CA2245728C - Isoquinoline derivatives and drugs - Google Patents

Abstract

The invention relates to a compound of the following general formula [I] or a medicinally acceptable salt thereof, or a solvate thereof, (see formula I) wherein R1 represents alkyl, alkenyl, alkynyl, alkoxy, hydroxy, cyano, or halogen; R2 represents hydrogen, hydroxy, or halogen; R3 represents hydrogen, alkyl, or amidino; Ring A represents a 5 to 11-membered cyclic amino group which may be substituted, which cyclic amino group may be bridged between two carbon atoms in optional positions. The compound of this invention is useful for the prevention or treatment of cerebral tissue impairment due to the vasospasm following cerebral hemorrhage.

Description

I
ISOQUINOLINE DERIVATIVES AND DRUGS
TECHNICAL FIELD
The present invention relates to an isoquinoline derivative having cerebral vasospasm-inhibiting activity and, thus, finding application as a medicine.
BACKGROUND ART
Cerebrovascular disease can be groupified into a hemorrhagic group and an ischemic group. The hemorrhagic group typically comprises subarachnoid hemorrhage arising ;from aneurysmal rupture, hyper-tensive cerebral hemorrhage, and head trauma.
Subarachnoid hemorrhage entails a delayed vasospasm of the major cerebral arteries and may lead to vascular constriction disorders and sometimes to death. The ischemic group is represented by cerebral infarction and transient ischemic attack (TIA). The vascular disorder and neuronal injury caused by infarction or hemorrhage may lead to dyskinesia such as numbness or motor paralysis of the limbs and neurologic and mental dysfunctions in the acute through chronic stage, with disturbance of consciousness and death ensuing in severe cases.
For the treatmentof such cerebrovasculardiseases, " CA 02245728 1998-07-31 '1 2 antithrombotics and enhancers of cerebral circulation and metabolism have been used to this day. However, few drugs are available which inhibit this fatal cerebral vasospasm or the neuronal injury leading to dementia and there exists a pressing need for an effective therapeutic agent.
By way of illustration, as subarachnoid hemorrhage takes place, narrowing of the vascular lumen persisting for several weeks is induced in the major cerebral arteries in 4~-5 days following the bleeding event. This phenomenon a.s known as cerebral vasospasm and once the ultimate ischemia triggers the onset of neurological symptoms, the functional prognosis and, at times, even the vital prognosis of the case are seriously influenced.
As the therapeutic drug for cerebral vasospasm subsequent to subarachnoid hemorrhage, fasudil [hexahydro-1-(5-isoquinolinylsulfonyl)-1H-1,4-diazepine] hydrochloride is the only drug that is used clinically today (Japanese Kokai Tokkyo Koho S61-227581) .
Aside from the above drug, it is known that compounds having an isoquinoline ring substituted by cyclic aminosulfonyl in its 5-position are useful as cerebrovascular drugs (vasodilators, enhancers of cerebral circulation and metabolism,antianginal drugs, prophylactic and therapeutic drugs f.or cerebrovascular or cardiovascular thrombosis, and prophylactic and therapeutic drugs for hypertension) jJapanese Kokai Tokkyo Koho S57-156463, S58-,.121279, and S6I-227561].
Not known, however, is a compound such that its isoquinoline skeleton has been substituted by a cyclic aminosulfonyl group in. its 5-positon and further substituted in its 4-position, DISCLOSURE OF THE INVENTION
The invention provides a compound which is structurally novel, only sparingly toxic, and superior to any known drug as a prophylactic or therapeutic drug f or cerebrovascular diseases, particularly as a cerebral vasospasm inhibitor.
To accomplish the above, the inventors of the present invention synthesized and screened a large number of structurally new compounds and found that a compound of the following general formula [I] has very satisfactory cerebral vasospasm-reversing activity.
The present invention has been developed on the basis-of the above finding.
According to one aspect of the present invention, there is provided a compound of the following general formula [I] or a pharmaceutically acceptable salt thereof, or a hydrate or ,. CA 02245728 1998-07-31 d solvate thereof, and a medicinal composition comprising it as an active ingredient, ~N
~S02 R~
i y ~N

[I~
wherein R1 represents alkyl, alkenyl, alkynyl, alkoxy, hydroxy, cyano, or halogen;
Rz represents hydrogen, hydroxy, or halogen;
R3 represents hydrogen, alkyl, or amidino;
Ring A represents a 5 to 11-membered cyclic amino group which may be substituted, which cyclic amino group may be bridged between two carbon atoms in optional positions.
In chemical structure, the compound of the invention is characterized in that the 4-position of an isoquinoline skeleton is substituted by a subs tituent selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, hydroxy, cyano, and halogen.
The present invention is now described in detail.
The "alkyl" in the context of the present invention includes straight-chain or branched alkyl groups of 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tart-butyl, n-pentyl, isopentyl, n-hexyl, and isohexyl. Among them, alkyl groups of 1 to 4 carbon atoms are preferred and methyl is particularly preferred.
The "alkenyl" includes straight-chain orbranched alkenyl groups of 2 to 6 carbon atoms, such as vinyl, allyl, isopropenyl, methallyl, 2-butenyl, and 3-butenyl. Among them, alkenyl groups of 2 to 4 carbon atoms are preferred.
The "alkynyl" includes straight-chain orbranched alkynyl groups of 2 to 6 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl. Among them, alkynyl groups of 2 to 9 carbon atoms are preferred.
The "alkoxy" includes straight-chain or branched alkoxy groups of 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy .
The "halogen" includes chlorine, fluorine, bromine, and iodine.
Ring A includes saturated 5 to 11-membered monocyclic or bridged heterocyclic groups each containing 2 nitrogen atoms as ring-constituent hetero atoms. Thus, for example, imidazolidyl, piperazino, hexahydro-1H-1,4-diazepin-1-yl, 1,5-diazacyclooctan-1-yl, 3,6-diazabicyclo(3.2.2]nonan-3-yl, 3,6-diaza-bicyclo[3.2.1]octan-3-yl, 2,5-diazabicyclo[2.2.1]-heptan-2-yl, and 2,5-diazabicyclo[2.2.2]octan-2-yl can be mentioned. This Ring A may be substituted by 1-4 same or different substituent(s) selected from the group consisting of alkyl, halogen, phenyl, and aminoalkyl on its carbon atom or atoms.
R1 is preferably Cl_, alkyl, particularly methyl.
R2 is preferably hydrogen. R' is preferably hydrogen.
Ring A is preferably a hexahydro-1H-1,4-diazepin-1-yl, particularly 2- or 7-methyl-hexahydro-1H-1,9-diazepin-1-yl.
The salt of compound [I] according to the invention includes salts with inorganic acids such as hydro-chloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid and hydrobromic acid. and salts with organic acids such as acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, malefic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfanic acid and camphorsulfonic acid.
The compound [ I ] of the invention can b.e produced by, for example, the following procedure.

.~ R3_ R 3~--~NH ~ N
S02 R~ ~/ ~SOZ R~
w, [J!1] i w -. --.,. ~ i ~ N (deprotection) ~ ~N

[I I] [ i ]
(wherein R1, Rs, R', and Ring A are respectively as defined hereinbefore; R'1 means R' or represents a protective group; L1 represents a leaving group) The leaving group L1 includes residues of the reactive derivatives of sulfonic acid to be mentioned hereinafter. The protective group R" includes aryl such as formyl, acetyl or benzoyl; aralkyloxycarbonyl such as benzyloxycarbonyl; alkoxycarbonyl such as tert-butyloxycarbonyl; and aralkyl such as benzyl.
An amine of general formula [III] is reacted With a sulfonic acid of general formula [II] or a reactive derivative thereof in a suitable solvent and, where necessary, the protective group is removed to provide compound [I]. The reaction solvent may be any solvent that does not interfere with the reaction, thus including ethers such as tetrahydrofuran, dioxane and .. CA 02245728 1998-07-31 diethyl ether; hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as methylene chloride and chloroform; aprotic solvents such as N,N-dimethylformamide and N,N-dimethylacetamide;
pyridine, acetonitrile, etc.; and mixtures of such solvents. The reactive derivative of sulfonic acid includes sulfonic acid halides (e. g. sulfonyl chloride and sulfonyl bromide), sulfonic anhydride, and N-sulfonylimidazolide, among others. Particularly preferred is a sulfonyl halide.
This reaction is preferably conducted in the presence of a base. The base includes various alkalies such as alkali metal hydrogencarbonates (e. g. sodium hydrogencarbonate), alkali metal carbonates (e. g.
potassium carbonate) , and alkali metal hydroxides (e.g.
sodium hydroxide and potassium hydroxide) and organic tertiary amines such as triethylamine and tri-ethylenediamina. When a basic solvent such as pyridine a.s used as the reaction solvent, said base need not be used. Therefore, a solvent of this kind can be used with advantage.
Thisreaction usually proceeds atroom temperature but may optionally be conducted under cooling or heating, for example at -78-15090 , preferably 0-12090 . When a base is used, the amount of the reactive derivative [ II ]

9.
relative to amine [III) is preferably Z-10 molar equivalents and more preferably 1-3 molar equivalents.
The amount of the base relative to amine [III) is preferably 1-10 molar equivalents and more preferably 1-3 equivalents. When the base is not used, the amount of reactive derivative [II]
relative to amine [III] is equimolar or less and preferably in the range of 0 . 5-0 . 1 molar equivalents .
The reaction time is dependent on the species of starting compounds and solvent used, reaction temperature, and other conditions but is generally 5 minutes to 70 hours. Where necessary, the protective group is removed by a per se known procedure after completion of the reaction.
groc~~~,~ 2 R31- ~ R3_~
~S02 R~ ~ ~S02 R~
----s .----s (deprotection) R2 _ _ R2 (wherein R~, R2, R', R'1, and Ring A are respectively as defined hereinbefore; Y represents oxygen, sulfur, or S02) A compound of general formula [IV) is treated with an acid or heated for aromatization and, where necessary, -c the protective group is removed to provide compound [ I ] .
This reaction can be carried out by a known method (J.
Chem. Soc. C., 1971, 1227).
Process 3 R3-N' p l R31 ~ , w 0~ 1 ~ 0~ 1 w I Y N ~ . --~ w I
(deprotection) N

f Vl C I
(wherein Ri, RZ, R3, R'1, Ring A, and Y are respectively as defined hereinbefore) A compound of general formula [V] is treated with an acid or heated for aromatization and, where necessary, the protective group is removed to provide compound [ I ] .
This reaction can be carried out by a known method (J.
Chem. Soc. C., 1971, 1227).
Process 4 (Compound of formula [I] wherein RZ is hydrogen and RI a.s a group other than halogen) R3_~ R3-\ 0~ ~0 Grignard reagent \ 0~ R~~
/ I ~ or Lithium reagent / I
w ~N ~ w ,N
Cla7 fl~l (wherein R3 and Ring A are as defined hereinbefore; Rii represents a group other than halogen among the species mentioned for R''; R''° represents halogen) The halogen for Rl° is preferably chlorine or bromine.
A halide of general formula [Ia] is treated with an organometallic reagent corresponding to R11 such as a Grignard reagent or alkyllithium; an alkali such as an alkali metal hydroxide (e.g. sodium hydroxide and potassium hydroxide) or a sodium alkoxide (e.g. sodium methoxide and sodium ethoxide); or potassium cyanide to provide compound [Ig] (compound of formula [I]
wherein R2 is hydrogen and R1 is a substituent other than halogen) . This reaction can be carried out by a known method (EP-A-429,341).
Compound [Ib] wherein Ring A represents a non-bridged cyclic amino group can be produced by the following method as well.
Process 5 (formula [I] wherein Ring A is a non-bridged cyclic amino group) L
G
L2 ~ R3_N
N~S02 R1 R3NH ~ S02 R~
z CIXI
~N ~ ~N

Cvi~ Cib7 (wherein R1, R2, and R3 are as defined hereinbefore; G

represents C2_5 alkylene and Q represents C1_, alkylene;
which alkylene groups may respectively have 1 to 4 same or different substituent(s) selected from among the substituents mentioned for Ring A in any G
substitutable positions; the cyclic group - ~ N-R' Q
which forms upon reaction of compound [VI] with compound [IX] represents -N A' N-R' wherein ring A' represents a non-bridged cyclic amino group; L2 represents a leaving group) The leaving group LZ includes halogen such as chlorine or bromine and acyloxy such as acetyloxy, mesyloxy or tosyloxy.
Compound [VI] (a halide or a reactive derivative) is reacted with compound [IX] (the amine, guanidine or ammonia corresponding to R') to provide compound [Ib] .
This reaction can be carried out by a known method (Acta.
Chemica. Scand., 1991, 45, 621).
Process 6 ~
R3-N' A, R NH-G 502 R1 ~2- Q - ~2 ~ S02 R1 ~ [XI]
t ~ ~ 1 ~N ~ ~N

R ~Ib] R2 [VII]

_ CA 02245728 1998-07-31 (wherein R1, R2, R', R31, L2, G, and Q are respectively as defined hereinbefore) Compound [XIJ (a halide or reactive derivative) is reacted with compound [VII] and, where necessary, the protective group is removed with an acid or an alkali to provide compound [Ib] . This reaction can be carried out by a known method (Acts. Chemica. Scand. , 1991, 45, 62 1 ) .
C~-OH
L1 ~ 1 I H ~H
HEN- G-OH 0~ 1 0~ 1 i I ~ CXII] ~ w ~ i w W ~ N 1 st ste ~ I ~ I
p ~ , N 2nd step W ~ N

CII] [Villa] [Vlllb]
~31 HO-Q-HN-~ HO-Q-N-~H IH

HO-Q-NHS 0' R 0~ 1 [X11 i ~ ~~ ~, i I w 3rd step ~ ~ N 4th step ~ ' N

[Vllic] ~Vllldl _ CA 02245728 1998-07-31 s.

~31 L,Z-Q-N~

0~ 1 ~ 0 R1 i y _ i w 5th ep ~ I ~ N 6th step ~ I i N

fVlIIeI ~Ib~
(wherein Rl, R2, R3, R31, Ring A~ , G, Q, L1, and L2 are respectively as defined hereinbefore) Step Aminoalkyl alcohol of formula [XII ] is reacted with compound [II] as in Process 1 to provide compound [VIIIa].
Bte~2 By a per se known procedure, the hydroxyl group of compound [VIIIa] is converted to halogen (e.g. C1, Br) or acyloxy (e. g. tosyloxy, methanesulfonyloxy, acetyloxy) to provide compound [VIIIb].
Btep 3 Compound [VIIIb] is reacted with aminoalkyl alcohol [XIII] in a suitable solvent, either in the absence or in the presence of a base, in otherwise the same manner as Process 1 to provide compound [VIIIc].
Step The secondary amino group of compound [VIIIc]
is protected by a per se known procedure to provide compound [VIIId]. The protective group may be any of the protective groups mentioned for Process 1.
stets In the routine manner, compound [VIIId] is ~ CA 02245728 1998-07-31 s converted to compound [VIIIe].
Step 6 Compound [VIIIe] a.s treated with a base in a suitable solvent and, where necessary, further treated with an acid or an alkali to remove the protective group, whereby compound [Ib] is obtained. The base which can be used includes various alkalies such as sodium hydride, sodium hydrogencarbonate, potassium carbonate, sodium hydroxide and potassium hydroxide and organic tertiary amines such as triethylamine and triethylenediamine.
This reaction is carried out using the same reaction solvent under the same conditions as mentioned for Process 1.
Compound [Ib] can also be obtained by subjecting compound [VIIId] to intramolecular dehydration reaction using triphenylphosphine and diethyl azodicarboxylate and removing the protective group.
The compound of formula [I] wherein R1 is alkenyl or CZ_6 alkyl can also be produced by reducing the compound [ Ic ] ( formula [ I ] in which R1 is alkynyl ) prepared by any of the above-described processes. For example, the compound [ I ] wherein Rl is alkenyl can be obtained by subjecting compound [Ic] to catalytic reduction in a solvent such as methanol, ethanol, ethyl acetate, or quinoline in the presence of palladium/barium carbonate, palladium/calcium a carbonate, or Rindlar catalyst at atmospheric temperature and pressure. The compound in which Rl is alkyl can be obtained by subjecting the compound in which R1 is alkynyl or alkenyl to catalytic reduction with the aid of a catalyst such as platinum, platinum oxide, palladium-on-carbon, or Raney nickel in a solvent such as methanol, ethanol, or acetic acid at atmospheric temperature and pressure or optionally at elevated temperature and pressure.
The compound of formula [I] in which R1 a.s alkyl and R2 is hydroxy or halogen can also be produced by oxidizing the compound [Id] (formula [I] in which R1 is alkyl and RZ is hydrogen) obtained by any of the above-described processes. Thus, the compound in which R2 is hydroxy can be obtained by heating compound [Id] together with an oxidizing agent such as hydroger~
peroxide, a peracid, or tert-butyl peroxide in a solvent such as acetic acid, methylene chloride, or chloroform to give isoquinoline N-oxide and hydrolyzing the same with acetic anhydride under heating. Furthermore, by heating said isoquinoline N-oxide together with phosphorus oxychloride or phosphorus tribromide, the compound in which RZ is halogen can be provided.
The compound [I] having a substituent on the nitrogen atom of Ring A, i.e. compound [Ie] (R' in _ CA 02245728 1998-07-31 formula [I] represents alkyl or amidino), can also be produced by introducing a substituent group into the compound [ If ] (R' a.n formula [ I ] represents hydrogen) obtained by any of the processes described hereinbefore.
For example, the compound having alkyl for R' can be obtained by reacting compound [If] with an alkylating agent in the presence of a base. The compound having amidino for R' can be obtained by reacting compound [If]
with an isourea derivative in the presence of a base.
The base which can be used here includes various alkalies such as sodium hydrogencarbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, and organic tertiary amines such as triethylamine and so forth. The reaction solvent which can be used includes but is not limited to ethanol, methanol, benzene, toluene, N,N-dimethylformamide, and dimethyl sulfoxide. Thus, the compound in which R' is amidino can be produced by reacting compound [If] with S-methylisothioureaor0-methylisoureain a solvent (e. g.
tetrahydrofuran, ethanol, or methanol) at room temperature or under heating.
In the above production processes, hydroxyl and amino groups can be protected, whenever necessary, with suitable known protective groups and, after completion of the contemplated reaction, deprotected by per se s known procedures such as acid treatment, alkali treatment, and catalytic reduction. The amino-protecting group that can be used includes but is not limited to benzyl, benzyloxycarbonyl, and tri-fluoroacetyl. The hydroxy-protecting group that can be used includes but is not limited to methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, tetra-hydropyranyl, tert-butyl, benzyl, trimethylsilyl, and tent-butyldimethylsilyl. When the hydroxyl group is protected with benzyl, the catalytic reduction results in simultaneous debenzylation to regenerate a free hydroxyl group.
The starting compound [ I I ] can be prepared by the procedure described in Reference Example 1.
The starting compound [ III ] can be purchased from a commercial source or prepared by the procedure described in Reference Example 2.
The starting compounds [IV] and [V] can be prepared by the method described in J. Chem. Soc. C. , 1971, 1227.
The starting compounds [VI] and [VII] can be prepared a.n accordance with the procedures described in Acta. Chemica. Scand., 1991, 45, 621.
The starting compounds [IX] and [XI] can be purchased from commercial sources.
The starting compounds [XII] and [XIII] can also be purchased from commercial sources.
While compound [I] wherein R2 represents hydroxy may exist in the following tautomeric forms, both isomers fall within the scope of the invention.
R~~N R~~Nw ~S02 R~ ~ S02 R1 i w ~ i y ~ N ~ ~ I NH

Some species of the compound [ I ] of the invention have asymmetric carbon atoms and, as such, each may occur as optical isomers. Such respective isomers and mixtures thereof also fall within the scope of the invention. Usually, a racemic modification is produced. While the racemic modification as such is pharmacologically active, each racemic modification may optionally be resolved into the component isomers .
Such a mixture of isomers can be fractionated into the respective isomers by known optical resolution techniques, for example the technique which comprises reacting the racemic modification with an optically active carboxylic acid (e.g. (+) - or (-) -tartaric acid or (+) - or (-) -malic acid) or sulfonic acid (e. g.
(+)-camphorsulfonic acid) to provide a salt and isolating the salt by fractional crystallization or the x technique which comprises using a chiral column.
Optical isomers can be also obtained by using the optically active form of starting compound [III] , [IV] , [~l. [~Il. [VIII. [XIII. [XIII], or [Ia7 configuration or R-configuration).
The salt of compound [ I ] of the present invention can be provided by a per se known method. For example, the hydrochloride of compound [I] can be prepared by dissolving compound [I] in a solution of hydrogen chloride in alcohol or ethyl ether.
Recrystallizing compound [I] or a salt thereof from.a suitable solvent (inclusive of water) may give rise to the corresponding solvate (inclusive of hydrate) . Such solvates also fall within the scope of the invention. For example, the hydrate of compound [I]
according to the invention may form upon recrystallization of compound [I] from an aqueous al cohol .
The compound of the invention may show polymorphism. Such polymorphs all fall within the scope of the invention.
The compound of the invention as produced in the above manner can be isolated and purified, in the form of a free base or an acid addition salt, by per se known procedures such as concentration, pH adjustment, redistribution, solvent extraction, crystallization, fractional distillation, and chromatography.
The compound of the invention has cerebral vasospasm-inhibiting activity and, as such, can be used with advantage in the prevention and treatment of cerebrovascular diseases, particularly brain tissue impairments due to the cerebral vasospasm following cerebral hemorrhage.
For use as a medicine, the compound of the invention can be administered either as it is or in the form of a medicinal composition containing it in a proportion of 0.1~-99.5, preferably 0.5-90$, in a medicinally acceptable, nontoxic, and inert carrier, to mammalian animals inclusive of humans.
As the carrier mentioned above, one or more members selected from among solid, semi-solid, or liquid diluents, fillers, and other formulating additives can be used. The medicinal composition is preferably administered in unit dosage forms. The medicinal composition of the invention can be administered orally, parenterally, locally (e.g. transdermally), or rectally. Of course, a dosage form suited for each route of administration should be selected. Among the above-mentioned routes of administration, the intravenous and oral routes are particularly preferred.

The dosage is preferably adjusted according to patient factors such as age and body weight, the route of administration, and the nature and severity of illness . For use as a prophylactic or therapeutic drug for cerebral vasospasm in adult patients, the daily intravenous dose as the active compound may be 0.1-100 mg/patient, preferably 1-30 mg/patient. For oral administration, the daily dose may be 1-1,000 mg/patient, preferably 1-30 mg/patient. Lower doses may suffice in certain cases, while higher doses may be needed in other cases. Moreover, the above daily dosage may be administered in a few divided doses.
Instructions for use would form part of <~ny commercial package containing a pharmaceutical composition comprising the compound of this invention.
Oral administration can be carried out using a solid or liquid unit dosage form, for example, bulk powders, powders,tablets, dragees, capsules,granules, suspens,ion,solution,syrup, drops, sublingual tablets, and so on.
Hulk powders can be produced by comminuting the compound of the invention to a suitable particle diameter. Powders can be manufactured by comminuting the compound to a suitable particle diameter and mixing the resulting powder with a pharmaceutical carrier, for example an edible carbohydrate such as starch or mannitol, which has also be similarly comminuted beforehand. Where necessary, the resulting powders may be further supplemented with a flavorant, preservative, dispersant, coloring agent, perfume, and/or other additives.
Capsules can be manufactured by filling gelatin or other capsule shells with said bulk powders or the powders prepared as above, or the granules prepared by the procedure described below for tablets. Lubricants and/or fluidizing agents, such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol, may be added in finely divided form prior to the filing operation described above.
Disintegrators and solubilizers, such as carboxy-methylce11u1ose, carboxymethylcellulose calcium, low-substitution hydroxypropylcellulose, cros-carmellose sodium, carboxymethylstarch sodium, calcium carbonate, and sodium carbonate can also be added, in which case the efficacy of the drug after ingestion of the capsules may be enhanced.
The finely divided compound of the invention can be suspended and dispersed in vegetable oil, poly-ethylene glycol, glycerin, or a surfactant and packaged in gelatin sheets to provide soft capsules. Tablets can be manufactured by preparing a powdery mixture of the compound with an excipient, processing a.t into granules or slags, adding a disintegrator and/or a lubricant, i.

and compressing the mixture. The powdery mixture can be prepared by mixing adequately pulverized powders of the active compound with any of said diluents or bases .
Where necessary, binders (e. g. carboxymethylcellulose sodium, methylcellulose,hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc.), dissolution retardants (e. g. paraffin), reabsorption agents (e. g. quaternary salts), and/or adsorbents (e. g. bentonite, kaolin, dicalcium phosphate, etc. ) can also be added. The powdery mixture can be made into granules by wetting it with a binder, such as a syrup, a starch paste, gum arabic, a cellulose solution, or a polymer solution, stirring the wet powder well, drying it, and pulverizing the same. Instead of converting the powders to granules in the above manner, the powders may be compressed with a tablet machine and the resulting crude slags be comminuted into granules .
The granules thus prepared can be protected against conglomeration by adding a lubricant such as stearic acid, a salt of stearic acid, talc or mineral oil. The thus-lubricated composition is then compressed. The resulting core tablets can be.coated with a film coating agent or a sugar coating agent.
As an alternative, the active compound can be directly mixed with a free-flowing inert carrier without being subjected to the above-mentioned granulation or slagging procedure and the mixture be directly compressed. A transparent or translucent protective coating capable of yielding a hermetic shellac or other film, a sugar coating, a polymer coating, or a glaze wax coating, for instance, can also be applied. Otherdosageformsfororal administration, such as solutions, syrups, and elixirs, can also be provided in unit dosage forms each containing a predetermined amount of the drug. Syrups are manufactured by dissolving the active compound in a suitable flavored aqueous medium, while elixirs are manufactured using a nontoxic alcoholic vehicle.
Suspensions are prepared by dispersing the active compound in nontoxic vehicles. Where necessary, solubilizers and emulsifiers (e. g. ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, etc.) as well as preservatives and flavorants (e. g.
peppermint oil, saccharin, etc.) can also be added.
If necessary, unit dosage formulations for oral administration can be microencapsulated. Such formulations can also be coated with, or embedded in, a polymer or wax matrix for prolonged action or sustained release.
Parenteral administrationcan becarriedoutusing liquid unit dosage forms, e.g. solutions or suspensions, for subcutaneous, intramuscular or intravenous injection. Such dosage forms can be manufactured by suspending or dissolving a predetermined amount of the active compound a.n an injectable nontoxic liquid vehicle, e.g. an aqueous medium or an oily medium, and sterilizing the resulting suspension or solution: To make an injection isotonic, a nontoxic salt or a solution thereof can be added. Moreover, stabilizers, preservatives, emulsifiers, and other additives can also be employed.
. Rectal administration can be made using suppositories manufactured by dissolving or suspending the active compound in a low-melting water-soluble or water-insolublesolid medium,e.g.polyethylene glycol, cacao butter, a semi-synthetic oleaginous base (e. g.
WitepsolT~), a higher fatty acid ester (e. g. myristyl palmitate) or a mixture thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
The following reference examples relating to the production of representative starting compounds, working examples concerning the production of the compound of the invention, and formulation and test examples for and using representative species of the compound of the invention are all intended to illustrate the present invention in further detail and should by no means be construed as defining the scope of the invention. It should be understood that the specific rotation was measured at 2090 .
Reference Example 1 5-Chlorosulfonyl-4-methylisoquinoline (I) 4-Methyl-5-nitroisoquinoline To 45 ml of concentrated sulfuric acid was added 12. 75 g of 4-methylisoquinoline (produced according to Tetrahedron, 1982, 38, 3347) under ice-cooling, and a solution of 9.02 g of potassium nitrate in 34 ml of concentrated sulfuric acid was added dropwise at a temperature not exceeding O°~C. After 30 minutes of stirring, the reaction mixture was poured in iced water containing aqueous ammonia and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate - 1/1) to provide 12.0 g of light-yellow crystals.
(2) 5-Amino-4-methylisoquinoline To 120 ml of a solution prepared by dissolving 12 . 0 g of 4-methyl-5-nitroisoquinoline obtained in (1) in methanol was added 0.73 g of platinum oxide, and catalytic reduction was carried out at 2590 for 2 hours in a hydrogen stream at 1 atmospheric pressure. This reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform/acetone - 9/1) to provide 9.12 g of light-brown crystals.

(3) 5-Chlorosulfonyl-4-methylisoquinoline To a suspension of 11.5 g of 5-amino-4-methylisoquinoline obtained in the same manner as (2) in concentrated hydrochloric acid was added 36 ml of an aqueous solution of 7.2 g of sodium nitrite dropwise at -5°~C and the mixture was stirred for 1 hour. This reaction mixture was added dropwise to a mixture of 200 ml of sulfur dioxide gas-saturated acetic acid and 4 . 1 g of cupric chloride hydrate at room temperature. After 1 hour of stirring, the reaction mixture was concentrated,madebasicwithsodium hydrogencarbonate, and extracted with chloroform. The extract was dried and concentrated and the resulting crude crystals were recrystallized from benzene to provide 8.1 g of the objective compound (light-yellow crystals).
m. p . 113-118°C
Reference Example 2 (S)-Hexahydro-2-methyl-1H-1,4-diazepine hydrobromide (1) (S)-3-[N-(t-Butoxycarbonyl)-N-[2-(N-p-toluene-sulfonyl)aminopropyl]amino]-1-propanol .. CA 02245728 1998-07-31 L-Alaninol was N,O-ditosylated in the routine manner and the O-tosyl moiety of the resulting compound was subjected to a substitution reaction with 3-amino-1-propanol. Thus, 17.7 g of tosyl chloride was added to a solution of 3.2 g of L-alaninol in 50 ml of pyridine under ice-cooling and the mixture was stirred at room temperature for 3 days . This reaction mixture was concentrated and the residue was diluted with ether, washed with 1N-hydrochloric acid and water, dried, and concentrated. The residue was dissolved in 150 ml of tetrahydrofuran, 3-aminopropanol was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then concentrated and chloroform was added to the residue. This mixture was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried, and concentrated. The residue was purified by silica gel column chromatography (methylene chloride/metha-nol/aqueous ammonia - 8:1:0.1) to provide 10.2 g of (S) -3- [N- [2- [N- [ (p-toluene) sulfonyl ] amino] propyl ] -amino]-1-propanol (brown oil) . This compound, 10.2 g, was dissolved in 90 ml of dioxane-water (2: 1) and, under ice-cooling, 50 ml of 1N aqueous sodium hydroxide solution and 11.6 g of di-tart-butyl dicarbonate were added, followed by stirring at room temperature overnight. This reaction mixture was concentrated, diluted with chloroform and water, neutralized with 5~
aqueous potassium hydrogensulfate, and extracted with chloroform. The extract was dried and filtered and the filtrate was distilled under reduced pressure to provide 13.7 g of (S)-3-[N-(tert-butoxycarbonyl)-N-[2-[N-[(p-toluene)sulfonyl]amino]propyl]amino]-1-propanol (light-yellow oil) . This oil was submitted to the next reaction without purification.
(2) (S)-(-)-Hexahydro-2-methyl-1H-1,4-diazepine hydrobromide To a tetrahydrofuran solution of 13.7 g of the compound obtained in (1), triphenylphosphine and diethyl azodicarboxylate (40~ in toluene) were added in bolus and the mixture was stirred under dryer heating for 20 minutes. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate - 3/1) to provide 13. 1 g of colorless oil. This oil was dissolved in 180 ml of 30~ hydrogen bromide/acetic acid and the mixture was stirred at room temperature for 30 minutes .
Then, 13.4 g of phenol was added and the mixture was further stirred for 7 hours at 6090. This reaction mixture was concentrated, a small amount of ethanol was added to the residue, and the resulting crystal crop was harvested by filtration and dried to provide 6.44 g of (S)-(-)-hexahydro-2-methyl-1H-1,4-diazepine hydrobromide (white crystals).
[ a ]D: -13. 60 (c=1. 12, H20) Reference Example 3 2,7-Dimethyl-hexahydro-1H-1,4-diazepine hydrobromide Using3-aminobutan-1-olinlieuof D-alaninol, the procedure of Reference Example 2 was otherwise repeated to provide the title compound.
Example 1 H~~c~hydro-1- f (4-methyl-5-isocru~ n~i ~ nyi ~ ~~~i fonv~] -H-1,4-diazenine dihydroc~ic~r;~A
(1) To 30 ml of a solution prepared by dissolving 1 g of 1-(tart-butoxycarbonyl)hexahydro-1H-1,4-diazepine and O. 97 g of triethylamine in chloroform was added 1 g of 5-chlorosulfonyl-4-methylisoquinoline under ice-cooling, and the mixture was stirred for 18 hours . This reaction mixture was poured in iced water and extracted with chloroform. The extract was dried and concentrated and the resulting oil was purified by silica gel column chromatography to provide 1.38 g of oil. This oil was dissolved in 30 ml of ethanol, and after 20 ml of 1N-hydrochloric acid was added, the mixture was refluxed for 1 hour . This reaction mixture ' 29981-13 was concentrated and the residue was made basic and extracted with chloroform. After drying, the solvent was distilled off to provide 0 . 72 g of white crystals .
(2) The above crystals were dissolved in chloroform, and hydrogen chloride-saturated ethanol was added thereto. The mixture was concentrated and the resulting white crystals were harvested to provide the objective compound (0.8 g).
Elemental analysis (for C15H19N302 ~ 2HC1 ~ H20) Calcd.(%): C, 45.42; H, 5.80; N, 10.61 Found (%): C, 45.82; H, 5.69; N, 10.56 IR spectrum (KHr) : v (cm-1) 3300, 1639, 1615, 1472, 1333, 1146, 764 Example 2 To a solution prepared by dissolving 0.56 g of piperazine and 0.66 g of triethylamine in chloroform was added 1.0 g of (4-bromo-5-chlorosulfonyl)isoquinoline (synthesized in accordance with JP 02-67274A) under ice-cooling. The mixture was stirred at room temperature for 2 hours, after which it was concentrated.
The residue was purified by silica_gel column chromatography (chloroform/methanol = 9/1) and further s..

treated as in Example 1 (2) to provide 0.45 g of the objective compound (white crystals).
m. p . 230-235°C
Elemental analysis (for Cl3HmBrN30zS ~ 2HC1 ~ 1/2Hz0) Calcd.(~): C, 35.62; H, 3.87; N, 9.59 Found (~): C, 35.38; H, 3.63; N, 9.45 Example 3 1-fl4-Ethynyl-5-isoc~uinolinyl)sulfony~]heYahv rn-1H-1,.4-diazepine dihydrochloride (1) To 30 ml of a solution prepared by dissolving 2. 72 g of 1-(tent-butoxycarbonyl)hexahydro-1H-1,4-diazepine and 2 . 74 g of triethylamine in chloroform was added 4 . 17 g of (4-bromo-5-chlorosulfonyl) isoquinoline under ice-cooling, and the mixture was stirred at room temperature for 12 hours and then concentrated. The residue was purified by silica gel column chromato-graphy (chloroform/acetone - 19/1) to provide 4.51 g of 1-(tert-butoxycarbonyl)-4-[(4-bromo-5-iso-quinolinyl)sulfonyl]hexahydro-1H-1,4-diazepine as white crystals.
(2) To a suspension prepared by suspending 2.72 g of the above compound, 0.12 g of dichlorobis(triphenylphosphine)palladium, and 0.06 g of copper iodide in 5 ml of triethylamine was added 1. 14 g of trimethylsilylacetylene, and the mixture was stirred in a sealed tube at 8090 for 12 hours. This reaction mixture was filtered and the filtrate was extracted with ethyl acetate. The extract was dried and concentrated and the residue was purified by silica gel column chromatography (chloroform/acetone = 9/1). The crystals obtained were dissolved in methanol and followed by the addition of 20 ml of 1N-potassium hydroxide/H20, the solution was stirred at room temperature for 5 minutes. This reaction mixture was diluted with water, extracted, dried, and concentrated to provide 2.06 g of 1-(tert-butoxycarbonyl)-4-[(4-ethynyl-5-isoquinolinyl)]hexahydro-1H-1,4-diazepine.
(3) To a solution prepared by dissolving O . 24 g of the above compound in chloroform was added 2 ml of trifluoroacetic acid under ice-cooling, and the mixture was stirred at room temperature for 1 hour. This reaction mixture was poured in iced water, made basic with 2N-sodium hydroxide/H20, and extracted with chloroform. The extract was dried and concentrated and the residue was further treated as in Example 1 (2) to provide 0.16 g of the objective compound as white crystals.
m. p . 190-196°C
Elemental analysis (for C16H1.,N302S ~ 2HC1 ~ 2H20) Calcd.(%): C, 45.29; H, 5.46; N, 9,90 Found (%): C, 45.61; H, 5.82; N, 9.49 Example 4 i_-( f 9-Ethenvl-5-isoQUinols ny~) sul ~o~x,l.l,hex~hvdro-yH-1,4-diaze~ine dihydrochloride To 30 ml of a solution prepared by dissolving 0. 62 g of 1-(tent-butoxycarbonyl)-4-[(4-ethynyl-5-isoquinolinyl)]hexahydro-1H-1,4-diazepineobtainedin Example 3 (2) in methanol was added 0.062 g of platinum oxide and catalytic reduction was carried out in a hydrogen stream for 25 minutes. This reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform/acetone - 9/1). To a solution of the crystal crop thus obtained in ethanol was added 1N-hydrochloric acid and the mixture was refluxed for 3 hours. The reaction mixture was then concentrated, made basic with 2N-sodium hydroxide/H20, and extracted with chloroform. The extract was dried and concentrated and the residue was purified by silica gel column chromatography (chloroform/methanol = 9/1) and further treated as in Example 1 (2) to provide 0.14 g of the objective compound (white crystals).
m.p. 210-215°C
Elemental analysis (for C16H19N~02S'2HC1'Hz0) Calcd.(~): C, 47.02; H, 5.63; N, 10.29 Found (~): C, 46.98; H, 5.90; N, 10.24 Example 5 1-fl4-Ethyl-5-isoauinolinyi)m~~if'onv~]hexahydro-1H-~,. 4-diazer>ine dihydroehi err; ~p Using 0.25 g of 1-(tert-butoxycarbonyl)-4-[(4-ethynyl-5-isoquinolinyl)]hexahydro-1H-1,4-diazepine, catalytic reduction was carried out for 10 hours and the reaction mixture after-treated as in Example 4 to provide 0.082 g of the objective compound as white crystals.
Elemental analysis ( for C16Hz1N30zs ~ 2HC1 ~ Hz0) Calcd.(sk): C, 46.80; H, 6.09; N, 10.24 Found ($): C, 46.50; H, 5.75; N, 10.47 IR spectrum (KBr) : v (cm-1) 3400, 1644, 1615, 1468, 1335, 1144, 1011, 589 Example 6 S-Methylisothiourea sulfate was benzyloxy-carbonylated in the routine manner (Jikken Kagaku Koza [Experimental Chemistry Series] 22, Yuki Gosei (Organic Synthesis) , Edition IV, 1992, 228) and then reacted with 4 molar equivalents of homopiperazine in tetra-hydrofuran to prepare hexahydro-1H-1,4-diazepine-1-carboximidamide. Using 0. 68 g of this compound and 0.5 g of 5-chlorosulfonyl-4-methylisoquinoline, the reaction procedure of Example I was otherwise repeated to provide 0.16 g of the objective compound as white crystals.
Elemental analysis (for C16HZ1N502S-2HC1~2H20) Calcd.(~): C, 42.07; H, 5.92; N, 15.34 Found (~): C, 42.73; H, 5.46; N, 15.27 IR spectrum (KBr) : v (cm-1) 3300, 1653, 1607, 1327, 1148, Example 7 To 30 ml of a suspension prepared by suspending 2.25 g of hexahydro-1-[(4-methyl-5-isoquinolinyl)-sulfonyl]-1H-1,4-diazepine in pyridine was added 2.0 g of acetic anhydride, and the mixture was stirred at 6090 for 30 minutes. This reaction mixture was concentrated, made basic with sodium hydrogencarbonate/H20, and extracted with chloroform.
The extract was dried and concentrated to provide 1. 91 g of 1-acetyl-hexahydro-4-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepine as oil.
In 30 ml of acetic acid was dissolved 1.91 g of the above compound, followed by addition of 0.94 g of 30~ hydrogen peroxide/H20 at room temperature, and the mixture was stirred at 7090 for 16 hours . This reaction mixture was poured in water and made basic with potassium carbonate and the resulting crystal crop was harvested by filtration to provide 1.87 g of 5-(4-acetyl-hexahydro-1H-1,4-diazepin-1-yl)sulfonyl-4-methylisoquinoline-2-oxide as white crystals.
A solution prepared by dissolving 1.87 g of the above compound in 40 ml of acetic anhydride was refluxed for 4 hours and then concentrated. The residue was dissolved in 20 ml of methanol, and after addition of ml of 2N-sodium hydroxide/H20, the mixture was stirred at 6090 for 5 minutes . The reaction mixture was poured in water, acidified with 1N-hydrochloric acid, and extracted with chloroform. The extract was dried and concentrated and the residue was purified by silica gel column chromatography (chloroform/methanol = 17/1) to provide 1.15 g of 1-acetyl-hexahydro-4-[(1-hydroxy-4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepine. A suspension of this compound in 1N-hydrochloric acid was refluxed for 11 hours and then concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol = 4/1) and treated as in Example 1 (1) to provide 0.487 g of the objective compound as white crystals.

Elemental analysis (for C15H19N303S ~ HC1) Calcd.(~): C, 50.34; H, 5.63; N, 11.74 Found ('k): C, 49.80; H, 5.57; N, 11.37 IR spectrum (KBr) : v (cm-=) 1636, 1593, 1323, 1146, 1011, 762, 596 Example 8 Hexahydro-1-ff4-(1-proDynyl)-5-isoauinol;nyi]-sulfonyi 1-1H-1,.4-diaze~,ine hydrochl~~-; ~p Using 0 .24 g of 1- (trimethylsilyl) -1-propyne and 0.55 g of 1-(tort-butoxycarbonyl)-4-[(4-bromo-5-isoquinolyl)sulfonyl]hexahydro-IH-1,4-diazepine, the procedure of Example 3 was otherwise repeated to provide 0.23 g of the objective compound (white crystals).
m.p. 250 (decomp.) Elemental analysis (for C1.,H19N302S ~ HC1 ~ 1/2H20) Calcd.(~): C, 54.40; H, 5.60; N, 11.20 Found (~): C, 54.29; H, 5.60; N, 11.28 Example 9 3-fl4-Methyl-5-isoauinolinyi~sLifonyi~-3,6-diaza-bi.cyclof3.2.21nonane hydroeh~~r;r;P
To a solution prepared by dissolving 0.4 g of 3-benzyl-6-ethoxycarbonyl-3,6-diazabicyclo[3.2.2]-nonane (synthesized in accordance with Japanese Kokai Tokkyo Koho S64-16783, Example 2) in 10 ml of acetic acid was added 0.4 g of platinum oxide, and hydrogenation reaction was carried out under a pressure of 4 atmospheres for 15 hours, followed by filtration.
The filtrate was concentrated, made basic with sodium hydrogencarbonate/H20, and extracted with chloroform.
The extract was dried and concentrated to provide 0.2 g of 6-ethoxycarbonyl-3,6-diazabicyclo[3.2.2]nonane.
This compound was further reacted with 0.336 g of 5-chlorosulfonyl-4-methylisoquinoline in the same manner as in Example 1 (1) to provide 0.5 g of 6-ethoxycarbonyl-3-[(4-methyl-5-isoquinolinyl)-sulfonyl]-3,6-diazabicyclo[3.2.2]nonane (pale yellow crystals). This compound was added to 30~ hydrogen bromide/acetic acid and the mixture was refluxed for 6 hours . This reaction mixture was concentrated and the residue was made basic with 10~ sodium hydroxide/Hz0 and extracted with chloroform. The extract was dried and concentrated and the residue was purified by silica gel column chromatography (chloroform/methanol/aqueous ammonia - 90/10/1) and further treated as a.n Example 1 (2) to provide 0.3 g of the objective hydrochloride (pale brown crystals).
Elemental analysis ( for C1~HZ1N302S ~ HC1 ~ H20) Calcd.(~): C, 52.91; H, 6.27; N, 10.89 Found (~): C, 52.95; H, 6.0I; N, 10.72 IR spectrum (KBr) : v (cm-1) 3480, 3350, 1641, 1610, 1309, 1149, 1034, 765, 652 Example 10 6-ff4-Methyl-5-isoQUinolinyl)sulfonyll-3.6-diaza-~~ ~~y~r,Z[~ ~ ~~] nonane hydrochl oride In accordance with the procedure described in Example 1,, 0.35 g of 3-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.2.2]nonane (synthesized in accordance with JP 64-16783A) was reacted with 0.374 g of 5-chlorosulfonyl-4-methylisoquinoline and the reaction mixture was deprotected with trifluoroacetic acidand converted to the hydrochloride to provide 0 . 4 g of the ob j ective compound (pale brown crystals).
Elemental analysis (for C1.,H2~N302S' HC1' H20) Calcd.(%): C, 52.91; H, 6.27; N, 10.89 Found (%): C, 53.23; H, 6.15; N, 10.76 IR spectrum (KBr) : v (cm-1) 3480, 3350, 1641, 1610, 1309, 1151, 1034, 765, 652 Example 11 6-f(4-Methyl-5-isoQUinoliny~.)sulfonyll-6.8-d~ azab~ cyalo [i3 . 2 . 2~] nonana dihydrochl onde Using 3.34 g of 6,8-diazabicyclo[3.2.2]nonane (synthesized in accordance with J. Med. Chem., 1991, 34, 662), the procedure of Example 1 was otherwise repeated to provide 0.2 g of the objective compound (pale brown crystals).
m.p. 249-25390 Elemental analysis (for C1.,H21N302S ~ 2H01 ~ 2H20) Calcd.(~): C, 46.36; H, 7.17; N, 9.54 Found (~): C, 46.72; H, 7.22; N, 9.14 Example 12 fS)-f+)-Hexahvdro-2-methyl-1-[(~-methyl-5 iso Qtii_ric?7 i_nyl a sub f'ony'1 1 -1H-1 , 4-diaz~~in~> hydroch~ ~.-; rlA
To a suspension prepared by suspending 24.0 g of (S)-hexahydro-2-methyl-1H-1,4-diazepine hydrobromide obtained in Reference Example 2 in 40 ml of tetra-hydrofuran were added 1.16 g of sodium hydroxide and 20 ml of O.1N-sodium hydroxide/H20 under ice-cooling.
Then, 1.58 g of di-tart-butyl Bicarbonate was added dropwise and the mixture was stirred at room temperature overnight. This reaction mixture was concentrated and extracted with chloroform. The extract was dried and concentrated and the residue was purified by silica gel column chromatography (chloroform/methanol = 10/1) to provide 1.5 g of colorless oil. This product was further reacted with 2.50 g of 5-chlorosulfonyl-4-methylisoquinoline as in Example 1 to provide 0.53 g of the objective compound (white crystals).
m . p . 14 6-150°0 Elemental analysis (for ClsH2~N~02S' HC1 ~ H20) Calcd.(~): C, 51.40; H, 6.47; N, 11.24 Found (~): C, 51.40; H, 6.68; N, 11.26 [ a ]D: +16.05 (c=1.07, HZO) Example 13 1-f(4-Bromo-5-isoquinolinyl~~~~if'ony »-hexahydro-1H-~,. 4-diazepine dihydrochl~~-; ~P
To a solution of 1.5 g of homopiperazine in methylene chloride were added triethylamine and 4-bromo-5-chlorosulfonylisoquinoline, and the mixture was stirred at room temperature and after-treated. The crude product was purified by silica gel column chromatography (chloroform/methanol - 10/1) and further treated as in Example 1 to provide 0.55 g of the objective compound (white crystals).
m.p. 250-26090 (decomp. ) Elemental analysis (for CisHI6BrN302S ~ 2H01) Calcd.($): C, 37.94; H, 3.64; N, 9.48 Found (~): C, 37.65; H, 3.94; N, 9.39 Example 14 Hexa_hyd~-o-1-'[ (4-methoxy-5-isocru; not ; nv> > ~m ion x 1 1 H-1 ,.4-diazex~ine dihydroehi er; rip In methanol was dissolved 0.35 g of sodium metal, followed by addition of 2.35 g of 1-(4-bromo-5-isoquinolinesulfonyl)homopiperazine and 60 mg of copper dust, and the mixture was refluxed for 48 hours.

This reaction mixture was filtered with the aid of Celite and the filtrate was concentrated. The residue was diluted with iced water and chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The oily residue, 0. 3 g, was dissolved in methylene chloride.
To this solution was added 3 ml of trifluoroacetic acid dropwise, and the mixture was stirred at room temperature for 2 hours. This reaction mixture was diluted with iced water, made weakly basic with potassium carbonate, and extracted with chloroform.
The extract was dried and concentrated and the residue was purified by silica gel column chromatography (chloroform/methanol - 30/1) and converted to the hydrochloride by the routine procedure to provide 0.1 g of the objective compound (white crystals).
m.p. 274-276 (decomp.) Elemental analysis (for C15H19N303S'2HC1) Calcd.(~): C, 45.69; H, 5.37; N, 10.66 Found (~): C, 45.50; H, 5.27; N, 10.36 Example 15 1 - f (4-Fluoro-5-iso~uino~ ~ nyi ) m~~ fony~~] -hexahydro-1H1 ,. 4-diazepine dihyd ~~t~1 ~,-.; r~.~
Using 25 g of 4-bromoisoquinoline (synthesized in accordance with J. Am. Chem. Soc., 1942, 64, 783 and 1951, 73, 687), 4-fluoroisoquinoline was prepared.
Using 5.87 g of this compound, 5-chlorosulfonyl-4-fluoroisoquinoline was synthesized by the same procedure as described in Reference Example 1. 1.0 g of the compound obtained was reacted with 1.6 g of 1-(tart-butoxycarbonyl)-hexahydro-1H-1,4-diazepine.
The reaction mixture was after-treated in the same manner as in Example 1 to provide 1.40 g of the objective compound (white crystals).
m.p. 255-260°C (decomp. ) Elemental analysis (for ClsHISFN30zS-2HC1) Calcd.(~): C, 43.99; H, 4.75; N, 10.99 Found (Rs): C, 43.72; H, 4.68; N, 10.85 Example 16 7 - f (4-Chloro-5-isoQUinol; nyi ) sm f'onx~ ] -hexahyd~-o-1H-1,.4-diaze~3_ne dihydroch~ nr; raa Using 2.08 g of 4-chloroisoquinoline (synthesized in accordance with J. Org. Chem., 1961, 26, 468), 4-chloro-5-chlorosulfonylisoquinoline wassynthesized as in Reference Example 1. Then, 1 . 30 g of this compound was reacted with 1.20 g of 1-(tart-butoxycarbonyl)-hexahydro-1H-1,4-diazepine and the reaction mixture was after-treated in the same manner as in Example 1 to provide 0.80 g of the objective compound (white crystals).

m.p. 251-253°~C (decomp. ) Elemental analysis (for ClsHISC1N302S~2HC1) Calcd.(~r): C, 42.17; H, 4.55; N, 10.54 Found (~): C, 42.19; H, 4.57; N, 10.24 Example 17 3-Methyl-1- ! l4-methyl-5-isocr~~i r,n1 ; n~,~ 1 ~"~ fon3,~ 1 _ t~i~erazine dihydrochloride Using 0. 60 g of 2-methylpiperazine and 0.49 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.47 g of the objective compound (white crystals).
m.p. 245-250°C (decomp. ) Elemental analysis (for C15H1sN3~2S ~ 2HC1 ) Calcd.(~): C, 47.62; H, 5.59; N, 11.11 Found (~): C, 47.53; H, 5.27; N, 11.12 Example 18 2-Methyl-1- ! l4-methyl-5-isoQUino~ ; ny'1 W"~ f'onp ]I -~i nerazi ne di hyd~-ochi o~-, de Using 0.40 g of 1-(tert-butoxycarbonyl)-3-methylpiperazine and 0.49 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.3 g of the objective compound (white crystals).
m.p. 250-255°~C (decomp. ) Elemental analysis (for ClSHisN302S'2HC1) Calcd.(~): C, 47.62; H, 5.59; N, 11.11 Found (~): C, 47.54; H, 5.81; N, 10.85 Example 19.
3,.5-Dimethyl-1-[(4-methyl-5-isoquinol; ny~y s~~ f'ony~~p~~pe~-az; ne dihydrochl~r; ~e Using 0.23 g of 2,6-dimethylpiperazine and 0.48 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.47 g of the objective compound (white crystals).
m.p. 266-274~C (decomp.) Elemental analysis (for C16H21N30zS'2HC1) Calcd.(Rs): C, 48.98; H, 5.91; N, 10.71 Found (~): C, 48.89; H, 6.14; N, 10.67 Example 20 Traps-2,.5-Dimethyl-1-!(4-methyl-5-isocruinoi;nyiy-sulfonyl 1_p; ~eraz; ne dihydr~ch~ err-; ~1P
Using 0.34 g of traps-1-(tert-butoxycarbonyl)-2,5-dimethylpiperazine and 0.64 g of 5-chloro-sulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.43 g of the objective compound (white crystals).
m.p. 260-271°C (decomp. ) Elemental analysis (for C16HZ1N302S-2HC1) Calcd.(~): C, 48.98; H, 5.91; N, 10.71 Found (~): C, 48.79; H, 6.03; N, 10.57 Example 21 Using 0.64 g of 1-(tart-butoxycarbonyl)hexa-hydro-5-methyl-1H-1,4-diazepine prepared by protecting the 1-position of hexahydro-5-methyl-1H-1,4-diazepine synthesized in accordance with USP
3,040029, the procedure of Example 1 was otherwise repeated to provide 0.27 g of the objective compound (white crystals).
m.p. 270-275gC (decomp. ) Elemental analysis (for C16HZ1N30~S ~ 2HC1 ) Calcd.(Rs): C, 48.98; H, 5.91; N, 10.71 Found (Rs): C, 48.84; H, 6.14; N, 10.63 Example 22 Hexahvdro-6-methyl-1-ff4-methyl-5-isot~uinol~nyl?-sul fon3rl 1 -1H-1 , 4-diazex>ine dihvd.-~nh1 r"--; ~P
Using 0.64 g of hexahydro-6-methyl-1H-1,4-diazepine synthesizedin accordance with USP3,040,029, the procedure of Example 1 was otherwise repeated to provide 0.79 g of the objective compound (white crystals).
m.p. 264-271°C (de comp.
Elemental analysis (for C16H21N302S~2HC1) Calcd.(~): C, 48.98; H, 5.91; N, 10.71 _ CA 02245728 1998-07-31 Found (~): C, 48.98; H, 6.02; N, 10.72 Example 23 Cis-2,5-Dimethyl-1-[l4-methyl-5-iso~uinol;nv~)-~ulfony~lp;perazine dihydrn~hinr;~.~
Using 0.43 g of cis-1-(tert-butoxycarbonyl)-2,5-dimethylpiperazine and 0.48 g of 5-chloro-sulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.2 g of the objective compound (white crystals).
m.p. 258-263°C (decomp. ) Elemental analysis (for C16Hz1N30zS'2HC1) Calcd.(Rs): C, 48.98; H, 5.91; N, 10.71 Found ($): C, 48.69; H, 6.15; N, 10.61 Example 24 Hexahvdr-o-5-methvl-1-f(4-mathy~-5-isoauinol;nyi~-sU] fonyl ~ -IH-1 ~ 4-dlazeT~; nP dlhy~rnt~~hl nr; r9Ea Using 0.29 g of hexahydro-5-methyl-1H-1,4-diazepine synthesized a.n accordance with USP 3,040,029 and 0.48 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.3 g of the objective compound (white crystals).
m.p. 271-274°C (decomp. ) Elemental analysis (for C16Hz1N3ozS'2HC1) Calcd.(~): C, 48.98; H, 5.91; N, 10.71 Found (~j: C, 48.83; H, 6.11; N, 10.46 Example 25 6-Fluoro-hexahydro-1-[(4-methyl-5-iso~uinolinyly-sulfonyll-1H-1,.4-diazenine hydrochloride Using 0.65 g of 6-fluoro-hexahydro-1H-1,4-diazepine synthesized in accordance with .T. Med. Chem. , 1990, 33, 142 and 0.72 g of 5-chlorosulfonyl- 4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.35 g of the objective compound (white crystals).
m. p . 184-185°C (decomp .
Elemental analysis (for C15H1eFN302S~HC1) Calcd.(~): C, 50.07; H, 5.32; N, 11.68 Found (~): C, 49.86; H, 5.51; N, 11.59 Example 26 Hexahydro-2-methyl-1-f(4-methyl-5-isoauin~i;nv »-sulfonyi 1-1H-1,.4-diazex>ine hydrocr~~~~;rta Using 1.07 g of 4-(tert-butoxycarbonyl)-hexahydro-2-methyl-1H-1,4-diazepine prepared by protecting the 4-position of hexahydro-2-methyl-1H-1,4-diazepine (2.8 g) synthesized in accordance with J. Med. Chem., 1990, 33, 142 and 1.21 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.27 g of the objective compound (white crystals).

m.p. 156-16290 (decomp.) Elemental analysis (for C16Hz1N30zS'HCl) Calcd.(~): C, 54.00; H, 6.23; N, 11.81 Found (~): C, 53.89; H, 6.38; N, 11.64 Example 27 (S)-3-Methyl-1-[(4-methyl-5-isoQUinolinyl)sulfonyllr~~~erazine hydrochlor~~P
Using 0.60 g of (S)-2-methylpiperazine and 0.49 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.66 g of the objective compound (white crystals).
m.p. 270-273°0 (decomp. ) Elemental analysis (for C15H19N30zS'HCl) Calcd.(~): C, 52.70; H, 5.90; N, 12.29 Found (~): C, 52.85; H, 5.78; N, 12.39 -13.26 Example 28 (R)-3-Methyl-1-[l4-methyl-5-isoguinolinyl)sulfony~lp~x>eraz~ne hvdrochlor~~~
Using 0.50 g of (R)-2-methylpiperazine and 0.40 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.52 g of the objective compound (white crystals).
m.p. 270-273°~C (de comp. ) Elemental analysis (for C15H19N30zS-HC1-1/2Hz0) . CA 02245728 1998-07-31 Calcd.(~): C, 51.35; H, 6.03; N, 11.97 Found (~): C, 51.78; H, 6.26; N, 11.71 [ cx l n ~ +17 . 97 Example 29 (S)-2-Methyl-1-fQ~-methyl-5-isoauinolinyl) sulfonyllbip~razine hydrochloride Using 1.0 g of (S)-1-(tort-butoxycarbonyl)-3-methylpiperazine and 1.21 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.85 g of the objective compound (white crystals).
m.p. 271-275°C (decomp. ) Elemental analysis (for C15H19N30~S~HCl) Calcd.(~): C, 52.70; H, 5.90; N, 12.29 Found (~): C, 52.40; H, 5.63; N, 12.00 [ a ]D: -14.23 ~ (c=1.02, H20) Example 30 (R)-2-Methyl-1-f(4-methyl-5-isoc~ui nol i nyl ) sul fonyl l~merazina hyd~-ochi ors de Using 0.34 g of (R)-1-(tert-butoxycarbonyl)-3-methylpiperazine and 0.40 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.15 g of the objective compound (white crystals).
m.p. 271-275°C (decomp.) Elemental analysis (for C15H19N302S-HC1) Calcd.(~): C, 52.70; H, 5.90; N, 12.29 Found (~): C, 52.37; H, 5.66; N, 12.17 Example 31 Using 15.0 g of D-alaninol, the procedures of Reference Example 2 and Example 12 were repeated to provide 1.42 g of the objective compound (white crystals).
m. p . 14 6-150'~C
Elemental analysis (for CI6H2iNs02S ~ HCl - 3/2H20) Calcd.(~): C, 50.19; H, 6.58; N, 10.97 Found (~): C, 50.15; H, 6.55; N, 10.82 -18.05 ~ (c=1. 14, HZO) Process 2 (1) To a solution of 1.0 g of D-alaninol in 50 ml of methylene chloride was added 2. 02 g of triethylamine, and after addition of 3.22 g of 5-chlorosulfonyl-4-methylisoquinoline under ice-cooling, the mixture was stirred for 2 hours. This reaction mixture was diluted with water and extracted with methylene chloride and the extract was dried and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol - 30/1) to provide 3.0 g of (R)-2-[(4-methyl-5-isoquinolinyl)sulfonylamino]-1-propanol (white crystals).
(2) To a solution of 1.1 g of the compound obtained in (1) above in 8 ml of pyridine was added 0.82 g of p-toluenesulfonyl chloride, and the mixture wasstirred overnight. The pyridine was then distilled off and the residue was diluted with water, extracted with chloroform, dried, and concentrated. The residue Was dissolved in 8 ml of tetrahydrofuran, followed by addition of 0.80 g of 3-amino-1-propanol, and the mixture was stirred at room temperature for 3 hours.
The solvent was then distilled off and the residue was purified by silica gel column chromatography (chloroform/methanol/aqueous ammonia - 90/10/1) to provide 1.3 g of (R)-3-[N-[2-[[(4-methyl-5-iso-quinolinyl)sulfonyl]amino]propyl]amino]-1-propanol (light-yellow oil).
(3) To a solution of 5.B g of the compound obtained in (2) above in 60 ml of tetrahydrofuran was added 50 ml of O.1N-aqueous sodium hydroxide solution. Under ice-cooling, a solution of 3.75 g of di-tert-butyl dicarbonate in 90 ml of tetrahydran was added dropwise and the mixture was stirred for 2 hours. The solvent was then distilled off and the residue was extracted . CA 02245728 1998-07-31 with chloroform, dried, and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol - 20/1) to provide 7.34 g of (R)-3-[N-(tert-butoxycarbonyl)-N-[2-[[(4-methyl-5-isoquinolinyl)sulfonyl]amino]propyl]amino]-1-propanol (light-yellow oil).
(4) To a solution of 1.8 g of the compound obtained in (3) above a.n 30 ml of dry tetrahydrofuran were added 1.62 g of triphenylphosphine and 1.07 g of diethyl azodicarboxylate, and the mixture was heated for 20 minutes. This reaction mixture was concentrated and the residue was dissolved in 30 ml of methylene chloride.
To the resulting solution was added 10 ml of tri-fluoroacetic acid under ice-cooling, and the mixture was stirred at room temperature for 1 hour. This reaction mixture was made basic with saturated sodium hydrogencarbonate/H20, extracted with methylene chloride, dried, and concentrated. The residua was purified by silica gel column chromatography (chloroform/methanol - 50/1) and converted to the hydrochloride as in Example 1 (2) to provide 0.9 g of the objective compound (white crystals).
m.p. 146-150°C
Elemental analysis (for C16Ha1N30z8' HC1 ~ 2H20) Calcd.(~): C, 49.03; H, 6.69; N, 10.72 Found (~): C, 48.70; H, 6.69; N, 10.80 [ a ]D: -17.50 ~ (c=1.11, Hz0) Example 32 -Ethyl-hexahydro-1-f(4-methyl-5-isoauinol;ny~Ji-sulf'onx~,_,_] -1H-~, 4-diazerW ne hydrochl ~.-; ~A
Using 0.68 g of 1-(tert-butoxycarbonyl)-3-ethyl-hexahydro-1H-1,4-diazepine and 0.72 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example l,was otherwise repeated to provide 0.38 g of the objective compound (white crystals).
m.p. 208-210°rC (de comp. ) Elemental analysis (for C17Hz3N30zS'HC1) Calcd.(RS): C, 55.20; H, 6.54; N, 11.36 Found (~): C, 55.30; H, 6.83; N, 11.08 Example 33 5,.7-Dim thyl-hexahydro-1-[(4-methyl-5-iso-cf,_a_i_n_ol i nyl ) ~ui fonyW -1H-1, 4-d3.aze~i~-~e h~dr ch nr; ~P
Using 0.77 g of 5,7-dimethyl-hexahydro-1H-I,4-diazepine and 0.48 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.50 g of the objective compound (white crystals).
m.p. 280-282qC (decomp.) Elemental analysis (for Cl~Hz3N30zS'HCl) Calcd.(~): C, 55.20; H, 6.54; N, 11.36 Found (~): C, 54.96; H, 6.44; N, 11.10 Example 34 Hexahydro-1-fl4-methyl-5-isoauinol~nv »~Wfony~]'-2-t~henyl-IH-1,. 4-diazei?ine hydroct-~~ o,-; ~P
Using 20.2 g of phenylglycinol, the procedure of Example 12 was otherwise repeated to provide 0. 15 g of the objective compound (white crystals).
m. p . 218-22190 Elemental analysis ( for CZ1H23N3028 ~ HC1 ~ 2H20) Calcd.(~): C, 55.56; H, 6.22; N, 9.26 Found (~): C, 55.55; H, 5.68; N, 9.36 Example 35 (R)-l-)-Hexahydro-1-[(1-hydroxy-4-methyl-5-iso-quinoli nyl ) sul fonyi ] -2-methyl-1H-~ 4-diazexW re hydrochloride Using 1.76 g of (R)-(-)-hexahydro-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepine, the procedure of Example 7 was otherwise repeated to provide 0.65 g of the objective compound (pale yellow crystals).
m. p . 232-235°~C (decomp . ) Elemental analysis (for C16H21N303S' HC1 ~ 1/4H20) Calcd.(~h): C, 51.06; H, 6.03; N, 11.16 Found (~): C, 51.17; H, 6.08; N, 11.04 [ cz ]D: -32. 14 ~ (c=1. 04, H20) Example 36 Using 1.06 g of (S)-(+)-hexahydro-7-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepine, the procedure of Example 7 was otherwise repeated to provide 0.30 g of the objective compound (white crystals) .
m.p. 215-218°C (decomp.) Elemental analysis (for C1sH21N303S'HC1'3H20) Calcd.(%): C, 45.12; H, 6.63; N, 9.87 Found (%): C, 45.25; H, 6.30; N, 9.52 [ a ]D: +26. 66 ~ (c=1. 13, H20) Example 37 3-f(4-Methxl-5-i,~osuinolinyl)sulfon,yl]-3,.6-diaza-~ic,yclo(3.2.iloctane hydrochloride Using 3.8 g of 3-benzyl-6-methoxycarbonyl-3,6-diazabicyclo[3.2.1]octane (synthesized in accordance with JP 64-16783A), the procedure of Example 9 was otherwise repeated to provide 2.50 g of the objective compound (white crystals).
m.p. 243-245 Elemental analysis (for ClsHisN302S'HCl'2/3H20) Calcd.(%): C, 52.52; H, 5.8B; N, 11.48 ' 29981-13 Found (%): C, 52.50; H, 5.97; N, 11.04 Example 38 6- f (4-Methyl-5-isocruinoli nyl ) sul fonyl 1~3,. 6-diazab?rsyclof3.2.?~loctane hydrochloride Using 1.0 g of 3-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.2.1]octane (synthesized in accordance with JP 64-16783A), the procedure of Example 10 was otherwise repeated to provide 1.5 g of the objective compound (pale brown crystals).
m. p . 200-205°C
Elemental analysis (for Ci6H~sN3~2S-HC1~3/.2H20) Calcd.(%): C, 50.45; H, 6.09; N, 11.03 Found (%): C, 50.36; H, 6.10; N, 10.89 Example 39 ~.5-Dimethvl-hexahydro-1-f(4-methyl-5-isoquinolin-.
y1) sulfony~,-1H-1,.4-diaze,pine hydrochloride To a suspension of 1.5 g of 2,7-dimethyl-hexahydro-1H-1,4-diazepine hydrobromide obtained in Reference Example 3 in 30 ml of pyridine was added 1.58 g of 1,8-diazabicyclo[5.4.0]-7-undecene, and after addition of 0.84 g of 5-chlorosulfonyl-4-methyl-isoquinoline, the mixture was stirred at room temperature for 1 hour. This reaction mixture was concentrated and the residue was diluted with water, extracted with chloroform, dried, and concentrated.
The residue was purified by silica gel column chromatography (chloroform/methanol - 30/I) and converted to the hydrochloride in the routine manner to provide 0.70 g of the objective compound (white crystals).
m.p. 287-290 (decomp.) Elemental analysis (for C1~H23N302S-HC1~1/2Hz0) Calcd.(~): C, 53.89; H, 6.65; N, 11.09 Found (~): C, 53.79; H, 6.47; N, 11.35 Example 40 Hexahydro-3-methyl-1-[(4-methyl-5-isoauinolinyl)sulfonyil-1H-1,4-diazep~ne hydrochloride Using 0.72 g of hexahydro-2-methyl-1H-1,4-diazepine hydrobromide synthesized as in Example 12, the procedure of Example 39 was otherwise repeated to provide 0.53 g of the objective compound (white crystals).
m.p. 290-294°C (decomp. ) Elemental analysis (for C16HZ1N302S' HC1 ~ H20) Calcd.(~): C, 51.40; H, 6.47; N, 11.23 Found (~): C, 51.98; H, 6.95; N, 11.18 Example 41 (S)-(-)-Hexahydro-7-methy~ 1 !l4 methv~ 5 iso ~uinolinyi)su~fonyil-1H-1,~4-diazer>ine hydrochlor;~P
Using 2 . 0 g of 3- (S) -aminobutan-I-of (synthesized in accordance with J. Org. Chem., 1977, 42, 1650) in lieu of D-alaninol, and 2-aminoethanol in lieu of 3-amino-1-propanol, the procedure of Example 31 Process was otherwise repeated to provide 1.10 g of the objective compound (white crystals).
m.p. 282-285'~C
Elemental analysis (for Cl6HziNsOzS' HC1 ~ 1/2Hz0) Calcd.(~): C, 52.67; H, 6.35; N, 11.52 Found (~): C, 52.79; H, 6.19; N, 11.51 [ a ]D: -1. 74 (c=1. 03, Hz0) Example 42 (R) - (+) -Hexahydro-7-methyl -1- f (4-methyl 5 iso cJUi. nol , nyl ) st,_~ f'pny~ 1 -1H-1, 4-dlaZPI?; T~~~ h~rdrochl~~-; ~'1P
Using 2 . O g of 3- (R) -aminobutan-1-of (synthesized in accordance with J. Org. Chem., 1977, 42, 1650) in lieu of D-alaninol, and 2-aminoethanol in lieu of 3-amino-1-propanol, the procedure of Example 31 Process 2_ was otherwise repeated to provide I.20 g of the objective compound (white crystals).
m.p. 278-282°C (decomp.) Elemental analysis (for Cl6HziNsOzS'HC1'3/2Hz0) Calcd.(~r): C, 50.19; H, 6.58; N, 10.97 Found (~): C, 50.01; H, 6.14; N, 10.91 [ a JD: +2. 53 ~ (c=1.02, H20) Example 43 y,~. 2-Dimeth~,l-hexahvdro-1- L(4-methyl-5-iso-s~tainolinv~,y sulfonyl~ -1H-1 , 4-diazepine hydrochloride Using 1.30 g of 2-amino-2-methyl-1-propanol in lieu of D-alaninol, and 2-aminoethanol in lieu of 3-amino-1-propanol, the procedure of Example 31 Process 2., was otherwise repeated to provide 0.30 g of the objective compound (white crystals).
m.p. 279-282°0 (decomp. ) Elemental analysis (for C1.,HZ~N302S-HC1~H20) Calcd.(~S): C, 52.63; H, 6.76; N, 10.83 Found (~): C, 52.22; H, 6.83; N, 10.63 Example 44 2,.7-Dimethyl-hexahydro-1-[(4-methyl-5-iso-auinoli n~lL~l~ Sul fonyl 1-1H-1,.4-diazepine hydrochloride Using 1.0 g of 3-aminobutan-1-of in lieu of D-alaninol, and 1-amino-2-propanol in lieu of 3.-amino-1-propanol, the procedure of Example 31 Process was otherwise repeated to provide 0.60 g of the objective compound (white crystals).
m.p. 256-26090 (decomp. ) Elemental analysis (for C1~H23N302S ~ HCl ~ 1/2H20) Calcd.(~): C, 53.89; H, 6.65; N, 11.09 Found (~): C, 54.19; H, 6.57; N, 11.14 Example 45 ~g)-(+)-Hexahydro-5-methyl-1-fla-methyl-5-iso-~u~no~~nyiysulfonyi]-1H-lf4-diazepine hydrochloride Using 0.83 g of 2-aminoethanol in lieu of D-alaninol, and 3-(R)-aminobutan-1-of (synthesized a.n accordance with J. Org. Chem. , 1977, 42, 1650) in lieu of 3-amino-1-propanol, the procedure of Example 31 Process 2 was otherwise repeated to provide 0.41 g of the objective compound (white crystals).
m.p. 284-288°~C
Elemental analysis (for C16H21N302S-HC1~1/2H20) Calcd.(~S): C, 52.67; H, 6.35; N, 11.52 Found (~): C, 52.36; H, 6.10; N, 11.37 +3.61 (c=1.05, HZO) Example 46 (S)-l-)-Hexahydro-5-methyl-1-[f4-methyl-5-iso-t,~uinolinyl)sulfonyl]-1H-1,4-diazenine hydrochloride Using 0.50 g of 2-aminoethanol in lieu of D-alaninol, and 3-(S)-aminobutan-1-of (synthesized in accordance with J. Org. Chem. , 1977, 42, 1650) in lieu of 3-amino-1-propanol, the procedure of Example 31 Process 2 was otherwise repeated to provide 0.27 g of the objective compound (white crystals).
m.p. 283-284°C
Elemental analysis (for C16HZ1N30zS ~ HCl - H20) Calcd.(%): C, 51.40; H, 6.47; N, 11.23 Found (%): C, 51.28; H, 6.16; N, 11.11 [ a ] D : -4 . 00 ~ ( c=1 . 10 , Hz0) Example 47 (~~ - (+Z-2- ~~4-Aminobutyl ) -hexahydro-1- [ l4-met~~.yl-5-i ~oau; nW ; n~,lL~,~fonyl] -1H-1 ~4-dia define _ts~,_=
hvdrochhride (1) Under argon gas, 20 ml of 1M borane--tetra-hydrofuran complex was added dropwise to a solution of 5.0 g of N-a -tert-butoxycarbonyl-N-F -benzyloxy-carbonyl-L-lysine in 3 ml of tetrahydrofuran with ice-cooling and the mixture was stirred at room temperature for 1 . 5 hours. To this reaction mixture was added 10 ml of water-tetrahydrofuran, and after the aqueous layer was saturated with anhydrous potassium carbonate, the organic layer was discarded. The aqueous layer was extracted with ether three times and the extract was dried and concentrated. The residue was dissolved in ethyl acetate, followed by addition of 25%
HC1/ethyl acetate under ice-cooling. The mixture was stirred at room temperature for 2 hours and then concentrated to provide 2.15 g of (S)-2-amino-6-(benzyloxycarbonylamino)-1-hexanol (colorle ss oil) .
(2) Using 2. 15 g of the compound obtained :in (1) above in lieu of D-alaninol, the procedure of Example 31 Process 2 was otherwise repeated to provide 0.47 g of the objective compound (white crystals).
m. p . 232-240°C (decomp . ) Elemental analysis (for C19H28NsO2S ~ 3HC1 ~ 9/2H20) Calcd.(~): C, 40.25; H, 7.11; N, 9.88 Found (~): C, 40.03; H, 7.67; N, 9.74 [ a ~D: +30. 68 (c=1.15, CH30H) Formulation Example 1 Recipe (per ml) Compound of Example 21 3 mg Sodium chloride 9mg Water for injection q.s.
1 ml Preparation protocol Dissolve the Compound of Example 26 and sodium chloride in water for injection, filter the solution through a membrane filter (0.22 ~ m) , fill the filtrate i.n ampules, and sterilize to provide an aqueous injection.
Formulation Example 2 Recipe (per vial) Compound of Example 26 3 mg Mannitol 50 mg Preparation protocol Dissolve the compound of Example 26 and mannitol in water for injection, filter the solution aseptically through a membrane filter (0.22 a m) , fill the filtrate in vials, and lyophilize i.n the routine manner to provide an injection for extemporaneous reconstitution.
Formulation Example 3 Recipe (in 180 mg per tablet) Compound of Example 31 10 mg Lactose 100 mg Corn starch 55 mg Low-substitution hydroxypropylcellulose 9 mg Polyvinyl alcohol (partial hydrolysate) 5 mg Magnesium stearate 1 mg Preparation protocol Mix the above components other than polyvinyl alcohol and magnesium stearate uniformly and wet-granulate the mixture using an aqueous solution of polyvinyl alcohol as the binder to prepare granules for compression. Mix magnesium stearate with the above granulation and, using a compression tablet machine, mold the composition into oral tablets each weighing 180 mg.
Formulation Example 4 Recipe (in 220 mg per capsule) Compound of Example 45 10 mg Lactose 187 mg Microcrystalline cellulose 20 mg Magnesium stearate 3 mg 220 mg Preparation protocol Mix the above components uniformly and, using a capsule filling machine, fill the mixture into hard capsule shells, 220 mg per capsule, to provide hard capsules.
Formulation Example 5 Recipe (in each 1 g of granules) Compound of Example 26 10 mg -I~-a-otosa - 880 mg Low-substitution hydroxypropylcellulose 70 mg Hydroxypropylcellulose 40 mg 1000 mg Preparation protocol Mix the above components other than hydroxypropylcellulose uniformly, knead the mixture using an aqueous solution of hydroxypropylcellulose as the binder, and granulate the kneadings with a granulating machine to provide granules.
Test Example 1 FffeGt on the calcium ~ onox>ho~-e-induced contraction of the rat aorta Rats (SD, male, 10-14 weeks old) were sacrificed by exsanguination under ether anesthesia and the thoracic aorta (ca 3 cm) was isolated. After removal of the fat and connective tissue, the isolated aorta was sliced into rings about 3 mm in width. The luminal wall of the ring-shaped aortic preparation was rubbed to remove the endothelial cells. This preparation was suspended to the isometric tension transducer of a Magnus equipment containing an organ bath medium and loaded with a static tension of 1 g. The Magnus bath was maintained at 37°C under aerated with a mixed gas ( 9'S~ 02 + 5~ C02) and, with the organ bath replaced with fresh one at intervals of about 20 minutes, the aortic preparation was equilibrated for about 1 hour. To this preparation, calcium ionophore A23187 was added at a final concentration of 1 a M, and after the constant contractile responses of the aortic preparation were confirmed, the test compound was cumulatively administered. The contraction-relaxation response during the time was recorded and the 50~ inhibitory concentration [ICSO ( ~ M) ] of the test compound against A23187-induced vascular contraction was determined.
As a result, the ICSO values of the compounds of Example 12 and Example 26 were found to be 1.1 and 0.74, respectively. On the other hand, the ICSa value of the positive control fasudil hydrochloride was 5.1. The composition of the organ bath used in this experiment was: NaCl 115.9 mM (the same applies below); KC1 5.9;
CaCl2 2 . 5 ; MgClz 1 . 2 ; NaHZP01 1 . 2 ; NaHC03 25 . 0 ; glucose 11.5. Those components were dissolved in deionized distilled water. The pH of the organ bath saturated with said mixed gas was 7.4.
The compound of the invention has the action to relieve the contractile response of blood vessels to calcium ionophore and the intensity of the action was remarkably highas compared with fasudil hydrochloride.
Test Example 2 Using rats (SD, male, 11-12 weeks old)under urethane anesthesia, the head of each animal was fixed and the skin of the left buccal region was incised.
After the buccinator muscle was removed, the zygomatic bone was exposed. In the cranial bone, immediately above the middle cerebral artery (MCA), a hole about mm in diameter was drilled using an electric dental drill for allowing direct visual access to the MCA. The probe (diameter: 1.0 mm) of a laser Doppler blood flowmeter was placed in close proximity with the MCA
to monitor the change in MCA blood flow. The test compound Was dissolved and diluted in saline and 3 mg/kg was administered via a cannula from the femoral vein.
The dose volume was adjusted to 0.1 m1/100 g and the whole amount was administered over about 30 seconds.
The effect of each test compound was expressed as the percent increase in blood flow from the pre-administration basalirie and the duration of action was expressed in the period of time till return to the baseline. As a result, the compound of the invention was equivalent to fasudil hydrochloride in the percent increase a.n blood flow but was by far superior to fasudil hydrochloride in the duration of action. Thus, whereas the duration of action of fasudil hydrochloride was 2 . 3 minutes, those of the compound of Example 26 and Example 31 were 31.2 minutes and 36.0 minutes, respectively.
The compound of the invention has the action to increase the rat middle cerebral arterial blood flow and the duration of this action was by far .longer than that of fasudil hydrochloride.
Test Example 3 Oerebral vasosx~asm-relieving effect a.n the rat model of subarachnoid hemorrhagg With rats (SD, male, 11-12 weeks old) fixed in prone position under pentobarbital anesthesia, a midline incision was made in the dorsocervical region.

Then, 0.20 ml of cerebrospinal fluid was removed from the cranial cavity by cervical vertebral paracentesis and 0.30 ml of arterial blood from another rat was infused into the cisterns magna. Then, the head was tilted down through an angle of 20 degrees for 20 minutes to allow the blood to be distributed uniformly from the basilar artery to Willis' cords. On the following day, with the animal fixed in supine position under urethane anesthesia, the cervical region was incised for tracheal cannulation. After the occipital bone was exposed, the dura mater, arachnoid, and pie mater were incised to expose the basilar artery. After the incision was covered with liquid paraffin, the basilar artery was recorded under microscopic magnification on a video recorder and the diameter of the basilar artery was determined by image analysis. The test compound was administered in a dose of 3 mg/kg from the left femoral vein over 1 minute. The effect of each compound was expressed in the percent increase in diameter at the maximum relaxation time as compared with the pre-administration baseline. As a result, whereas the compounds of Example 1 and Example 21 caused increases of 21.4 and 15.1, respectively, in basilar artery diameter,fasudilhydrochloride causedonly anincrease of 7.5~.

Test Example 4 Cerebral vasoggasm-relieving effect in the canine model of subarachnoid hemorrhage According to the method of Varsos et al. (J.
Neurosurgery, ,~, 11-17, 1983] , a two-hemorrhage canine model was developed by twice injection of autologous blood into the cisterns magna. On day 1 of experiment, a control angiogram of the basilar artery prior to medication was recorded underpentobarbital anesthesia.
Then, 4 ml of cerebrospinal fluid was removed from the cisterns magna and the same volume of autologous blood was injected at a rate of 2 ml/min. After this blood injection, the head was tilted down through an angle of 30 degrees for 30 minutes to allow the blood to be distributed uniformly throughout Willis' cords. On day 3 of experiment, 4 ml of autologous blood was injected again into the cisterns magna. On day 7, a cerebral angiogram was taken under pentobarbital anesthesia to verify the induction of delayed cerebral vasospasm and the evaluation of the drug was then carried out. The test compound, 3 mg/kg, was administered from the left femoral vein over 1 minute .
Angiography was performed immediately before drug administration and 10, 20, 30, and 60 minutes after the start of administration. The action of each test compound was expressed i.n the percent increase in maximal sectional area of the basilar artery as compared with the baseline value prior to administration. As a result, the percent increases obtained with the compounds of Example 21, Example 26, and Example 31 were found to be 27. 9~, 37. 1~, and 34. 1~, respectively. On the other hand, the percent increase with the positive control fasudil hydrochloride was 9.1~. Thus, compared with fasudil hydrochloride, the compound of the invention showed very potent vasospasm-reversing activity and caused recovery of the caliber of the basilar artery substantially to the pre-treatment baseline value in the canine modal of subarachnoid hemorrhage.
Test Example 5 Rats (SD, male, 11-13 weeks old) were fixed in prone position under pentobarbital anesthesia and a midline incision was made in the dorsocervical region.
After 0.2 ml of cerebrospinal fluid was removed from the cranial cavity by cervical vertebral paracentesis, 0.30 ml of either artificial cerebrospinal fluid or rat arterial blood was injected into the cisterna magna over 1 minute. Then, the head was tilted down through 20 degrees for 10 minutes to allow the basilar arterial blood to be distributed uniformly in Willis' cords. The incision was treated with Terramycin and sutured and mg of Viccillin was administered intramuscularly.
After 24 hours, the rat was anesthetized with urethane (1.1 g/kg, i.p.) and fixed in supine position. The brain tissue was fixed by retrograde perfusion With PBS/formalin from the descending aorta and stained by infusing 0.8 ml of Monastral Blue from the descending aorta. After the brain was removed, the basilar arterial region was photographed and the diameter of the basilar artery was determined. The drug was dissolved in saline and administered over 1 minute into the right femoral vein 20 minutes after blood injection.
As a result, the group treated with 3 mg/kg i.v.
of the compound of Example 31 showed no evidence of the basilar artery vasospasm which was otherwise induced at 24 hours after blood infusion. With the positive control fasudil hydrochloride, the basilar artery vasospasm at 24 hours after blood injection was not observed in the group treated with 10 mg/kg i.v.
Test Example 6 Effect on cerebral infarction in the rat model of transient middle cerebral art--Pry occlusion With male rats (Slc:SD strain, 7 weeks old) anesthesized with halothane, the common carotid artery was incised and a nylon thread was inserted from the incision and advanced through the internal carotid artery to the origin of the middle cerebral artery.
After this arrest of middle cerebral arterial blood flow, the anesthesia was terminated and 2 hours later the nylon thread was removed for reperfusion. After 6 hours of reperfusion, the brain was removed and stained with triphenyltetrazolium chloride (TTC) for identification of the infarcted region. The infarct volume was determined for each of the cerebral cortex and the striatum. The drug was administered intravenously over 1 minute for a total of 3 times, i.e. 30 minutes before occlusion of the middle cerebral artery, immediately after occlusion, and one hour later.
Saline was administered as a control . The results were expressed in mean ~ standard error and analyzed for significant difference by the Dunnett method. As a result, the compound of Example 31, administered three' times at each dose of O. 1 or 0.3 mg/kg and the compound of Example 26, administered three times at 0.1 mg/kg respectively showed significant protection against infarction in both the cerebral cortex and the striat.
On the other hand, fasudil hydrochloride administered three times at 5 mg/kg showed significant antiinfarct effect for the striate body only.

Test Example 7 F:ffE~c-t- on cerebral infarction in the rat mod 1 of x~hotochemically inducP~ thrombot~~ (PIT) middle cerebral artery occlusion Male rats (Slc:SD strain, 7 weeks old) were inhalation-anesthetized with a 1-2~ halothane-containing mixed gas (nitrous oxide: oxygen = 70:30) and using an electric dental drill, a hole about 5 mm a.n diameter was drilled in the cranial bone immediately above the middle cerebral artery (MCA) to provide a direct visual access to the MCA. Rose Bengal (RB) , 20 mg/kg, was administered intravenously. After 5 minutes, using a three-dimensional manipulator, alight guide (diameter 3. O mm) as a light source for generating thrombosis was brought close to the MCA for irradiating the artery with green light for 10 minutes. After 24 hours, the animal was decapitated and the brain was removed. Coronal sections at 2 mm intervals were prepared and stained with TTC and the infarct volume for the whole brain was determined. The drug was administered intravenously over 1 minute for a total of 3 times, i.e. immediately after completion of green-light irradiation and 1 and 2 hours later. Saline was administered in a same way as a control . The results were expressed in mean ~ standard error and analyzed for significant difference by the Dunnett method. As a result, the compound of Example 31 showed a significant antiinfarct effect at the dose of 0.3 or 3 mg/kg x 3. On the other hand, fasudil hydrochloride showed a significant antiinfarct effect at 10 mg/kg x 3.
Test Example 8 Acute toxicitv Using 5-week-old male ddY mice (6 per group) , the test drug was administered over 60 seconds from the caudal vain and the animal was observed for mortality over the subsequent 24-hour period. The test drug was used as dissolved and diluted in saline or dimethyl sulfoxide (DMSO) . As the test drugs, the compounds of Example l, Example 21, Example 22, and Example 24 and fasudil hydrochloride were used_ As a result, none of the compounds of the invention and fasudil hydrochloride caused death at the dose of 40 mg/kg.
INDUSTRIAL APPLICABILITY
Thus, compared with the control fasudil hydrochloride, the compound of the invention showed sufficient cerebral vasospasm-reversing activity in much lower dose. Moreover, the duration of action of the compound of the invention was also considerably longer. Those findings suggest the usefulness of the compound of the invention in the prevention and treatment of cerebrovascular diseases, particularly brain tissue impairments due to the cerebral vasospasm subsequent to cerebral hemorrhage. Furthermore, the compound of the invention has cerebral vasodilating activity and protectant activity against ischemic neuronal death, thus being useful for the management of sequelae of cerebral hemorrhage, cerebral infarction, transient cerebral ischemic attack, or head trauma.

Claims (22)

CLAIMS:

1. A compound of general formula [I]:

wherein:
R1 is C1-C6 alkyl or a halogen atom;
R2 is H, hydroxy or a halogen atom;
R3 is H, C1-C6 alkyl or amidino; and Ring A is a 5 to 11-membered cyclic amino group which may be bridged between two carbon atoms in optional positions and which is optionally substituted by a C1-C6 alkyl group, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

2. The compound according to claim 1, wherein R1 is C1-C6 alkyl.

3. The compound according to claim 2, wherein the alkyl has 1-4 carbon atoms.

4. The compound according to claim 2, wherein the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and isohexyl.

5. The compound according to any one of claims 2 to 4, wherein the alkyl is methyl.

6. The compound according to any one of claims 1 to 5, wherein R2 is H.

7. The compound according to any one of claims 1 to 6, wherein R3 is H.

8. The compound according to any one of claims 1 to 7, wherein ring A is hexahydro-1H-1,4-diazepin-1-yl, the ring carbon atom or atoms of which may be substituted by a C1-C6 alkyl moiety.

9. The compound according to claim 8, wherein ring A
is selected from the group consisting of 2-methyl-hexahydro-1H-1,4-diazepin-1-yl and 7-methyl-hexahydro-1H-1,4-diazepin-1-yl.

10. A compound according to claim 1, selected from the group consisting of hexahydro-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepine dihydrochloride, (S) -(+)-hexahydro-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepine hydrochloride, hexahydro-7-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepine dihydrochloride, hexahydro-5-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepine dihydrochloride, hexahydro-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepine hydrochloride, (R)-(-)-hexahydro-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-d iazepine hydrochloride and (R) -(+)-hexahydro-5-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]-1H-1,4-diazepine hydrochloride.

11. A pharmaceutical composition for treating cerebrovascular disease comprising a therapeutically effective amount of the compound according to any one of claims 1 to 10, in combination with a pharmaceutically acceptable carrier or diluent.

12. A pharmaceutical composition for reducing the risk of cerebral vasospasm in a subject at risk, comprising as active ingredient the compound according to any one of claims 1 to 10, in an amount effective to reduce the risk of cerebral vasospasm following a subarachanoid hemorrhage, in admixture with a pharmaceutically acceptable carrier or diluent.

13. A pharmaceutical composition for the prevention or inhibition of cerebral vasospasm following a subarachanoid hemorrhage in a subject at risk, comprising as active ingredient the compound according to any one of claims 1 to 10, in an amount effective to inhibit or prevent cerebral vasospasm following a subarachanoid hemorrhage in a subject at risk, in admixture with a pharmaceutically acceptable carrier or diluent.

14. A pharmaceutical composition for increasing cerebral blood flow volume in a subject, comprising as active ingredient the compound according to any one of claims 1 to 10, in an amount effective to increase cerebral blood flow volume in a subject, in admixture with a pharmaceutically acceptable carrier or diluent.

15. Use of a compound according to any one of claims 1 to 10 to reduce the risk of cerebral vasospasm in a subject at risk.

16. Use of a compound according to any one of claims 1 to 10 to treat a subject suffering from a cerebrovascular disease.

17. Use of a compound according to any one of claims 1 to 10 to inhibit or prevent cerebral vasospasm following a subarachanoid hemorrhage in a subject at risk.

18. Use of a compound according to any one of claims 1 to 10 to increase cerebral blood flow volume in a subject.

19. A commercial package containing as active pharmaceutical ingredient the compound of any one of claims 1 to 10, together with instructions for the use thereof for reducing the risk of cerebral vasospasm following a subarachanoid hemorrhage in a subject at risk.

20. A commercial package containing as active pharmaceutical ingredient the compound of any one of claims 1 to 10, together with instructions for the use thereof for the treatment of cerebrovascular disease.

21. A commercial package containing as active pharmaceutical ingredient the compound of any one of claims 1 to 10, together with instructions for the use thereof for the inhibition or prevention of cerebral vasospasm following a subarachanoid hemorrhage in a subject at risk.

22. A commercial package containing as active pharmaceutical ingredient the compound of any one of claims 1 to 10, together with instructions for the use thereof for increasing cerebral blood flow volume in a subject.