JPS63179872A - Novel compound, manufacture and medicinal composition - 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 (Industrial Application Field) The present invention relates to a group of novel heterocyclic compounds having α2-7 drenocebuta monoantagonistic GH, to methods for producing these compounds, and to pharmaceutical compositions containing these compounds. Furthermore, it relates to the use of these compounds and compositions in medicine.

[Conventional technology]

GB Publication No. 2021100A MfJv and European Patent Publication No. 0.072,954 disclose heterocyclic compounds which are described as having persistent antihypertensive activity.

[Summary of the invention]

A new group of heterocyclic compounds has been found which is structurally different from the compounds described in GB 2021100A and EP 0.072,954. The novel heterocyclic compounds surprisingly exhibit good α2-adrenoceptor antagonistic activity and they are therefore useful in the treatment and/or prevention of hyperglycemia and/or glaucoma and/or of hypertension and/or depression. Potential uses include therapy and/or prevention of platelet aggregation.

Therefore, the present invention provides formula (1) [wherein 2 represents a substituted or unsubstituted aryl group residue; AI represents a substituted or unsubstituted methylene group or a substituted or unsubstituted ethylene group; A2 represents a substituted or represents an unsubstituted methylene group or a substituted or unsubstituted ethylene group; however, at least one AI or Al represents a substituted methylene group or a substituted ethylene group; X is O or NRO (in the formula, go is a hydrogen atom, a substituted or represents an unsubstituted alkyl group, a substituted or unsubstituted 7-aryl group, an alkanoyl group substituted or unsubstituted with an alkyl moiety, or an arylalkyl moiety substituted or unsubstituted with an aryl moiety; p is an integer 2 or 3; and q represents an integer ranging from 1 to 12] or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof.

Suitably z#i represents the residue of a substituted or unsubstituted aryl group containing a single or fused 5- or 6-membered ring, such as phenyl, naphthyl, anthracyl or a 7-enanthrenyl group.

Preferably 2 represents the residue of a substituted or unsubstituted phenyl or naphthyl group.

Preferably 2 represents a substituted or unsubstituted phenyl group residue.

Suitably AI or Al represents a substituted or unsubstituted methylene group.

In one preferred form of the invention A1 represents a substituted methylene group and As represents an unsubstituted methylene group.

Suitable optional substituents on any aryl group or moiety include halogen, alkyl, alkenyl, alkynyl, phenyl, haloalkyl, hydroxyl, alkoxy, arylalkyloxy, amino, mono- and di-alkylamino, aminoalkyl, mono- and di-alkylaminoalkyl, nitro, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkylcarbonyl or the moiety SO! NR8Rt(
In the formula, R8 and Rt each independently represent hydrogen or alkyl, or RI' and gt form a saturated 5- or 6-membered ring with the nitrogen to which they are bonded.
It contains up to 5 groups, preferably up to 3 groups selected from the following.

Suitable optional substituents on any alkyl, alkenyl or alkynyl group, moiety include those described above with respect to an alkyl group.

The aforementioned substituents of aryl groups and aryl moieties include those substituents of aryl groups in which 2 represents a residue; A1
or the 7-aryl group substituent and aryl moiety of A2 are A1
or form an aralkyl substituent of A2; the aryl group is represented by Ha; and the aryl moiety is RO
It will be understood that they form part of other groups represented by.

The above-mentioned substituents of the alkyl, alkenyl or alkynyl groups include the alkyl, alkenyl or alkynyl substituents of A1 or A2; the substituents of these alkyl groups represented by RO and the substituents of these alkyl moieties are R
It will be understood that it forms part of other groups represented by O.

A preferred substituent for 2 is a halogen atom, especially a fluorine atom or a chlorine atom.

Appropriate substituents for Al or A2 include up to 4 groups selected from substituted or unsubstituted alkyl; substituted or unsubstituted fulkenyl; substituted or unsubstituted fulkynyl; substituted or unsubstituted 7-aryl or aralkyl. include.

Suitable substituents for AI or A2 include alkyl, substituted or unsubstituted phenyl or benzyl.

Preferred substituents for Al or A2 are alkyl special KC1
-6 alkyl and especially 11CC+ -4 alkyl such as methyl, ethyl or iso-propyl.

Preferred substituents for Al or A2 are phenyl groups or suitably halogen atoms in % fluorine or chlorine atoms, alkyl groups especially C1-6 alkyl groups and especially 01-4 alkyl groups such as methyl groups, flukoxy groups especially C1-6 - a substituted phenyl group substituted (by a flukoxy group and especially a KCI-4C1-6 alkoxy group).

A preferred substituent for A1 or At is a beyzyl group.

Suitably X represents NR6.

Suitably RO represents hydrogen, alkyl or alkanoyl.

Preferably Ho represents hydrogen.

Suitably q represents an integer ranging from 1 to 6.

In one aspect, the aA of the present invention has a formula (II) that falls entirely within the scope of formula (1) (II) (where z, x, p and q are the same as defined for formula (1), L R and R1 is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted fulkenyl, substituted or unsubstituted fulkynyl, substituted or unsubstituted 7aryl, or substituted or unsubstituted alkyl with an aryl moiety; or a pharmaceutically acceptable salt, ester or ester thereof, or a pharmaceutically acceptable solvate thereof.

Suitably R and R1 each independently represent hydrogen. □- Suitably R and R1 each independently represent hydrogen, alkyl or substituted or unsubstituted 7-aryl, provided that 1 of R and R1
Only these represent hydrogen.

Preferably R and R1 each independently represent hydrogen, alkyl, substituted or unsubstituted phenyl or benzyl, provided that only one of R and Ht represents hydrogen.

Preferably aRl represents hydrogen.

When R or R1 represents an alkyl group, it is preferably an unsubstituted alkyl group, in particular an unsubstituted C1-6 alkyl group such as methyl, ethyl or propyl.

A preferred aryl group represented by R or R1 is a substituted or unsubstituted phenyl group.

A preferred aralkyl group represented by R or R1 is a benzyl group.

Preferably R represents alkyl, especially C1-6 alkyl and especially O1-4 alkyl, such as methyl, ethyl or propyl, and R1 represents hydrogen.

An example of a propyl group is an iso-propyl group.

Preferably R represents phenyl or substituted phenyl and R1 represents hydrogen.

Preferably R represents a benzyl group and R1 represents hydrogen.

In particular, therefore, R represents alkyl, a substituted or unsubstituted phenyl or benzyl group and R1 represents hydrogen.

Suitable substituents for R and R1 include halogen, hydroxyl,
Alkyl, alkoxy, carboxy, alpoxycarbonyl, aminocarbonyl, mono- and di-alkylaminocarbonyl or groups SO! In the NHRC formula, R represents alkyl).

Preferably R or R1 is independently hydrogen y C1-6 alkyl, especially methyl, ethyl or propyl; phenyl; halophenyl, especially chlorophenyl or hafluorophenyl; alkylphenyl %KC1-6 alk/l/7 Phenyl; alkoxyphenyl especially 0
1 to 6 alkoxyphenyl, such as methoxyphenyl or benzyl, with only one R1 and R20 representing hydrogen.

Therefore, in particular, R is C1-6 alkyl, especially methyl, ethyl or hapropyl; phenyl; chlorophenyl or hafluorophenyl in halophenyl/L/%; alkylphenyl, especially 0
1-6 alkyl phenyl e.g. methylphenyl; alkoxyphenyl% K C1-6 al:ff xy7:
r-=yv Examples Evamethoxyphenyl or habenzyl and R1 represents hydrogen.

Most preferably R or R1 are independently hydrogen; methyl; ethyl; furovir; phenyl; monochlorophenyl, especially 3
-Also u4-chlorophenyl; monofluorophenyl% 4-fluorophenyl; monoalkylphenyl, especially mono C+~6-furkylphenyl, e.g. 4-methylphenyl; monoalkoxyphenyl, especially mono C3-6-alkoxyphenyl, e.g. -Methoxyphenyl or benzyl.

Therefore, in particular, R is hydrogen; methyl; ethyl; propyl; phenyl; monochlorophenyl%, 3- or 1d4-chlorophenyl; monofluorophenyl, especially di-4-fluorophenyl; monoalkylphenyl, especially mono-01-6 alkyl phenyl, e.g. 4-Methylphenyl; monoalkoxyphenyl, especially 27-01-6-alkoxyphenyl, for example 4-methoxyphenyl or benzyl, and R1
represents hydrogen.

In a particularly preferred embodiment R represents methyl, ethyl or isopropyl, especially methyl or ethyl and R1 represents hydrogen.

In particularly preferred embodiments, R is phenyl, 4-fluorophenyl, 3-chlorophenyl, 4-/lorophenyl,
4-methylphenyl, 4-methoxyphenyl or benzyl, and R1 represents hydrogen.

In the most preferred embodiment R represents methyl or ethyl and R1 represents hydrogen.

Preferably X represents NH.

Preferably p represents the integer 2.

Preferably q represents the integer 1.

The invention particularly relates to formula (III) (l) falling within the scope of formula (1).
it) (wherein R, R'', X, p and q are the same as above, and R1 and R3 are each independently hydrogen, alkyl, amino, mononu is di-alkylamino, hydroxyl, alkoxy, carboxy or halogen or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof.

Suitably R2 or R3 independently represents hydrogen or halogen.

Suitably R2 represents halogen, especially fluorine or chlorine.

Suitably R3 represents hydrogen.

Preferably R1 represents halogen, especially fluorine or chlorine, and R3 represents hydrogen.

In another preferred embodiment R2 and R3 both represent hydrogen.

Certain of the compounds of the present invention may exist in one or more stereoisomeric forms. The present invention encompasses all such isomeric forms, either free of other isomers or mixed with any other isomers in any proportion, and thus includes racemic mixtures of tonal isomers. .

Suitable pharmaceutically acceptable salts of compounds of formula (1) include acid addition salts, salts of carboxy groups and salts of hydroxyl groups, especially acid addition salts.

Suitable pharmaceutically acceptable acid addition salts of compound (1) include pharmaceutically acceptable inorganic salts such as sulfates and nitrates.

sinate, phosphate, hydrochloride and hydrobromide, as well as pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate. salt, ascorbate, methanesulfonate, α-ketogel tarrate, α-glycerophosphate, glucose-
Contains 1-phosphate. Preferably the acid addition salts are hemisuccinates, hydrochlorides, alpha-geltarates, alpha-glycerophosphates or hydrochlorides including glucose-1-phosphate, particularly the dihydrochloride.

Suitable pharmaceutically acceptable salts of the carboxy group include metal salts such as aluminum, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted anthonium salts such as lower alkyl amines such as triethylamine, Hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri(2-hydroxyethyl)-amine, cycloalkylamines such as those with bicyclohexylamine or procaine, dibenzylpiperidine, N -Benzyl-
β-7 enetelamine, tehydroabiethylamine, N
, N'-bisdehydroabiethylamine, glucamine,
Includes N-methylglucamine or pyridine type bases such as pyridine, collidine or quinoline.

Suitable pharmaceutically acceptable salts of hydrosil groups include metal salts, especially alkali metal salts such as IJum and potassium salts.

Suitable pharmaceutically acceptable esters of compounds of formula (1) include esters of carboxy and hydroxyl groups.

Preferred pharmaceutically acceptable esters are in vivo hydrolyzable esters of carboxy and hydroxyl groups.

Examples of suitable in vivo hydrolyzable esters of carboxyl groups include those that readily decompose in the human body to leave the parent acid or its salt. A suitable ester group of this type has the subformula (1)
, (I+) and cm)-co wing CH-0,CO,R
b(1) d -CChR-N (if) He -CO2α! 0Rf(iff) (wherein R1 is hydrogen, methyl or phenyl, Rb1
dCt~6 alkyl, C1-6 alkoxy or phenyl; or R'' and Rb together represent a 1,2-phenylene group optionally substituted with 1 or 2 methoxy groups; forming; He represents InC1-S alkylene optionally substituted with methyl or ethyl groups; Rd and R@ independently represent 01-6 fulgyl; R'#i01-6
(representing alkyl).

Examples of suitable in vivo hydrolyzable ester groups are, for example, acyloxyalkyl groups such as dimethyl in acetate, pivaloyloxy-methyl, α-acetoxyethyl and α-
pivaloyloxyether group; alkoxycarbonyloxyalkyl group examples eba-ethoxycarbonyloxymethyl and α-ethoxycarbonyloxyethyl; dialkylaminoalkyl especially di-lower alkylaminoalkyl group such as dimethylaminomethyl, dimethylaminoethyl, diethylaminemethyl or diethylaminoethyl and lactone groups such as phthalidyl and dimethoxyphthalidyl.

Suitable in vivo hydrolyzable esters of hydroxyl groups include those provided by 01-6 alkyl carboxylic acids.

A suitable pharmaceutically acceptable amide has the formula -〇〇, NR'Rt
(In the formula, R8 and Ht are each independently hydrogen or 01
~6 alkyl; or R8 and Rt together with the nitrogen to which they are attached represent a saturated 5- or 6-membered ring).

Suitable pharmaceutically acceptable solvates include hydrates.

The term "halogen" as used herein relates to fluorine, chlorine, bromine and iodine, preferably chlorine.

As used herein, the term "in vivo hydrolyzable ester" refers to an in vivo hydrolyzable ester that is easily degraded in the human or non-human animal body, e.g. With respect to in vivo hydrolysable esters that leave groups or salts thereof, such as hydroxyl groups, it relates to pharmaceutically acceptable esters that leave free hydroxyl groups or salts thereof.

As used herein, the terms "alkyl,""alkenyl,""alkynyl or Hralkoxy" relate to groups with straight or branched chains containing up to 12 carbon atoms.

Suitable alkyl groups are C1-1! Alkyl group special KCI~6
Alkyl groups are, for example, methyl, ethyl% n-propyl, iso-propyl, n-butyl, isobutyl or tertiary-butyl groups.

Suitable alkenyl groups are 02-12 groups, especially Cm-6 alkenyl groups.

The suitable alkynyl group is C! ~1 qualkynyl group, especially Cm
~6 fulkynyl group.

The present invention provides a method for producing a compound of Wenmu (1) or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof, which method comprises the formula CF/) I (It/ ) [In the formula, Z e A" e A" *p and q are the formula (1
), where Xi is 0 or NH
and Y represents ORg (wherein Hg is hydrogen or a hydrosilicyl protecting group) or -NHRh (wherein Rh represents hydrogen or a nitrogen protecting group); provided that when Xl is O, Y is ORg and Xl is NH
where Y is NHRh]; and then, if necessary, any of the following optional steps of 1 m or more: (1) removing any protecting groups; (II) compound of formula (1); (111) converting the compound of formula (1) into a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof; Including doing.

Preferably ah represents hydrogen.

The compound of formula (It/) is a compound of formula (V) (V) [wherein Z e A' a A'' and q are as defined for formula (]), and Xl is CN or C (hR
'C in which R4 represents hydrogen or an alkyl group)] and a compound of formula (M) HEN (CHz )p-Y (M) where p is defined with respect to formula (1) and Y is -C(
When hR', ORg t-represents and Y is Xl is C
When N represents -NRh).

Preferably Y represents -NRh as defined above and X8 represents CN.

A compound of formula (V) is a compound of formula (■) in which Z , AI and A3 are the same as defined in relation to formula (1) and HX represents a leaving group) and a compound of formula (W) HEN ( CH, )(! sell.

Suitably HX represents a halogen atom, preferably a chlorine or a bromine atom, especially a bromine atom.

Compounds of formula (M) and (M) are either well known commercially available compounds or can be made using methods analogous to those for making such compounds.

Compounds of formula (■) are known compounds or may be prepared using methods analogous to those used to prepare known compounds, or may be prepared using methods analogous to those used to prepare known compounds, such as the
lv-Chim-Acta) J 1977.60°28
72, rJ, Chem, Sosa, Parkin (Chsm, So
c.

Perkin) I J1972, 2732 and “Bull, Soc, Chl
M, France) J1953.321 is used.

Cyclization of compounds of formula (IV) may be carried out under any suitable conditions using any suitable solvent system and temperature range (usually elevated temperature).

Preferably, for compounds of formula (1) in which X represents O, the compound of formula (mV
) is carried out in the presence of a dehydrating agent such as phosphoryl chloride. Conveniently, the reaction is carried out in toluene or any other suitable solvent, preferably at the reflux temperature of the chosen solvent.

In the preparation of compounds of formula (1), suitably where It is converted to the compound (1).

For the preparation of compounds of formula (1), where X preferably represents -NR(+), suitable compounds of formula (V) and formula (M) are prepared in any suitable solvent preferably within the range of 80°C to 130°C. is 11
are allowed to react with each other at elevated temperatures such as 0°C; the reaction is preferably carried out using the formula (V[)
using a suitable compound; preferably the reaction is carried out under an atmosphere of nitrogen. The compound of formula (IV) initially formed under the conditions described above undergoes cyclization to yield the compound of formula (1).

Accordingly, in another aspect, the invention provides a method for preparing compounds of formula (1) in which X represents NRO, the method comprising
is CN′f: the compound of the above formula (V) and Y is NR
' and then, if necessary, la! Any of the following steps described above: (1) Step of removing any protecting group; (11) Step of converting the compound of formula (1) to another compound of formula (1); (iii) Step of converting the compound of formula (1) to another compound of formula (1); The method includes converting the compound into its rA-compatible salt, ester, or amide, or its pharmaceutically acceptable solvate.

The reaction between compounds of formula (Vll) and (■) is conveniently carried out in an afrotic solvent such as dimethylformamide, preferably at a temperature between 20°C and ω°C; conventional monitoring techniques will determine whether the reaction is suitable. The reaction continues until it indicates completion.

Suitable hydroxyl and nitrogen protecting groups are those conventionally used by those skilled in the art; for example, a suitable hydroxyl protecting group is the benzyl group.

A preferred nitrogen protecting group is the moiety R6 defined for K in formula (1) but containing no hydrogen.

Compounds of formula () can be converted to other compounds of formula (1) using any suitable conventional method, for example compounds where Ro is hydrogen, can be converted to other compounds of formula (1) using any suitable conventional method, such as compounds in which Ro is hydrogen, by conventional alkylation, arylation, flukylation or aralkylation. may be converted to compounds in which R0 is other than hydrogen. Similarly, the formula (
The compound 1) can be converted to R' by a conventional dealkylation, dealylation, dealkanoylation or dealaryl-alkanoylation method.
may be converted to a compound of formula (1) where is hydrogen.

Salts, esters, amides and solvates of compounds of formula (1) are prepared using any suitable conventional method that is compatible with the properties of the salts, esters, amides or solvates and compounds of formula (1). It can be done.

Any individual isomer of the compound of formula (1) or its pharmaceutically acceptable salt, ester or amide or pharmaceutically acceptable solvate thereof may be prepared using any suitable well-known method. For example, any mixture of enantiomers can be separated into individual stereoisomers by using an optically active acid as a resolving agent. Suitable optically active acids that can be used as resolving agents are described in Topics in Stereochemistry.
emistry ) J Volume 6.

Wiley Interscience, 1971, Allinger (AAl11n@r) N, L. and Ellel W.L., eds. If appropriate, the compounds of formula (1) may be separated into the enantiomers of the diastereomeric combination, for example by fractional crystallization from a suitable solvent such as methanol, ethyl acetate or mixtures thereof.

Any necessary enantiomer of the compound of Wenmu (1) or its pharmaceutically acceptable salt, ester or amide or its pharmaceutically acceptable solvate is obtained using optically pure raw materials of known configuration. It can be obtained by conventional stereospecific synthesis.

The absolute stereochemistry of any compound of formula (1) or its substrate may be determined by conventional methods such as X-ray crystallography.

The present invention also provides a compound of formula (1) or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof for use as an active therapeutic substance.

The present invention provides a compound of formula (1) or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof for use in the treatment and/or prevention of hyperglycemia.

In another aspect, the invention also provides a compound of formula (1) or a pharmaceutically acceptable salt, ester or Amides or pharmaceutically acceptable solvates thereof are provided.

In another aspect, the invention provides a compound of formula (1) or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof for use in the treatment of hypertension.

A compound of formula () or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof may be administered as such or preferably in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. It can be administered as a substance.

Accordingly, the present invention provides a pharmaceutical composition comprising a compound of Wenwu (l) or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof and a pharmaceutically acceptable carrier therefor. .

As used herein, the term "pharmaceutically acceptable" includes compounds, compositions and components used for both human and veterinary uses; for example, the term "pharmaceutically acceptable salts" includes veterinary pharmaceutically acceptable salts. Contains acceptable salt.

The compositions may, if desired, be in the form of a pack containing a handwritten or printed insert for use.

Generally, the pharmaceutical compositions of the invention will be adapted for oral administration, but other routes such as injection, administration by skin absorption, and compositions for topical application to the eye, particularly for the treatment and/or prevention of glaucoma, are also contemplated.

Compositions particularly suitable for oral administration are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as powders presented in packs, may also be used.

In accordance with conventional pharmaceutical practice, the carrier comprises diluents, fillers, disintegrants, wetting agents, lubricants, colorants, flavoring agents or other conventional additives.

Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycolate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate,
Contains sodium lauryl sulfate or sandate.

Most suitably, the composition will be formulated in unit dosage form. Such unit doses are usually between 0.1 and 1000j9, more usually between 0.1 and 500, and even more particularly between 0.1 and 2.
It will contain an amount of active ingredient within the range of 50 μm.

As mentioned above regarding the treatment and/or prevention of glaucoma,
A compound of 1) or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof may also be administered as a topical formulation with conventional topical additives. Such formulations could of course be suitably adapted for ocular administration.

The topical formulations of the present invention may be provided, for example, as eye ointments, creams or lotions or eye drops or other conventional formulations suitable for administration to the eye and include suitable conventional additives, such as preservatives, solvents to aid penetration of the drug. and emollients V in ointments and creams. The formulations may also include compatible conventional carriers such as eye ointments, creams or lotions and solvents suitable for ocular administration. Such carriers have approximately 20
It can be provided as a formulation of ~99.5%.

Suitable eye ointments, creams or lotions, eye drops or other conventional formulations suitable for administration to the eye are described, for example, in standard textbooks of pharmacology and cosmetology, such as by Leonard Hill 11 Books. "Harry's O Cosmeticology"(Harry's O Cosmeticology) published by
ry's Cogmeticology) J + r
Remington's Pharmaceutica A/@Sciences (Remington's Pharmaceuti
CalScleneeg) J and is a conventional formulation well known to those skilled in the art as described in the British and US Pharmacopoeia.

Suitably the compound of formula () or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof is about 0.5 to 20% by weight, preferably about 1 to 10%.
%, for example, 2-5% of the formulation.

The present invention further provides human or non-human t9. Provided is a method for the treatment and/or prevention of hyperglycemia in mammals, which comprises administering an effective and non-toxic amount of a compound of general formula (1) or a pharmaceutically acceptable dose thereof to a human or non-human mammal in need thereof. Uru salt,
ester or amide or solvate thereof.

The present invention further provides a method for the treatment of hypertension in humans or non-human mammals, which comprises an effective and non-toxic amount of a compound of general formula () or a pharmaceutical preparation thereof for humans or non-human mammals in need thereof. or a pharmaceutically acceptable solvate thereof.

The present invention also provides a method for the treatment and/or prevention of glaucoma and/or the treatment of depression and/or inhibition of platelet aggregation in a human or non-human mammal, which method may be used in a human or non-human mammal in need thereof. Other methods include administering to a mammal an effective and non-toxic amount of a compound of formula (1), or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof.

Conveniently the active ingredient is administered as a pharmaceutical composition as described above and this forms a particular aspect of the invention.

For the treatment and/or prevention of hyperglycemia in humans or the treatment of hypertension in humans, the compound of formula (1) or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof may be used. The total daily dose for an adult of 70 kg, taken from 1 to 6 times a day, with dosages such as those described above, is generally from 0.1 to 6000 rn9 and more usually from 1 to 150 rn.
It will be in the 0mg range.

For the treatment and/or prevention of hyperglycemia in non-human mammals, especially dogs, the active ingredient is usually administered once or twice a day and at approximately
．． 025■/kg~25■/Icy e.g. 0.1~/
It may be administered orally in an amount ranging from ky -20 /Icy.

In the treatment and/or prevention of glaucoma in humans or non-human mammals (non-topical formulations) and in the treatment of depression and inhibition of platelet aggregation, the formulation for administration is in humans or non-human mammals with hyperglycemia. This is the general information mentioned above regarding treatment and/or prevention.

The present invention also provides a compound of formula (1) or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of hyperglycemia and/or the treatment of hypertension. The present invention provides uses for water-soluble solvates.

The present invention further provides a compound of formula (1) or a pharmaceutically acceptable salt, ester or Uses of amides or pharmaceutically acceptable solvates thereof are provided.

A compound of formula (1) or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof exhibits no toxicological effects when administered in any of the aforementioned dosage ranges.

EXAMPLES The following examples illustrate, but do not limit, the invention.

A summary of embodiments of the invention is provided below.

Example 1 3.44 g (20 mM) of 2-(2H-(1-methyl-1,3-dihydroisoindole)methyl)-4,5-dihydroimidazole of 2H-(1-methyl-1,3
-dihydroisoindole)-2-acetonitrile, 1
．． A mixture of 229 (20 mM) 1,2-diaminoethane and a catalytic amount of carbon disulfide was heated at 110° C. under nitrogen for 6 hours.
heated with. The mixture was allowed to cool and solidify, and 50 at of water was added to obtain a crystalline solid, which was filtered to obtain a yellow solid. Recrystallization from ethyl acetate gave the title compound as a white solid. m, P, 121-125°G (decomposition)
.

7.3-7.1 (4H, m), 5.2-4.8 (IH,
Broad m a D! OK exchange), 4.21 (II
(, dd), 3.91 (IH, (t), 3.8-3.5
(6H, m); 3.40 (IH, d) tl, 41 (3)
i, d).

IR (KBr): 1612 crn-' Example 2 2-(2H-(1-ethy/l/-1,3-dihydroisoindole)methyl)-4,5-dihydroimidazole dihydrochloride This compound has 3.72 ．． ! i' (20mM) of 2H-(
1-ethyl-1,3-dihydroisoindole)-2-
Acetonitrile and 1.22. ! 1 of i' (20mM)
, 2-diaminoethane in a similar manner to Example 1.

The crude product obtained was dissolved in ethanol and treated with dry hydrogen chloride. The title compound crystallized from solution on cooling. m, p, 182-184°C.

'H-nmrδ (DMSO) 11\0, -10.5 (3H, exchanged by broad s + DzO); 7.5-7.2 C4'H= m) s 4
．． 7-4.6 (IH-m); 4-4-4.1 (
2H1nt) 4, 0-3-7 (6H-m) p 2-
2-1.7 (2H-m) p O-94 (3H-t
).

Example 3 2-(2H-(5-chloro-1-methyl-1,3-dihydroisoindole)methyl)-415-dihydroimidazole dihydrochloride This compound has a 3.50. ! i' (20mM) of 2H-(
5-chloro-1-methyl-1,3-dihydroisoindole)-2-acetonitrile and 1.22. ! i'(2
Prepared in a manner similar to Example 1 from 0 m'& of 1,2-diaminoethane. m, p, 152-3°C (isopropanol/ethyl acetate).

"H-nmrδ (DMSO) 10.7-10.4 (3H, replaced by broad seD*o); 7.5-7.2 (3H, m); 4.5-4
．． 0 (5H, m); 3.88 (4H, s);
1.52cau, a).

Example 4 2-(2H-(6-chloro-1-methy/I/-1,3-
dihydroisoindole)methyl) -4,5-dihydroimidazole This compound contains 2.50 JF (12 mM) of 2H-(6-
chloro-1-methyl-1,3-dihydroisoindole)-2-acetonitrile and 1. Prepared in a similar manner to Example 11c from IJF (18mM) in 1,2-diaminoethane. m, p, 158-160°C (ethyl acetate)
.

7, :(-7,0(3H,m):5.0-4.5(IH
, Bu4-dott*D*O exchange); 4.24(
IH, d); 3.95 (IH, (1); 3.7-3.5
(6H, m); 3.41 (IH#d); 1.39 (3H
#d).

Example 5 A compound with 2-(2H-(5-fluoro-1-methyl-1,3-dihydroisoindole)methyl)-4,5-dihydroimidazole is 2.11. jil (11mM) 2H-(
5-fluoro-1-methyl-C3-dihydroisoindole)-2-acetonitrile and 1. IJ (18mM)
was prepared from C2-diaminoethane in a manner similar to Example IH. m, p, 120-122°C (ethyl acetate).

'H= nmrδ (CDCl s ) 7.3-7.0 (I H-m ); 6.9-6.
8 (2H-m); 5.0-4.5 CI H broad exchanged with IhO); 4.17 (IH,
d); 3.78 (IH.

q); 3.7-3.5 (6H-nl);
3.40 (I H * d ); 1-39 (3H
*d) Filial piety.

Example 6 2-C2H-(1-C4-chloropheniA-)-1,3
-dihydroisoindole)methyl) -4,5-dihydroimidazole title compound (m, p, 167-9°C (ethyl acetate)) was prepared by a method similar to that described in Example 1.
g (38mM) of 2H-(1-(4-chloro7enyl)
-1,3-dihydroisoindole)-2-acetonitrile and 2.43. ! i' (40mM) of 1,2-diaminoethane.

"H-nmrδ (DMSO) 6.67-7.6 (8H, m); 5.0 (IH, br+
s); 4.4 (IH.

dd); 3.9 (IH, dd) and 3.35 (6H1b
rl).

Example 7 2-(2H-(1-(3-chlorophenyl)-1,3-
dihydroisoindole) methyl) -4,5-dihydroimidazole title compound (m, p, 159-160°C ethyl acetate)]
by a method similar to that described in Example 1! 014.7
, lit (54 mM) of 2H-1-(1-(3-chloropheni#)-1s3-dihydroisoindole)-2-acetonitrile and 3.41 (57 mM) of 1,2-diaminoethane.

"H" nmrδ (CDCl g) 6°65-7.45 (8H, m); 4.8 (IH, br
s); 4.55 (IH.

brseD+o exchange); 4.4 (IH, dd);
3.85 (IH.

d d ); 3.48 (2H=s) and /3
．． 4 (4H, brs).

Example 8 2-(2H-(1-(4-fluorophene/I/)-
1,3-dihydroisoindo-/I/)methyl) -4
,5-dihydroimidazole title compound [m, p, 168-169°C (ethyl acetate)
7.0 by a method similar to that described in Example 1.
g (27 crystal 0 2H-(1-(4-fluorophenyl)
1#3-dihydroisoindole)-2-acetonitrile and 1.8. ! i' (30mM) of 1,2-diaminomethane.

"H-nmr δ (DMSO) 6.65-7.55 (8H, m); 4.8 (IH, br
s); 4.5 (IH.

bra*D goose 0 exchange): 4.4 (IHld
d) s 3.9 (IH-dd); 3.45 (2
H=s) and 3.35 (4H, br+s).

Example 9 2-(2H-(1-phenyl-1,3-dihydroisoindole)methyl)-4,5-dihydroimidazole Title compound (m, p, 168-170°C (ethyl acetate)
] was prepared using a method similar to that described in Example 1.
．． 9 (15 mM) of 2H-(1-pheny#-L3-dihydroisoindole)-2-acetonitrile and 0.9
g (15mM) of 1,2-diaminoethane.

"Hnmrδ(CDCl s ) 7.4-6.6 (9H*m); 4.75 (IH
-brs) ;4.35 (IH-dd);3.8
2 (IH, dd); 3.5 (2H, !l) and 3.4 (
4H.

brs).

Example 10 2-(2H-(1-(1-methylethyl)-1,3-
dihydroisoindole comethyl) -4,5-dihydroimidazole dihydrochloride hemihydrate This compound was prepared by preparing 1-Og (5□) of 2H-(1-(1-methylethyl)) in a manner similar to Example 1. -1,3-dihydroisoindole-2-acetonitrile and 0.4m
t (7.4 mM) of 1,2-diaminoethane to yield a crude product. Chromatography on neutral alumina eluting with dichloromethane/methanol (0→3%) produced an oil. This oil was dissolved in ethanol and converted to the sinihydrochloride salt with hydrogen chloride. The ethanol was evaporated and the residue was crystallized from ethanol/ethyl acetate to give the title compound. m, p. 188-190
℃.

"H-nmrδ (DMSO) 10.2-10.0 (2H, broad signal, D20
(by υ exchange); 7.27 (4H, s); 4.7-4.3
(IH, Broad Signal, exchanged by D-O); 4.
47 (IH, d); 4.17 (IH, a); 4.00 (
I Hld); 3.6-3-4 (6H1m)
; 2.2-2.20 (I H-m); 0.93
(3H, d); 0.89 (3H, d).

Example 11 2-(2H-(1-(4-methylphenyl)-1,3-
(dihydroisoindole)methyl) -4,5-dihydroimidazole Title compound (m, p, 158-160°C (ethyl acetate)
] 1110.] by a method similar to that described in Example 1.
3,! 9 (41 mM) of 2H-(1-(4-methylphenyl)-1,3-dihydroisoindole)-2-acetonitrile and 2.7 g (45 mM) of 1,2-diaminoethane.

"H-nmrδ (D!viso + CDCl s )
6.6-7.45 (8H, m); 4.8 (IH, brs
); 4.35 (IH.

dd); 3.82 (IH9dd): 3.38
(6H-brs) and 2.3(3H+s) Example 12 2-(2H-(1-(4-methoxyphenyl)-1#3
-dihydroisoindole)methyl) -4,5-dihydroimidazole Title compound (m, p, 162-163°C (ethyl acetate)
] by a method similar to that described in Example 1.
4g (39mM) of 2H-(1-methoxyphenyl)-
Prepared from 1,3-dihydroisoindole)-2-acetonitrile and 2.6g (43mM) of 1,2-diaminoethane.

"H-nmrδ (CDCl g) 6.65-7.4 (8H, m): 4.75 (IH, s)
: 4.4 (IH, dd) 3.85 (IH, dd); 3.
8(3H,a)y3.5(2H,bra) and 3.4(
4H, brs).

Example 13 2-(2H-(1-benzyl-1,3-dihydroisoindole)methyl)-4,5-dihydroimidazole This compound (m, p, 132-134°C (ethyl acetate)
] was prepared by a method similar to that described in Example 1 to obtain 4 g (
16 mM) of 2H-(1-benzyl-1,3-dihydroisoindole)-2-acetonitrile and 1.19
(18mM) of 1,2-diaminoethane.

7.35-7.0 (9H, m); 4.25 (2H, rn
); 3.75 (IH, d) 3.55 (4H, brs);
3.4 (2H, q) and 3.05 (2H, d).

Reference Example
) was added dropwise with stirring.

After heating at reflux for 6 hours, the mixture was cooled and water resistant to 12 hours.

It was poured deeply into 12 #L/10% sodium hydroxide solution and U-water. The solution was filtered and the filtrate was dried over magnesium sulfate, filtered and evaporated to give the title compound as a colorless waxy solid.

7.4-7.0 (4H-m); 4.9 (I
H-q); 4.48 (I H-Broads)
; 3.98 (2H-broad exchanged with 5eDzO); 1.4 (3H, d).

Reference Example
44,7mM) of 1-(1-hydroxyethyl)-2-
56IILt (611 mM) of sulfur tribromide in 250 aj of diethyl ether was added dropwise to the solution of hydroxymethylbenzene with stirring while maintaining the temperature of the reaction below 30°C. After stirring at room temperature for 18 hours, the resulting solution was placed on ice/
Pour into water (500 ILt). The aqueous layer was saturated with sodium chloride and the organic layer was separated, dried and evaporated to give the title compound. b, p, 115-117℃ 10.5m
.

'I(-nmrδ(CDC15) 7.8-7.4 (IH-m) p 7.4-7.2
(3H-m) * 5.60 (IH-q); 4゜78
(1) i, d); 4.39 (IH, d); 2.05 (3
I(,d).

Reference Example x3 To a mixture of 2H-(1-methyl-1,3-dihydroisoindole)-2-acetonitrile and 4011 (1 (294 mM) of triethylamine was added 27 g (97 mM) of 1- in 100 ffiA of dry dimethylformamide. (1-bromoethyl)-2-bromomethylbenzene was added dropwise with stirring.

The reaction temperature was kept below ω°C during the addition. After stirring overnight at room temperature, the mixture was poured into 600 atm of water to remove the organic product in 3×50
Extracted with 0 d of diethyl ether. The organic layer was washed with water (x1) and saturated sodium chloride solution (x1), dried and evaporated to give the crude nitrile. Vacuum distillation gave the title compound as a pale yellow oil. b, p.

108-112℃10゜4w0"H-nmrδ (CDC
A! s) 7.4-7.0 (4H, m); 4.3-3.7 (3H,
m); 3.7B (2H.

s); 1.39 (3H,, d).

Reference Example X4 1-(1-Hydroxypropyl)-2- and dimethylbenzene. ! i' (56 mM) propiophenone-2-carboxylic acid and lithium aluminum hydride in a manner similar to Example X1 to give the title compound as an oil.

7.5-7.2 (4H-m) p 4.8-4.5
(3H-m) e 3-9-3.5 (2H, exchanged by broad 8=D!O) y 1.9-1.6 (2H-
m); 0.86 (3H, t).

Reference Example X5 1-(1-bromopropyl)-2-bromomethylbenzene This compound has 7.3. ! i' (44mM) l-(1-
The title compound was prepared from dipropyl)-2-hydroxymethylbenzene and phosphorus tribromide in a similar manner to Reference Example X2 as a pale yellow oil.

"H-nmrδ (CDCA!s) 7-5-7.1 (4H-m) s 5.31 (IH
-t) ; 4.71 (L H-d) p4.4
1 (IH=d): 2.6-2.1 (2H9
m); 1.09 (3H-t) -Reference Example X6 2H-(1-ethyl-1,3-dihydroisoindole)-2-acetonitrile This compound has 13. ! i' (44 mM) of 1-(1-bromopropyl)-z-bromomethylbenzene and 6 g of
Reference Example
The title compound was prepared in a manner similar to 3 and crystallized on cooling to give the title compound as a pale red oil.

'H-nmrδ (CDC7!s) 7.4-7.1 (4H2m); 4.24 (i
H-d) 14.2-4.0 (I H-m); 3
．． 98 (IH, d); 3.72 (2H, s); 2.0-
1.7 (2H.

m); 0.85 (3H, t).

Reference Example x7 4-Chloro-1-(1-hydroxyethyl)-2-hydroxymethylbenzene This compound has 6.0 Fi (32.8mM) of 4-
The title compound was prepared from chloro-2-formylacetophenone and lithium aluminum hydride in a manner similar to Reference Example X1 to give the title compound as a colorless oil.

7.4-71. . (3H, m): 4.95 (IHt(1
);4.68(,IH,d)4.38(IH,d);3
．． 8-3.5 (2H, broad a + Dz OK exchange); 1.45 (3) 1. t).

Reference example The title compound was prepared as an oil from (1-hydroxyethyl)-2-hydroxymethylbenzene in a manner similar to Reference Example X2.

7.5-7.1 (3H, m); 5.50 (IH, (1)
; 4.88 (IH, d) 4.56 (IH, d); 1.9
8 (3H, d).

Reference Example X9 The compound with 2H-(5-chloro-neemethyl-1,3-dihydroisoindole)-2-acetonitrile is 3.
0IC13,4mM) of 1-(1-chloride)
-2-chloromethyl-4-chlorobenzene and 2.0g
(21 mM) of aminoacetonitrile hydrochloride in a manner similar to Reference Example X3 to obtain the title compound as a crystalline solid.

7.3-7.2 (2H, m); 7.05 (IH, d);
4.18 (IH, d); 4.03 (2H* 11 )
y 3.87 (IHld) p 3.77 (IH
ld) sl, 40 (3H, d).

Reference Example XIO 2-(4-chloro-2-formylphenyl)-4,4-
Dimethyl-4,5-dihydroxazole 161 (76 mM) of 2-(4-chlorophenyl) in 60 d' dry tetrahydro7 run at -78°C under an inert atmosphere.
-1.4 M sec-butyllithium in hexane to a solution of 4,4-dimethyl-4,5-dihydroxazole 75
1111t was added dropwise. After 1 hour 20-9,7 j! in tetrahydrofuran! J of freshly distilled dimethylformamide was added and stirring was continued for 2 hours at room temperature. The mixture was poured into water (200jLt) and extracted with diethyl ether (2xlOOaj), dried and evaporated to give the crude product. Vacuum distillation (b, p, 140-1
The title compound was obtained as a pale yellow oil.

"H-nmrδ (CDCl s ) 10.78 (IH, a); 8.0-7.7 (2H, m)
;7.6-7.4(111゜);4.11(2H,s
); 1.35 (6H, 8).

Reference Example X11 0.84.9 (35
2.18 rtrt in a suspension of magnesium metal (mM)
(35 mffl) of iodomethane was added dropwise. When all the magnesium has dissolved, prepare a solution of 6.3 g (23,5 mmol) of 2- in diethyl ether of 10- at 5 °C.
(4-chloro-2-formylphenyl)-4,4-dimethyl-4,5-dihydroxazole.

After stirring overnight at room temperature, the mixture was poured with 4 C of water (200 IILt) and extracted with diethyl ether (2 x 100 aj). Drying and evaporation gave the title compound as a pale yellow oil.

”H-nmrδ(CDCl s ) 7.75 (IH, d); 7.5-7.2 (2H+m) near, 05 (IHlIhOK) crossed; 5.00 (IH,
q); 4.10 (2H, s); 1.50 (3H, d);
1.34 (6H, s).

Reference Example X12 5-Chloro-7-methylphthalide 6.39 (25 mM) of 2-
(4-chloro-2-(1-hydroxyethyl)phenyl]-4,4-dimethyl-4,5-dihydroxazole was heated at reflux in an inert atmosphere for 1.5 hours. The mixture was cooled and added with ethyl acetate. After drying and evaporating the organic extracts, the title compound was obtained as a pale yellow solid.

7-84 (I H= d) t 7.6-7-4
(2H-ni); 5-42 (I H-q)1.
60 (3H, d).

Reference Example X13 5-chloro-1-(1-hydroxyethyl)-2-human 1:I-? Dimethylbenzene This compound is 4.6,! It was prepared as an oil from 5-rioo-7-methyl 7-thallide of i+ (25triM) and lithium aluminum hydride in a manner similar to Reference Example X1.

7.38 (IH=m) near, 3-7.0 (2H1m);
4.91 (iH-q); 4.62 (IH, d); 4.3
3 (IH, d); 4.0-3.7 (2H, blow)”
s, g exchanged to DzO) sl, 40 (3H1s).

Reference example X14 1-(1-bromoethyl)-2-7' lomomethyl-5-
Chlorobenzene This compound is 4.0. F (21.4mM) was produced as an oil from 5-chloroa-1-(1-hydroxyethyl)-2-human dioxymethylbenzene and syntribromide in a manner similar to Reference Example x2. .

lH-nmrδ(CDCjls) 7.58 (IH=8); 7.4-7.1 (
2He m); 5.50 (IHs q) y4.
72 (IH, d); 4.39 (IH, d); 2.10 (
3H, d).

Reference Example X15 2H-(6-chloro-1-methyl-1,3-dihydroisoindole)-2-acetonitrile This compound is 5.
0. ! i' (16mM) of 1-(1-bromoethyl)
-2-7' methyl-5-chlorobenzene and 2.0
& (21 mM) of aminoacetonitrile hydrochloride in a manner similar to Example X3 and obtained as an oil.

"H-nmrδ(CDCl s ) 7.3-7.1 (3H-m) p 4.3-4-0
(3H1m); 3-91 (IH-d); 3.7
8 (IH, d); 1.40 (3H, d).

Reference Example
3-Methylphthalide was partially treated with 13.7.9 (19.8 mM) sodium nitrite. After stirring for 1.5 hours, 55 g (550 mM) of sodium tetrafluoroborate (501 Lt of water) were added and the mixture was left overnight at 5.degree. The acetone was carefully evaporated under reduced pressure and the resulting solid was filtered and dried under vacuum.

The obtained diazonium tetrafluoroborate was converted into 75I
Add ILt nitrogen to purged xylene and add 0.2
Heated at 130°C for 5 hours. On cooling, the mixture was treated with saturated sodium bicarbonate solution until alkaline and extracted with diethyl ether (3x50 ad).

After drying and evaporation the crude product was obtained as a dark brown oil.

Chromatography on silica gel eluting with dichloromethane gave the title compound as a low melting solid.

"H-nmr δ (CDCA's) 7.7-7.3
(3H1m); 5.64 (IH-q); 1.72 (
3H-d) Reference Example X17 4-Fluoro-1-(1-hydroxyethyl)-2- and dimethylbenzene. It was produced in a similar manner to Reference Example X1 and was obtained as a yellow oil.

"H-nmrδ (CDCA!s) 7.5-7.2 (IH-m): 7.1-6.9
(2H-m); 4.95 (IHlq); 4.65
(IH, d); 4.40 (IH, d); 3.9-3.6
(2H.

Broad s + replaced by D20); 1.42 (3H
, d).

Reference example X18 1-(1-bromoethyl)-2-7'romometyl-4-
Fluorobenzene This compound was prepared from 7.517 (544 mM) of 4-fluoro-1-(1-hydroxyethyl)-2-hydroxymethylbenzene and phosphorus tribromide in a manner similar to Reference Example Obtained as a crystallizing oil.

7.8-7.4 (I H-rn); 7.3-6
．． 8 (2H-m) p 5.56 (I H-q)
; 4.75 (IH, d); 4.40 (IH, d); 2.
10(3H,d) Reference Example X19 2H-(5-fluoro-1-methyl-1,3-dihydroisoindole)-2-acetonitrile This compound is 9
．． 3g (31.4mM) of 1-(1-bromoethyl)
-2-bromomethyl-4-fluorobenzene and 3.0
g (32.4 mM) of aminoacetonitrile hydrochloride in a manner similar to Reference Example X3 and obtained as a pale yellow oil.

7.3-6.9 (3H, m): 4.3-3.8
(3H, m); 3.80 (2H.

i); 1.35 (3H-d).

Reference example Heat to reflux. The mixture was evaporated and the residue was transferred to dichloromethane and washed permanently with aqueous sodium bicarbonate. Dry and evaporate the dichloromethane. The residue was reduced with lithium aluminum hydrogen/lide in a manner similar to that described in Reference Example XI to give the title compound.

7.22 (8H, m); 5.72 (IH, s); 4.3
5 (4H, brs.

2H, D! (replaced by O).

Reference Example
8.9 (0,11M) α-(4-chlorophenyl)-
The solution of 1,2-benzenedimetatool was bubbled through.

After stirring for 12 hours at room temperature, the mixture was evaporated to dry beans to give the title compound.

"Hnmrδ (CDCJ 7.3 (8H, m); 6.72 (IH, g) and 4.
56 (2H, (1).

Reference Example X22 2H-(1-(4-chlorophenyl)-1,3-dihydroisoindole)-2-acetonitrile The title compound was prepared as 37.
3F (0,1M) α-(2-bromomethylphenyl)-4-chlorophenylmethylbromide, 13.82 g
(0,15M) of aminoacetonitrile hydrochloride and 4
214 (0.3M) of triethylamine.

5Hnmr δ (CDCIm) 6.68-7
．． 53 (8H, m), 4.92 (IH, bra), 4.
2 (2H.

m) and 3.8 (2H, (1).

Reference Example X23 α-(3-chlorophenyl)-1,2-benzenedimetatool
4M) of 2-(3-chlorobenzoyl)benzoic acid was bubbled through the solution. The mixture was then stirred for 12 hours at room temperature. The mixture was evaporated and the residue was transferred to dichloromethane and washed with an aqueous solution of IJ (permanently bicarbonated). Dichloromethane was evaporated off the dry beans. The residue was reduced with lithium aluminum hydride in a manner similar to that described in Example XIK.

7.18 (8H, m); 5.75 (IH, s); 4.3
5 (exchanged for 4H, bray2H, D*O).

Reference Example
! i' (84mM) of α-(3-chlorophenyl)-1
, 2-benzene methanol solution.9. n at room temperature
After stirring for an hour the mixture was evaporated to dry beans to give the title compound.

] Wy Town J (CDCJl 7.4 (8H, m); 6.65 (IH, a) and 4.5
3 (2H, Q).

Reference example
(74.8mM) of α-(2-bromomethylphenyl)-3-chlorophenylmethylfuromide, 11.5. l
i' (0,12mM) of aminoacetonitrile hydrochloride and 34.5! Prepared from ILt (0.25M) triethylamine.

"Hnmrδ(CDc- 6,68-7,63(8H,m); 4.85(IH,b
rs); 4.25 (2H*m) and 3.62 (2H,b
rs).

Reference Example X26 α-(4-Fluorophenyl)-1,2-benzenedimetatool
The solution of 4-fluorobenzoyl)benzoic acid was bubbled through.

The mixture was then stirred for 12 hours at room temperature, the mixture was evaporated and the residue was transferred to dichloromethane and washed permanently with aqueous sodium bicarbonate solution.

Dichloromethane was evaporated off the dry beans. The residue in ether was reduced with 5.6 g of lithium borohydride under nitrogen gas. The ether was evaporated and the residue was partitioned between water and dichloromethane. Evaporation of dichloromethane from dry beans affords the title compound.
) 6.7-7.32 (8Hem); 5.82 (IHsbr
s) and 4.3 (2H.

bra).

Reference example O40,9
α-(4-fluorophenyl)-1 of (0,17M)
, 2-benzenedimetatool and 4011t (0,42
M) was produced from tribromide.

"Hnmrδ (CDC) 3) 6.78-7.7 (8H, m); 6.83 (IH,
s ) and 4.5 (2H, (1) Reference Example X28 2H-(1-(4-fluorophenyl)-1,3-dihydroisoindole)-2-acetonitrile The title compound was described in Reference Example X3 In the same way as 52
．． 2. α-(2-bromomethylphenyl)-4-fluorophenylmethylbromide of S'(0,16M), 1
6. Aminoacetonitrile hydrochloride of B (0,17M) and 62IL7! (0.44M) of triethylamine.

6.7-7.55 (8H, m); 4.9 (IH, bra
): 4.2 (2H, m) and 3.62 (2H, bra)
.

Reference example 17.4F (51 mM) of α-(2-prosomethylphenyl)phenylmethylbromide, 7. IJ (76
0 aminoacetonitrile hydrochloride and 21.5jll
j (154mM) of triethylamine.

'Hnmrδ(CDCl5) 7.4-6.6 (9H, m); 4.85 (IH,
br 8 ); 4.25 (2H.

m) and 3.68 (2H, s).

Reference Example X30 1-(1-methylethyl)phthalide 200#! A mixture of 4g (22.9mM) of 1-(1-methylethynyl)7thallide and 50g of Adam's catalyst in ethanol of J was hydrogenated at atmospheric pressure.

After consuming the required amount of hydrogen, the mixture was filtered and evaporated to give the title compound as a pale yellow oil.

"H-nmrδ (CDCl s ) 8.0-7.4 (4H, m); 5.40 (IH, d);
2.5-7.1 (IH.

nl); 1.10 (3Hed); 0.81 (3H*d)
- Reference Example X31 1-Hydroxymethyl-2-(1-hydroxy-2-methylpropyl)benzene This compound has 3.9. ! i' (22mM) of 1-(1-
It was prepared as an oil from methyl ethyl) phthalide and lithium aluminum hydride in a manner similar to Reference Example Xl.

1-nmrδ (CDCl s ) 7.5-7.0 (4H, m); 4.48 (2Hta);
4.33 (IH, d) 4.0-3.5 (2H, broad singlet, exchanged for D20); 2.3-1-8
(I H-rn); 1.05 (3H-d)
tO,68(3Htd) -Reference Example X32 1-Bromomethyl-2-(l-bromo2-methylpropyl)benzene This compound has 3.5! i' (19,4 m' night) of 1-hydroxymethy/l/-2-(1-hydroxy-2
-Methylpropyl)benzene and silicon tribromide in a manner similar to Reference Example X2 and obtained as an oil.

'H-nmrδ (CDC1js) 7.6-7.1 (4H, m); 5.05 (IH, d);
4.65 (IH, d) 4.40 (IH, d); 2.8-
2.3 (IH, m); 1.28 (3H, d) 0.86
(3H, d).

Reference example
-bromomethyl-2-(1-bromo-2-methylpropyl)benzene and 1.5 g (16.2 mM) of aminoacetonitrile hydrochloride in a manner similar to Reference Example X3 to obtain the crude compound as an oil. . This was dissolved in ethyl acetate and converted to the hydrochloride salt with hydrogen cyclization to give the title compound.

"H-nmr δ (IMSO) 11.0-10.5 (IH, broad singlet, D
! 0) 7.5-7.2 (4H, m); 4.8
1 (IH, d); 5.50 (IH, d); 4.44 (
IHtd); 3.34 (2H, 8); 2.5-2.3 (
IHtm): 1.03 (3H, d); 0.94 (3H,
d).

REFERENCE EXAMPLE .

6.9-7.37 (8H, rn): 5.9 (I
H, brs ): 4.3 (2H, m) and 2.3 (
3H,s).

Reference Example (4-MethylpheniA/)-1,2-benzenedimetatool and H50ILt
(0,53M) of sulfur tribromide.

6.88-7.8 (8H, m); 6.7 (IH, s);
4.5 (2H, (1) and 2.27 (3Hesi) - Reference Example Shift 0 by a method similar to that described in
α-(2-bromomethylphenyl)- of g(0,2M)
4-methylphenylmethylbromide, 22. ! ii'(
0.23M) of aminoacetonitrile hydrochloride and 831
d(0.6M) from triethylamine.

6.7-7.6 (8H-m); 4.83 (IH-brs
); 4.15 (2H-m); 3.6 (2HIm) and 2
．． 18 (3H, s).

Reference Example X37 α-(4-methoxyphenyl)-1,2-benzenedimetatool The title compound was prepared from 2-(4-methoxybenzoyl)benzoic acid by a method similar to that described in Reference Example .

"H-nmrδ (CDCA!s) 6.7-7.3 (8H, m); 5.73 (IH,
brs): 4.3 (2H, brs) and 3.6
3 (3H, s).

Reference Example , 2M)
of α-(4-methoxyphenyl)-1,2-benzenedimetatool and 5 oi (0, saM) of sulfur tribromide.

1H-nmrδ (DC 6,85” 7.9 (8H1m): 6-7 (
I H-si ) s 4-4 (2H, q) and 3.
7 (3H,B).

Reference Example X39 2H-(1-(4-methoxyphenyl)-1,3-dihydroisoindole)-2-acetonitrile The title compound 53
,9(0,14M) of α-(2-bromomethylphenyl)-4-methoxyphenylmethylbromide, 16g
(0,17M) of aminoacetonitrile hydrochloride and 60
Prepared from triethylamine at WLt (0.43M).

lH-nmrδCCDCIm> 6.5-7.5 (8H-m); 4.9 (IHlb
rs ); 4.2 (2H-m) and 3.7 (5H,
m+s).

REFERENCE EXAMPLE 1-hydroxymethyl)-2-(2-phenyl-1-hydroxyethyl)
It was prepared from tribromide of benzene and 5.7rILt (60mM).

7.9-6.85 (9H, m); 5.5 (IH, t);
4.35 (2H,Q,) and 3.5 (2H,d).

Reference example J7 in a certain way
19.89 (56mM) of 1-(bromomethyl)-2
-(2-phenyl-1-bromoethyl)benzene,
7.8. ! i' (84mM) of aminoacetonitrile hydrochloride and 23.4zz (16.8mM) of triethylamine.

"H-nmrδ (CDCJg) 7.4-7-1 (9H-m): 4.4 (I
H-m); 4.3 (IH, d d): 4
．． 05 (i H= d d ); 3-5 (I
I(,d); 3.25 (2H-rn); and 2.8 (IH,dd).

Approximately 25 (9) CFLP female mice were fasted for an hour and then given water (10 IILt/J) or the compound orally.

(To) 9 days later glucose (Lj9/kf/) and epinephrine (300μ97) were injected subcutaneously. Administration of glucose 0.30 to blood sample for glucose analysis
After 90 and 120 minutes, samples were taken serially from the tail of each mouse, and the results are shown below as the decrease in the area under the blood glucose curve, and the group treated with the compound was compared with the control group administered water. . Six mice were used for each treatment group.

Dose Reduction in area under the blood sugar curve Example Arashi (μmol/#) Chi (
B) Membranes of α2-adrenoceptor-bound human platelets were treated with various concentrations of the drug (0.1-10.
Rauwolaclne (0,5
~1. OnM). Binding assays were stopped by filtration and rinsing onto GF/B glass fiber filters.

binding affinity Example Na Ki (nM) 11.7 24.1 33.4 46.4 50.8 63.6 71.8 82.7 96.9 10 34.0 11 25.0 12 2.0 13 40.0 Agent Patent Attorney Masaaki Aki Sawa 1 other person Voluntary procedure amendment 1986/Monday/7th

Claims (19)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, Z represents a substituted or unsubstituted aryl group residue; A^1 is a substituted or unsubstituted methylene group, or represents a substituted or unsubstituted ethylene group; A^2 represents a substituted or unsubstituted methylene group, or a substituted or unsubstituted ethylene group; provided that at least one of A^1 or A^2 is substituted methylene represents a group or a substituted ethylene group; p represents an integer 2 or 3; and q represents an integer in the range of 1 to 12] or a pharmaceutically acceptable compound thereof Salts, esters or amides or pharmaceutically acceptable solvates thereof. (2) The compound according to claim (1), wherein Z represents a substituted or unsubstituted phenyl group residue. (3) The compound according to claim (1) or (2), wherein A^1 represents a substituted methylene group and A^2 represents an unsubstituted methylene group. (4) Formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (In the formula, Z, X, p, and q are as defined for formula (I), and R and R^1 are each independent. represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl with an aryl moiety; provided that R and R^ or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof. (5) The compound according to claim (4), wherein R and R^1 each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or aralkyl. (6) Claim 4 or (
5) Compound described in section 5). (7) A compound according to any one of claims (4) to (6), wherein R represents alkyl, substituted or unsubstituted phenyl or benzyl group, and R^1 represents hydrogen. (8) Formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (In the formula, R, R^1, X, p and q are as defined above, and R^2 and R^3 each independently hydrogen, alkyl, amino, mono- or di-alkylamino,
hydroxyl, alkoxy, carboxy or halogen atom) or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable salt, ester or amide thereof; Acceptable Solvates. (9) The compound according to claim (8), wherein R^2 represents halogen and R^3 represents hydrogen. (10) The compound according to claim (8), wherein R^2 and R^3 both represent hydrogen. (11) Claims Nos. (1) to (11) where X represents NH.
10) A compound according to any one of the items. (12) Claims Nos. (1)--where p represents an integer 2
A compound described in any one of (11). (13) Claims Nos. (1) to 1 where q represents an integer 1
(12) A compound described in any one of the items. (14) 2-[2H-(1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole; 2-[2H-(1-ethyl-1,3-dihydroisoindole)methyl ]-4,5-dihydroimidazole; 2-[2H-(5-chloro-1-methyl-1,3-dihydroisoindole)methyl-4,5-dihydroimidazole; 2-[2H-(6-chloro- 1-Methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole; 2-[2H-(5-fluoro-1-methyl-1,3-dihydroisoindole)methyl]-4,5 -dihydroimidazole; 2-[2H-(1-(4-chlorophenyl)-1,3-
2-[2H-1-(3-chlorophenyl)-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole; 2-[2H- (1-(4-fluorophenyl)-1,3
-dihydroisoindole)methyl]-4,5-dihydroimidazole; 2-[2H-(1-phenyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole; 2-(2H-[1 -(1-methylethyl)-1,3-dihydroisoindole]methyl)-4,5-dihydroimidazole; 2-[2H-(1-(4-methylphenyl)-1,3-
dihydroisoindole)methyl]-4,5-dihydroimidazole; 2-[2H-(1-(4-methoxyphenyl)-1,3
-dihydroisoindole)methyl]-4,5-dihydroimidazole; and 2-[2H-(1-benzyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole; or a pharmaceutically acceptable form thereof. The compound according to claim 1, which is selected from the group consisting of a salt, an ester or an amide thereof, or a pharmaceutically acceptable solvate thereof. (15) (i) Formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) [In the formula, Z, A^1, A^2, p and q are as specified for formula (I). , X^1 represents O or NH and Y represents OR^g (wherein R^g is hydrogen or a hydroxyl protecting group) or -NHR^h (wherein R
^h represents hydrogen or a nitrogen protecting group); where, when X^1 is O, Y is OR^g and X^1 is N
or (ii) in the preparation of a compound of formula (I) where X represents NR^0, a compound of formula (V ) and a compound of formula (VI) in which Y represents NR^0; and then, if necessary, one or more of the following optional steps: (i) removing any protecting groups; (ii) converting the compound of formula (I) into another compound of formula (I); (iii) converting the compound of formula (I) into a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvent thereof; A method of manufacturing Japanese products. (16) A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof and a suitable pharmaceutically acceptable carrier thereof. (17) General formula (I) used as active therapeutic substance
or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof. (18) A compound of formula (I) or a pharmaceutically acceptable salt thereof used for the treatment and/or prevention of hyperglycemic glaucoma and/or the treatment of depression and/or the inhibition of platelet aggregation and/or the treatment of hypertension , ester or amide or a pharmaceutically acceptable solvate thereof. (19) A compound of formula (I) or its compound for the manufacture of a drug for the treatment and/or prevention of hyperglycemia and/or the treatment of hypertension and/or glaucoma and/or depression and/or the inhibition of platelet aggregation. Uses of pharmaceutically acceptable salts, esters or amides or pharmaceutically acceptable solvates thereof.