J = 8.5Hz), 9.35 (1H, b
r), 10.91 (1H, t, J = 6.0Hz), 11.30 (1H, br s)

Example 11 A solution of sodium hydroxide (330 mg) in water (2 ml) was prepared by adding 2- [4- [2- (N'-benzoylthioureido) ethyl] phenyl] amino-2-thiazoline (1.
2 g) to a suspension in methanol (50 ml). The mixture was heated at 60 ° C. for 9 hours. The solvent was removed under reduced pressure and the residue was suspended in water (100ml). The mixture was neutralized with a 1N hydrochloric acid solution and then ethyl acetate (150 m
l) and extracted with a mixture of tetrahydrofuran (30 ml). The extract was dried over magnesium sulfate and the solvent was removed under reduced pressure. Recrystallization from a mixture of methanol and diisopropyl ether gave 2- [4- (2-thioureidoethyl) phenyl] amino-2-thiazoline (1.
2 g) were obtained. mp: 167-168 ° C IR (Nujol): 3370, 3210, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 2.69 (2H, t, J = 7.4Hz), 3.26 (2H,
t, J = 7.4Hz), 3.54 (2H, br s), 3.92 (2H, br s), 6.94
(1H, br s), 7.00-7.65 (7H, m) Elemental analysis _{C 12 H 16 N 4 S 2} · 1 / 5H 2 calculated for O: C 50.7
5, H 5.82, N 19.94 Found: C 50.99, H 5.59, N 19.66

Example 12 2- [4- (2-thioureidoethyl) phenyl] amino-2-thiazoline (200 mg) and ethyl iodide (11
1 mg) in ethanol (20 ml).
The mixture was refluxed for 5 hours. The solvent was removed under reduced pressure. Crystallized from ethyl acetate to give 2- [4- [2- (2-ethylisothioureido) ethyl] phenyl] amino-2-
Thiazoline hydroiodide (290 mg) was obtained. NMR (DMSO-d ₆ , δ): 1.22 (3H, t, J = 7.3Hz), 2.80 (2H,
t, J = 7.3Hz), 3.15 (2H, q, J = 7.3Hz), 3.28-3.56 (4H, m),
3.91 (2H, t, J = 7.3Hz), 7.16 (2H, d, J = 8.4Hz), 7.36 (2
(H, d, J = 8.4Hz), 9.12 (2H, br s), 9.52 (2H, br s)

Example 13 A suspension of 2- [4- (2-thioureidoethyl) phenyl] amino-2-thiazoline (470 mg) and bromoacetone (300 mg) in ethanol (10 ml) was heated under reflux for 1 hour. I let it. The solvent was removed under reduced pressure and the residue was water (20 ml) and tetrahydrofuran (5 ml)
Was dissolved in the mixture. The mixture was adjusted to pH 10 with 30% potassium carbonate solution and then extracted with ethyl acetate. The extract was dried over magnesium sulfate. The solution was concentrated, and the resulting precipitate was collected by filtration. Recrystallization from a methanol-tetrahydrofuran-diisopropyl ether mixture gave 2- [4- [2- (4-methylthiazol-2-yl) aminoethyl] phenyl] amino-2-thiazoline (470 mg). mp: 195-196 ° C IR (Nujol): 3060, 1620, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 2.09 (3H, s), 2.75 (2H, t, J = 7.7H)
z), 3.23-3.40 (4H, m), 3.80-4.00 (2H, m), 6.13 (1H,
s), 7.09 (2H, d , J = 8.4Hz), 7.25-7.50 (3H, m) Elemental analysis _{C 15 H 18 N 4 S 2} · 1 / 5H 2 calculated for O: C 55.9
4, H 5.76, N 17.40 Found: C 56.23, H 5.64, N 17.19

Example 14 4- (2-benzoylaminoethyl) phenylamine (1.2 g) and 3-chloropropyl isocyanate (6
80 mg) in chloroform (30 ml).
Stir at room temperature for 20.5 hours and then heat at 50 ° C. for 24 hours. The solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with a 20: 1 mixture of chloroform: methanol. The corresponding fractions were collected, the solvent was removed under reduced pressure, and 2- [4- (2-benzoylaminoethyl) phenyl] amino-5,6-dihydro-4H-1,3-thiazine hydrochloride (1. 67g) was obtained as a foam. NMR (DMSO-d ₆ , δ): 2.00-2.12 (2H, m), 2.89 (2H, t, J =
(7.3Hz), 3.23 (2H, t, J = 5.8Hz), 3.43-3.56 (4H, m), 7.22-7.56 (7H, m), 7.
84-7.89 (2H, m), 8.70 (1H, t, J = 5.5Hz), 10.66 (2H, br
s)

Example 15 2- [4- (2-aminoethyl) phenyl] amino-2
-Thiazoline (700 mg) and 3-chloropropyl isocyanate (430 mg) in chloroform (20 m
The suspension in 1) was heated to reflux for 24 hours. The solvent was removed under reduced pressure, and the residue was dissolved in a mixture of water (70 ml) -tetrahydrofuran (20 ml). 30% mixture
The pH was adjusted to 10 with a potassium carbonate solution, and then extracted with ethyl acetate (70 ml). The extract was dried over magnesium sulfate. After removing the solvent under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with a mixture of methanol and diisopropyl ether to give 2-
[4- [2- (5,6-dihydro-4H-1,3-thiazin-2-yl) aminoethyl] phenyl] amino-2
-Thiazoline (340 mg) was obtained. mp: 125-126 ° C IR (Nujol): 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 1.60-1.72 (2H, m), 2.64 (2H, t, J =
7.5Hz), 2.97 (2H, t, J = 6.1Hz), 3.17-3.29 (4H, m), 3.4
0 (2H, t, J = 5.5Hz), 3.90 (2H, t, J = 7.2Hz), 7.04 (2H, d,
J = 8.4Hz), 7.34 (2H, d, J = 8.4Hz)

Example 16 2- [4- (2-aminoethyl) phenyl] amino-
5,6-dihydro-4H-1,3-thiazine dihydrochloride (500 mg), 2-methylthio-2-thiazoline (2
16 mg) and triethylamine (164 mg)
Suspension in methoxyethanol (10 ml)
Heated at ° C for 24 hours. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of water (50ml) and tetrahydrofuran (10ml). The mixture was adjusted to pH 10 with 30% potassium carbonate solution and then extracted with ethyl acetate.
The extract was dried over magnesium sulfate. After removing the solvent under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with a 20: 1 mixture of chloroform: methanol to give 2- [4- [2- (2-thiazoline-
2-yl) aminoethyl] phenyl] amino-5,6-
Dihydro-4H-1,3-thiazine (150 mg) was obtained as a foam. NMR (DMSO-d ₆ , δ): 1.70-1.90 (2H, m), 2.66 (2H, t, J =
7.5Hz), 3.03 (2H, t, J = 7.0Hz), 3.18-3.31 (4H, m), 3.4
0-3.50 (2H, m), 3.82 (2H, t, J = 7.3Hz), 6.99 (2H, d, J =
(8.3Hz), 7.20-7.40 (2H, m)

Example 17 2- [4- (2-aminoethyl) phenyl] amino-2
-Thiazoline (400 mg) and 1-methylthio-3,4
A suspension of -dihydroisoquinoline (552 mg) in 2-methoxyethanol (10 ml) was heated at 120 <0> C for 8 hours. The solvent was removed under reduced pressure and the residue was washed with water (50
ml) and tetrahydrofuran (20 ml). PH of the mixture with 1N sodium hydroxide solution
The mixture was adjusted to 12 and then extracted with ethyl acetate (50 ml). The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure to give 2- [4- [2- (3,4-dihydroisoquinolin-1-yl) aminoethyl] phenyl] amino-2-thiazoline (540 mg) as a foam. NMR (DMSO-d ₆ , δ): 2.64 (2H, t, J = 6.5Hz), 2.80 (2H,
t, J = 7.4Hz), 3.15-3.40 (6H, m), 3.75-3.95 (2H, m), 7.1
0-7.38 (8H, m), 7.60-7.70 (1H, m)

Example 18 N-acetyl-4-[(2-thiazolin-2-yl) aminophenyl] alanine methyl ester (700 mg)
And a 6N hydrochloric acid solution (50 ml) were heated at 100 ° C. for 3 days. The solvent was removed under reduced pressure and the residue was crystallized from acetone. Recrystallization from a mixture of methanol and diisopropyl ether gave 4-[(2-thiazolin-2-yl) aminophenyl] alanine dihydrochloride (600 mg). mp: 231-232 ° C IR (Nujol): 3350, 1735, 1630 cm ^-1 NMR (DMSO-d ₆ , δ): 3.16-3.21 (2H, m), 3.59 (2H, t, J =
7.4Hz), 3.94 (2H, t, J = 7.4Hz), 4.10-4.25 (1H, m), 7.3
2 (2H, d, J = 7.9Hz), 7.42 (2H, d, J = 7.9Hz), 8.57 (3H, br
s)

Example 19 4-[(pyridin-2-yl) methylaminocarbonylmethylphenyl] amine (2.0 g), 2-methylthio-2-thiazoline (1.1 g) and a concentrated hydrochloric acid solution (0.1 g).
A mixture in 69 ml) of 2-methoxyethanol (20 ml) was heated at 120 ° C. for 18.5 hours. The solvent was removed under reduced pressure and the residue was dissolved in water (100ml).
The solution was washed with ethyl acetate (100 ml) and then 30%
The pH was adjusted to 10 with a potassium carbonate solution. Ethyl acetate (120 ml) and tetrahydrofuran (30 ml)
And extracted with a mixture. The extract was dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was crystallized from a mixture of methanol and diisopropyl ether to give 2- [4- (pyridin-2-yl) methylaminocarbonylmethylphenyl] amino-2-thiazoline (1.0 g). mp: 174-175 ° C IR (Nujol): 3270, 1635, 1605 cm ^-1 NMR (DMSO-d ₆ , δ): 3.27 (2H, t, J = 7.4Hz), 3.42 (2H,
s), 3.91 (2H, br s), 4.35 (2H, d, J = 5.9Hz), 7.13-7.27
(5H, m), 7.40 (2H, br s), 7.72 (1H, dt, J = 1.8 and
7.7Hz), 8.48-8.55 (2H, m ) Elemental analysis _{C 17 H 18 N 4 OS ·} 1 / 4H 2 calculated for O: C 61.7
0, H 5.64, N 16.93 Found: C 61.55, H 5.50, N 16.73

Example 20 The following compounds were prepared in the same manner as in Example 19. (1) 2- [3- [3- (pyrrolidin-1-ylmethyl) phenoxy] phenyl] amino-2-thiazoline dioxalate mp: 201-203 ° C IR (nujol): 1720, 1650 cm ^-1 NMR (DMSO -d ₆ , δ): 1.94 (4H, s), 3.19 (4H, s), 3.28
(2H, t, J = 7.5Hz), 3.90 (2H, t, J = 7.5Hz), 4.31 (2H, s),
6.60 (1H, dd, J = 2 and 8Hz), 7.05 (1H, dd, J = 2 and
8Hz), 7.13-7.29 (5H, m), 7.45 (1H, t, J = 8Hz) (2) 2- [4- (benzylaminocarbonylmethyl) phenyl] amino-2-thiazoline mp: 150-152 ° C IR (Nujol): 3250, 3175, 1640, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 3.27 (2H, t, J = 7.3Hz), 3.34 (2H,
t, J = 7.3Hz), 3.90 (2H, br s), 4.25 (2H, d, J = 5.8Hz),
7.14 (2H, d, J = 8.3Hz), 7.19-7.35 (7H, m), 8.46 (1H, t, J
= 5.8Hz) (3) 2- [4- (2-ethoxycarbonylethyl)
Phenyl] amino-2-thiazoline mp: 69-70 ° C IR (nujol): 3350, 1715, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 1.15 (3H, t, J = 7.1 Hz), 2.55 ( 2H,
t, J = 7.2Hz), 2.76 (2H, t, J = 7.2Hz), 3.26 (2H, t, J = 7.2H
z), 3.80-3.96 (2H, m), 4.03 (2H, q, J = 7.1Hz), 7.07 (2
(H, d, J = 8.4Hz), 7.32 (2H, br) (4) 2- [4- [2- (N'-phenylureido)
Ethyl] phenyl] amino-2-thiazoline mp: 164-165 ° C IR (nujol): 3380, 1630 cm ^-1 NMR (DMSO-d ₆ , δ): 2.66 (2H, t, J = 7.2Hz), 3.16- 3.34
(4H, m), 3.91 (2H, br s), 6.06 (1H, t, J = 5.6Hz), 6.87
(1H, t, J = 7.2Hz), 7.07-7.24 (5H, m), 7.35-7.40 (4H,
m), 8.45 (1H, s ) Elemental analysis C ₁₈ H ₂₀ N ₄ calculated for OS: C 63.51, H 5.9
2, N 16.46 Found: C 63.39, H 5.95, N 16.28 (5) 2- [4- (2-benzoylaminoethyl) phenyl] amino-2-thiazoline mp: 169-170 ° C IR (Nujol): 3300, 1630, 1605 cm ^-1 NMR (DMSO-d ₆ , δ): 2.76 (2H, t, J = 7.9Hz), 3.26 (2H,
(t, J = 7.2Hz), 3.39-3.49 (2H, m), 3.91 (2H, br), 7.10
(2H, d, J = 8.4Hz), 7.40-7.55 (5H, m), 7.82 (2H, dd, J = 1.4
And 7.5Hz), 8.53 (1H, t, J = 5.5Hz)

(6) 2- [4- (2-dimethylaminoethyl) phenyl] amino-2-thiazoline mp: 60-61 ° C. IR (nujol): 3400, 1630, 1600 cm ⁻¹ NMR (DMSO-d ₆ , δ): 2.16 (6H, s), 2.40 (2H, t, J = 7.3H
z), 2.62 (2H, t, J = 7.3Hz), 3.26 (2H, t, J = 7.2Hz), 3.80
-4.00 (2H, m), 7.06 (2H, d, J = 8.4Hz), 7.32 (2H, br s),
9.88 (1H, br) (7) 2- [3- [3- (N, N-dimethylamino)
Propoxy] phenyl] amino-2-thiazoline NMR (DMSO-d ₆ , δ): 2.11-2.25 (2H, m), 2.75 (6H, d, J =
(3.9Hz), 3.10-3.28 (2H, m), 3.59 (2H, t, J = 7.6Hz), 3.97
(2H, t, J = 7.6Hz), 4.04-4.14 (2H, m), 6.92-6.97 (3H,
m), 7.34-7.44 (1H, m), 11.07 (1H, br) (8) 2- [4- (2-pyrimidin-2-yl) aminoethyl] phenyl] amino-2-thiazoline mp: 177-178 ° C IR (Nujol): 3230, 1630, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 2.74 (2H, t, J = 7.5Hz), 3.26 (2H,
t, J = 7.3Hz), 3.38-3.48 (2H, m), 3.91 (2H, br), 6.54 (1
(H, t, J = 4.7Hz), 7.06-7.13 (3H, m), 7.42 (1H, br), 8.26
(2H, d, J = 4.7Hz) (9) N-acetyl-4-[(2-thiazoline-2-
Yl) aminophenyl] alanine methyl ester mp: 167-168 ° C IR (nujol): 3330, 3150, 1720, 1660 cm ^-1 NMR (DMSO-d ₆ , δ): 1.79 (3H, s), 2.78 (1H, dd, J = 9.0
And 13.7Hz), 2.92 (1H, dd, J = 5.8 and 13.7Hz),
3.26 (2H, t, J = 7.3Hz), 3.58 (3H, s), 3.92 (2H, br), 4.
33-4.44 (1H, m), 7.06 (2H, d, J = 8.4Hz), 7.36 (2H, br),
8.30 (1H, d, J = 7.7 Hz) (10) 2- [4- (3-phenylaminocarbonylpropyl) phenyl] amino-2-thiazoline mp: 186-187 ° C. IR (nujol): 3310, 1660, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 1.81-1.92 (2H, m), 2.30 (2H, t, J =
(7.4Hz), 2.49-2.58 (2H, m), 3.26 (2H, t, J = 7.3Hz), 3.91
(2H, brs), 6.97-7.09 (3H, m), 7.24-7.31 (2H, m), 7.3
7 (2H, br s), 7.59 (2H, d, J = 7.6Hz), 9.00 (1H, br s),
9.86 (1H, s) (11) 2- [4- (3-Methoxycarbonylpropyl] phenyl] amino-2-thiazoline NMR (DMSO-d ₆ , δ): 1.70-1.85 (2H, m), 2.28 (2H , t, J =
7.4Hz), 2.50 (2H, t, J = 7.6Hz), 3.26 (2H, t, J = 7.3Hz),
3.58 (3H, s), 3.86-3.94 (2H, m), 7.04 (2H, d, J = 8.4Hz),
7.35 (2H, br), 8.91 (1H, br) (12) 2- [2- (2-acetylaminoethyl) phenyl] amino-2-thiazoline hydrochloride NMR (DMSO-d ₆ , δ): 1.79 (3H , s), 2.74 (2H, t, J = 7.4H
z), 3.20-3.28 (2H, m), 3.56-3.62 (2H, m), 3.92 (2H, b
rs), 6.76 (2H, br s), 7.29-7.43 (4H, m), 8.14 (1H, t,
(J = 5.8Hz)

Example 21 The following compounds were prepared in the same manner as in Example 2. (1) 2- [3- (2-thiazolin-2-ylamino) phenyl] amino-2-thiazoline mp: 205-206 ° C IR (nujol): 3150, 3100, 1630 cm ^-1 NMR (DMSO-d ₆ , δ): 3.25 (4H, t, J = 7Hz), 3.88 (4H, t, J
= 7Hz), 7.04 (3H, brs), 7.44 (1H, s) (2) 2- [4- (2-thiazolin-2-ylaminomethyl) phenyl] amino-2-thiazoline mp: 123-124 ° C IR (Nujol): 3340, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 3.16-3.31 (4H, m), 3.77-3.89 (4
H, m), 4.25 (2H, s), 7.13 (2H, d, J = 8.5Hz), 7.33 (2H, br
s) Elemental analysis _{C 13 H 16 N 4 S 2} · 1 / 2H 2 calculated for O: C 51.8
0, H 5.68, N 18.59 Found: C 51.89, H 5.40, N 18.49 (3) 2- [4- [3- (2-thiazolin-2-yl) aminopropyl] phenyl] amino-2-thiazoline mp: 151-152 ° C IR (Nujol): 3300, 1615, 1590 cm ^-1 NMR (DMSO-d ₆ , δ): 1.64-1.79 (2H, m), 2.46-2.54 (2
H, m), 3.08-3.29 (6H, m), 3.76-3.94 (4H, m), 7.04 (2H,
d, J = 8.4Hz), 7.32-7.36 (2H, m) Elemental analysis _{C 15 H 20 N 4 S 2} · 1 / 4H 2 calculated for O: C 55.4
4, H 6.36, N 17.24 Found: C 55.58, H 6.34, N 16.99 (4) 2- [3- [2- (2-thiazolin-2-yl) aminoethyl] phenyl] amino-2-thiazoline dihydrochloride Salt NMR (DMSO-d ₆ , δ): 2.87-2.98 (4H, m), 3.23-3.55 (6
H, m), 3.83-3.97 (2H, m), 6.94-7.05 (1H, m), 7.23-7.3
5 (3H, m), 8.22 (2H, br), 9.90 (2H, br) (5) 2- [2- [2- (2-thiazolin-2-yl) aminoethyl] phenyl] amino-2-thiazoline Dihydrochloride NMR (DMSO-d ₆ , δ): 2.90-3.02 (4H, m), 3.48-3.90 (8
H, m), 7.34-7.49 (6H, m), 10.30-10.70 (2H, m)

Example 22 The following compounds were prepared in the same manner as in Example 1. 2- [4- [2- (pyridin-2-yl) aminoethyl] phenyl] amino-2-thiazoline trihydrochloride NMR (DMSO-d ₆ , δ): 3.05-3.30 (4H, m), 3.59 (2H , t, J =
7.7Hz), 3.95 (2H, t, J = 7.6Hz), 4.30-4.50 (2H, m), 7.3
0-7.51 (5H, m), 7.61 (1H, d, J = 7.7Hz), 7.94 (1H, dt, J =
1.0 and 7.7Hz), 8.66 (1H, d, J = 4.8Hz), 9.65 (2H, b
r), 10.10 (1H, br), 12.48 (1H, br)

Example 23 The following compounds were prepared in the same manner as in Example 4. 2- [4- (2-aminoethyl) phenyl] amino-
5,6-dihydro-4H-1,3-thiazine dihydrochloride mp: 275-276 ° C. IR (nujol): 1610 cm ⁻¹ NMR (DMSO-d ₆ , δ): 2.05-2.12 (2H, m), 2.90-3.15 (4
H, m), 3.25 (2H, t, J = 5.8Hz), 3.39-3.46 (2H, m), 7.26
(2H, d, J = 8.3Hz), 7.39 (2H, d, J = 8.3Hz), 8.25 (2H, br
s), 9.93 (1H, br s), 11.61 (1H, br s)

Example 24 The following compounds were prepared in the same manner as in Example 14. 2- [4- [2- (5,6-dihydro-4H-1,3-
Thiazin-2-yl) aminoethyl] phenyl] amino-5,6-dihydro-4H-1,3-thiazine dihydrochloride NMR (DMSO-d ₆ , δ): 1.85-2.20 (4H, m), 2.89 ( 2H, t, J =
(7.3Hz), 3.17-3.28 (4H, m), 3.35-3.55 (4H, m), 3.55-3.
70 (2H, m), 7.25 (2H, d, J = 8.3Hz), 7.42 (2H, d, J = 8.3H
z), 9.68 (1H, t, J = 5.9Hz), 9.98 (1H, br s), 10.31 (1H,
br s), 11.65 (1H, br s)

Example 25 The following compounds were prepared in the same manner as in Example 17. 2- [4- [2-[(amino) (2-thiophenyl) methylene] aminoethyl] phenyl] amino-2-thiazoline mp: 57-58 ° C IR (nujol): 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 2.76 (2H, t, J = 7.6Hz), 3.17-3.36
(4H, m), 3.85-4.00 (2H, m), 6.33 (1H, br), 7.02 (1H, d
d, J = 3.6 and 5.1Hz), 7.15 (2H, d, J = 8.4Hz), 7.33
(2H, br), 7.46 (1H, dd, J = 1.0 and 5.1Hz), 7.52 (1H,
(dd, J = 1.0 and 3.6Hz)

Example 26 The following compound was prepared in the same manner as in Example 18. 4- [4-[(2-thiazolin-2-yl) amino] phenyl] butyric acid salt mp: 45-50 ° C. IR (nujol): 3300, 1730, 1630 cm ⁻¹ NMR (DMSO-d ₆ , δ) : 1.72-1.88 (2H, m), 2.24 (2H, t, J =
7.2Hz), 2.62 (2H, t, J = 7.5Hz), 3.59 (2H, t, J = 7.4Hz),
3.96 (2H, t, J = 7.4Hz), 7.25-7.34 (4H, m), 10.15 (1H, b
r), 12.67 (1H, br)

Example 27 The following compounds were prepared in the same manner as in Example 16. 2- [4- [2- (2-imidazolin-2-yl) aminoethyl] phenyl] amino-2-thiazoline NMR (DMSO-d ₆ , δ): 2.68 (2H, t, J = 7.8Hz), 3.23 -3.30
(4H, m), 3.51 (4H, s), 3.90 (2H, br), 7.12 (2H, d, J = 8.
4Hz), 7.36 (2H, br)

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/425 ADT A61K 31/425 ADT AED AED AGZ AGZ 31/44 ADD 31/44 ADD 31/47 ABN 31/47 ABN 31 / 505 ACL 31/505 ACL 31/54 ACD 31/54 ACD C07D 279/06 C07D 279/06 417/12 207 417/12 207 213 213 217 217 239 239 249 249 277 277 // C07D 295/12 295/12 Z 295/18 295/18 A

Claims (1)

[Claims] (1) Formula (1) Wherein R ¹ is amino, di-lower alkylamino, heterocyclic amino, heterocyclic lower alkylamino, ar-lower alkylamino, 2-lower alkylisothioureido, acylamino, hydrazino, arylamino, diaminomethyleneamino, [( Amino) (2-thienyl) methylene] amino, optionally substituted aryl, lower alkoxy,
Optionally protected carboxy or (optionally protected carboxy) (optionally protected amino)
X is CO, O or (CH ₂ ) _a (a is 0 or 1), m and n are each 0 to 3, and q is 2 or 3. And a pharmaceutically acceptable salt thereof.