DD296684A5 - Kumarin derivatives, their preparation and their use in the treatment of cerebrovascular diseases - Google Patents

Abstract

Coumarin derivatives of the formula wherein A is a group of the formula (II) or (III); R1, R2 and R3 are hydrogen, lower alkyl or halogen groups; R4 is hydrogen, a lower alkyl or aralkyl group; R5 and R6 are hydrogen or lower alkyl groups; or R7 and R8 together are alkylene; and m is 1 or 2 and their pharmaceutically acceptable salts are useful in the treatment of cardiovascular disorders. Formulas (I) to (III) {coumarin derivatives; pharmaceutically acceptable salts of these coumarin derivatives; Treatment of cardiovascular disorders}

Description

The invention relates to the use of a particular group of 7- (substituted alkoxy) coumarin derivatives in the medical treatment of cerebrovascular disorders and to pharmaceutical compositions containing these compounds. Further provided in the invention are certain novel and useful compounds of this group and methods for their preparation.

The compounds known hitherto for the treatment of cerebrovascular disorders can be classified into two groups as follows: one group consists of compounds which improve cerebral circulation, the other group consists of compounds which activate brain metabolism. Cerebral perfusion enhancers such as nicardipine and pentoxifylline improve cerebral blood flow by relaxing the cerebrovascular smooth muscle or by improving brain microcirculation, resulting in an improvement in any brain dysfunction. Compounds that activate brain metabolism, such as tiapride and indeloxazine, improve the mental symptoms by activating the nerve-transmitting monoamine compounds, such as serotonin, norepinephrine, and dopamine. Some compounds have been developed, both of which have the mentioned activities, but so far there is no compound of this kind which has sufficient clinical activity.

Known are the 7- (substituted alkoxy) coumarin derivatives as a group, it is also known that these compounds have certain limited therapeutic effects, yet they have not heretofore been proposed for the treatment of cerebrovascular disorders. Known compounds are included in the following: Indian J. Appl. Chem., 32 (1), 65-68 (1969) / see Chem. Abs., 75, 20107s (1971); Res. Commun. Chem. Pathol. Pharmacol., 9 (3), 555-560 (1974) / see Chem. Abs., 82, 93490 r

(1975) /; UK patent no. 1 524260; Japanese Patent Application Kokai No. Sho. 45-23145; Indian J. Chem. Sect. B, 20B (2), 171-174 (1981) / see Chem. Abs., 95, 6981 d (1981) /; Japanese Patent Application Kokai No. Sho. 42-4340; and PCT Publication No. WO 89/05289. The examples of compounds set forth in the prior publications include the compounds A to F shown below.

Compound A:

H ₅ C ₂ *

N- (CH ₂ ) 2- ° - '' / I II

H ₅ C ₂

Compound B:

H3C

WW

N- (CH ₂ ) 3 -O- · · ·

/ I Il I

H3C · · ·

WW

• ·

CH ₃ compound C:

Λ Λ / °

N- (CH ₂ ) ₂ -O- ···

/ I Il I

OH

Compound D:

CH ₂ CH = CH ₂

• O O

/ WW

H ₂ N- (CH ₂ ) ₃ -O-. ·

I Il

WW

• ·

CH ₃ compound E:

.00

/ WW

WW

• ·

I i

CH ₃ C CH ₃ Compound F: q

H5C2 «00

WW

N- (CH ₂ ) 2 -O- · · ·

/ I Il I

H ₅ C ₂

W W \

, CH ₂ COOCH ₂ CH ₃

The most relevant of the previous publications is Res. Commun. Chem. Pathol. Pharmacol., 9 (3), 555-560 (1974), which discloses certain compounds which we believe to be useful in the medical treatment of cerebrovascular disorders and the use of which forms part of this invention. However, none of the related prior art compounds has been presented in terms of the effect addressed in this invention.

Our discovery is that a group of 7- (substituted alkoxy) coumarin derivatives has the ability to enhance the ischemia-induced hyperviscosity of the blood, to exhibit anti-reserpine activity, and therefore of value in the treatment of patients with cerebrovascular disease Interference, including z. Myocardial infarction and arteriosclerotic dementia.

Accordingly, an object of this invention is a group of 7- (substituted alkoxy) coumarin derivatives for the medical treatment of cerebrovascular disorders.

Another object of this invention are certain novel 7- (substituted alkoxy) coumarin derivatives as novel compounds of the invention.

Other objects and advantages of this invention will become apparent in the further description.

The compounds according to the invention therefore have the following formula (I):

I COO

/ WW

A- (CH ₂ ) _m -O-C CC

I Il I ^(l)

H-C C C

WWX ₁

CCR ¹

I L

HR ²

in the:

A represents a group of the formula (II) or (III):

H ₂ C CH ₂ ""

I i

H ₂ C HC-

X /

\ N-CH-CH-

ί ¹ V 'a ^(III);

R ⁶ R ⁷ R ⁸

R ¹ , R ² and R ³ are independently selected from the group consisting of hydrogen atoms, alkyl groups of 1 to 4 carbon atoms and halogen atoms;

R ⁴ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, said alkyl group being unsubstituted or having at least one substituent selected from the group consisting of aryl groups having 6 to 10 carbon atoms, said aryl group being unsubstituted or at least one substituent from the group which consists of the substituents (a) defined below;

R ⁵ and R ⁶ are independently selected from the group consisting of hydrogen atoms and alkyl groups of 1 to 4 carbon atoms;

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen atoms and alkyl groups of 1 to 4 carbon atoms; or R ⁷ and R ⁸ together are an alkene group having 3 or 4 carbon atoms; m is 1 or 2.

Substituents (a):

Alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, trifluoromethyl groups, nitro groups, cyano groups and halogen atoms; and their pharmaceutically acceptable salts.

In the broadest sense, the invention relates to the use of the above-mentioned compounds of the formula (I) and their salts in the medical treatment of cerebrovascular disorders.

All of the above compounds of formula (I) are novel except those in which A represents a group of formula (III). Accordingly, the invention also relates, as novel compounds, to the compounds of the formula (I) and their pharmaceutically acceptable salts explained above, with the proviso that R ⁵ and R ^{6 are} not identical and are either a methyl group or an ethyl group, if A is a group of the formula (II) III) and R ¹ , R ³ , R ⁷ and R ⁸ together represent hydrogen atoms and R ^{2 represents} a methyl group and m is 1.

The invention also relates to a pharmaceutical composition for the treatment of cerebrovascular disorders comprising a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt of said compound as an adjunct to a pharmaceutically acceptable carrier, diluent or excipient.

Of the compounds of the present invention, a class of the compounds can be represented by the following formula (Ia); r4

NR ³

H ₂ C CH ₂ COO

H ₂ C CH- (CH ₂ ) _m -O-CCC _{(| a)}

I Il

O H-C C C

HR ²

where R ¹ , R ² , R ³ , R ⁴ and m are as explained above and m may be 1, for example.

Another class of the compounds according to the invention are the compounds of formula (Ib):

r5 'C O. O

WW

N-CH-CH- (CH ₂ ) _m -O-CCC

I ₇ LI II ^(lb)

r7 h-C C C

WWX ₁

CCR ¹

HR ²

wherein R ¹ , R ² , R ³ , R ⁶ , R ⁶ , R ⁷ , R ⁸ and m explained above and R ⁷ and R ^{8 may be,} for example, hydrogen atoms.

In the compounds according to the invention in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ^{8 represents} an alkyl group, this has 1 to 4 carbon atoms and may be a straight- or branched-chain group. Examples of these groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups, of which the methyl group is preferred. Where R ¹ , R ² or R ^{3 represents} a halogen atom, this may be a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom.

When R ^{4 represents} an alkyl group having an aryl substituent, that is, an aralkyl group, then the alkyl portion may be any of the above-mentioned alkyl groups, but preferably a methyl, ethyl, propyl or isopropyl group, more preferably a methyl or ethyl group and best a methyl group. The aryl portion has 6 to 10 ring atoms, and is preferably a phenyl, α-naphthyl or β-naphthyl group, and more preferably a phenyl group. In particular, when the aryl part is a phenyl group, there may be 2 or more of these aryl parts, but such an aryl part is preferable. Examples of unsubstituted aralkyl groups are the benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, benzhydryl and a-naphthylmethyl groups, of which the benzyl, phenethyl and 3-phenylpropyl groups have priority and the benzyl group most preferred. These groups may be unsubstituted or substituted by at least one of the abovementioned substituents (a). Examples of substituents (a) include the above-mentioned alkyl groups, alkoxy groups corresponding to these mentioned alkyl groups, trifluoromethyl groups, nitro groups, cyano groups and halogen groups. However, preferred are the unsubstituted groups.

When R ⁷ and R ⁸ together form an alkene group having 3 or 4 carbon atoms, then the group of formula (III) represents a cyclo-pentyl (C ₃ -alkylene) or a cyclohexyl (C ₄ -alkylene) group with 2-amino Substituents.

All compounds of this invention in which A represents a group of formula (II) are novel and those compounds which contain compounds of formula (Ia), taken alone, form part of the invention. The compounds of formula (I) wherein A represents a group of formula (III) and R ⁵ and R ^{6 are the} same and either a methyl group or an ethyl group and R ¹ , R ³ , R ⁷ and R ^{8 are} hydrogen and R ^{2 is} a methyl group and m is 1 are not claimed per se, but are suitable in the medical treatment of cerebrovascular disorders. Of the compounds of the formula (Ia), the following are preferred:

(A) the compounds in which R ^{1 represents} a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a fluorine atom or a chlorine atom;

(B) the compounds in which R ^{2 represents} a hydrogen atom, a methyl group, an ethyl group, a propyl group or an isopropyl group;

(C) the compounds in which R ^{3 represents} a hydrogen atom, a methyl group, an ethyl group or an isopropyl group;

(D) the compounds in which R ^{4 represents} a hydrogen atom; and particularly preferred are the compounds in which:

(E) R ^{1 represents} a hydrogen atom, a methyl group, a fluorine atom or a chlorine atom, R ² and R ^{3 are the} same or different and each represents a hydrogen atom or a methyl group, and R ^{4 represents} a hydrogen atom;

(F) m is equal to 1.

Of the compounds of the formula (Ib), the following are preferred:

(G) the compounds in which both R ⁶ and R ^{6 are} hydrogen atoms;

(H) the compounds in which R ^{5 represents} a hydrogen atom and R ^{6 represents} an alkyl group of 1 to 4 carbon atoms; more preferred are the compounds in which R ^{5 represents} a hydrogen atom and R ^{6 represents} a methyl group;

(I) the compounds in which R ⁶ and R ^{6 are the} same or different and each represents a methyl or ethyl group;

(J) the compounds in which R ^{1 represents} a hydrogen atom, a chlorine atom or a methyl group;

(K) the compounds in which R ^{2 represents} a hydrogen atom or a methyl group;

(L) the compounds in which R ^{3 represents} a hydrogen atom or a methyl group.

Sequence Compounds of the formula (Ib) are more preferred:

(M) the compounds in which

R ¹ , R ² and R ^{3 represent} methyl groups;

R ⁵ and R ^{6 represent} hydrogen atoms and

R ⁷ and R ^{8 are} independently selected from the group consisting of hydrogen atoms, methyl groups, ethyl groups and isopropyl groups;

(N) the compounds in which

R ¹ , R ² and R ^{3 represent} methyl groups;

R ^{6 represents} a hydrogen atom;

R ^{6 represents} a methyl group and

R ⁷ and R ^{8 are} independently selected from the group consisting of hydrogen atoms, methyl groups, ethyl groups and isopropyl groups:

(O) the compounds in which

R ¹ , R ² and R ^{3 represent} methyl groups;

R ^s and R ^{6 represent} methyl groups and

R ⁷ and R ^{8 were} independently selected from the group consisting of hydrogen atoms, methyl groups, ethyl groups and isopropyl groups.

Although the compounds of the present invention are all represented by a single general formula (I), the compounds may exist in the form of various isomers depending on the kinds of the substituent groups. In particular, the compounds of the formula (Ia) can exist as two kinds of optical isomers, in the R form and in the S form, since the 2-morpholinylmethoxy group contains the asymmetric carbon atom; likewise, the compounds of formula (Ib) may occur as two or four kinds of optical isomers, ie in the R-form and in the S-form, due to the asymmetric carbon atom (s) when R ⁷ and or R ^{8 represents} an alkyl group. This invention includes both the individual isolated isomers and their mixtures, including the racemic mixtures (those of equimolar

Reagent mixtures may arise). As is known, sometimes some compounds as the isomer pair have greater activity or more desirable properties than the other pair, and in that case it is appropriate to use the better isomer alone. On the other hand, if necessary, the compounds may be used as a mixture of two or more isomers without any disadvantage. If individual isomers are required, they can be prepared by the stereospecific synthetic methods explained below and exemplified. Deviating from this, mixtures of the compounds according to the invention can be prepared and then separated off by conventional separation processes. The compounds according to the invention contain a basic nitrogen atom and can therefore form salts with suitable acids. There is basically no restriction on the nature of the acids used to form these salts. However, when the resulting salt is to be used for therapeutic purposes, the salt is required to be pharmaceutically acceptable, which is known to mean that the effect will not be reduced (or unacceptably reduced) or increased in toxicity (or unacceptably increased toxicity) Comparison to the free base is present. When using this salt for other purposes, eg. As an intermediate in the preparation of another and possibly more active compound, this restriction is out of the question. Examples of suitable acids are: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; organic carboxylic acids such as oxalic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid, and inorganic sulfonic acids such as methanesulfonic acid. Examples of specific compounds of the present invention are represented by the following formulas (1-1) to (I-3) in which the substituents are as explained in Table 1 to 3, i. Table 1 relates to formula (1-1), table 2 formula (I-2) and table 3 formula (I-3).

r4

NR ³

H ₂ C CH ₂ COO

I / WW

H ₂ C 1 -C 4 CH-CH ₂ -OC CC _(M)

O H-C C C

WWV ₁

CCR ¹

HR ²

_R 3

I r5 COO

V λ W W

N- (CHO) _n -OC CC

/ I Il I (1-2)

r6 H-C C C

WWV ₁

CCR ¹ HR ²

I r5 COO

N-CH-CH-CH ₂ -OC CC

ZII I Il I ^{( ]}

RO r7 r8 H-C C C

WWV ₁

CCR ¹

I L

HR ²

In Table 3, the compounds 3-11 and 3-12, R ⁷ and R ⁸ together represent either a trimethylene group or a tetramethylene group which, with the carbon atom to which they are attached, form either a cyclopentane ring or a cyclohexane ring.

The following tables use abbreviations that have the following meanings:

Bu Table 1 R ¹ butyl R ³ R ⁴ R ⁶ η et Cpd H ethyl H H me 3 me No. H methyl H H me 4 iPr 1-1 H isopropyl me H me 3 1-2 me me H me 4 1-3 me H H et 3 1 ^ 1 Cl R ² H H et 4 1-5 me H me me me 3 1-6 et me me H me 4 1-7 et me H H me 3 1-8 iPr me me H me 4 1-9 iPr me H H me 3 1-10 Bu me me H me 4 1-11 Bu me H H me 3 1-12 H me H H me 4 1-13 me me 3 1-14 me me 4 Table 2 R ¹ me R ³ R ⁶ me 3 Cpd me me me H me 4 No. me me me H iPr 3 2-1 Cl pr me H iPr 4 2-2 Cl me H me 3 2-3 me me H me 3 2-4 me R ² me H me 3 2-5 me me H H me 4 2-6 me me H H me 3 2-7 H me me H et 3 2-8 H me me H et 3 2-9 H me H H me 3 2-10 H me H H me 4 2-11 H me me H H 3 2-12 H me me H H 4 2-13 me me H H H 3 2-14 me me H H H 4 2-15 H me H H 2-16 H me H H 2-17 me H me H 2-18 me H me H 2-19 F H me H 2-20 F H H H 2-21 me H me me 2-22 me H me me 2-23 F me me me 2-24 me me me me 2-25 me me me et 2-26 me me H me 2-27 me me H me 2-28 me me me H 2-29 me me me H 2-30 me me H H 2-31 me me H H 2-32 me 2-33 me me me me me

R ¹ R ² R ³ R ⁵ 1-3,1-4,1-5, 1-7,2-1,2-2, 2-5, 2-7, 2-23,2-24,2-28, 2-30 R ⁶ R ⁷ -C ₃ H ₆ - me -12- 296 684 R ⁸ Table 3 me me me H H me -C ₄ H ₈ - me H Cpd me me me H H H me me No. me me me H H et me H 3-1 me me me H H et me et 3-2 me me me H H iPr me H 3-3 me me me H H H me iPr 3-4 me me me H me me me H 3-5 me me me me me me me H 3-6 me me me H me me H me 3-7 me me me H me et me H 3-8 me me me H H 3-9 me me me H H 2-32,3-1,3-2,3-5, 3-10 me me H H H H 3-11 H me me H H H 3-12 H H H H H H 3-13 H me H H H H 3-14 H et H H H H 3-15 et me H H H H 3-16 et me me H H H 3-17 H me et H H H 3-18 me me et H H H 3-19 me me me H H et 3-20 me me me H H et 3-21 Of the compounds listed above, the following are preferred: 3-22 1-1,1-2, , 2-31, 3-7 3-8 and 3-11. Even stronger 3-23

preferred are the following compounds:

1-1,1-2,1-4,1-5,1-7,2-1, 2-23, 2-30,3-1,3-5,3-8 and 3-11.

The most preferred compounds are as follows:

1-4. 3,4,8-trimethyl-7- (2-rnorpholinyl) methoxycoumarin; 1-5.3,4-dimethyl-7- (2-morpho ynyl) methoxycumarine; 1-7.3,4,8-trimethyl-7- (4-methyl-2-morpholinyl) methoxycoumarin; 2-23. 7- (3-N, N-dimethylamino) -3,4,8-trimethylcoumarin; 2-30. 7- (3-aminopropoxy) -3,4,8-trimethylcoumarin and 3-1.7- (3-aminobutoxy) -3,4,8-trimethylcoumarin.

Also preferred are pharmaceutically acceptable salts of the above compounds, especially hydrochlorides and fumarates.

The compounds of the invention can be prepared by a variety of known methods for compounds of this type. Generally speaking, the compounds can be prepared as follows:

(a) by reaction of a compound of formula (IV):

r3

I COO

HO-C C C

I Il I (IV)

H-C C C

HR ²

(wherein R ¹ , R ² and R ³ as explained above) with a compound of formula (V):

Y- (CH ₂ LA '(V)

(where m is as explained above, Y is a halogen atom, a sulphonyloxy group or a hydroxy group and A 'is a group of the formula (H') or (MI '):

H ₂ C CH ₂ ^(ΙΠ

IIH ₂ C HC-

VcH-CH- ^(Ι1Π

r6 'R ⁷ R ⁸

(wherein R ⁶ , R ⁷ and R ⁸ as explained above, R ^{4 represents} an amino-protecting group or an alkyl group having 1 to 4 carbon atoms and this alkyl group is unsubstituted or at least one substituent selected from the group consisting of aryl groups having 6 to 10 Having carbon atoms or at least one substituent selected from the group consisting of the substituents (a) as explained above, and R ^{6 represents} an amino-protecting group or an alkyl group having 1 to 4 carbon atoms, and

if necessary, by eliminating the amino-protecting group with one of the steps (b) or (c):

(b) when A 'said group of formula (ΙΓ) and R ^{4 represents} an amino-protecting group or said group of formula (III') and R ^{e represents} an amino-protecting group;

(c) when the product is a compound in which R ⁵ or R ⁶ or both represent a hydrogen atom, by alkylating the hydrogen atom for conversion to an alkyl group having 1 to 4 carbon atoms; and by optionally transferring the product to a salt.

More specifically, the preferred methods of this invention can be illustrated by the following reaction schemes:

Reaction Scheme A:

IOO · OH X- (CH ₂ ) _m O

WWW W \

/ \ / w w

Rl · N

'R ² R ⁴

(IV) (VI)

base

-HX [Step Al

IO (CH ₂ ) _m -O COO

/ V / WWW

H ₂ C HC CCC

Il Il I I

HoC CH ₂ HC CC

\ I WWV

N CCR ¹

r4 "HR ²

(Ia)

Reaction Scheme B:

OO · OH X- (CH ₂ ) _m 0

WWW V / V

I Il ⁺ Il

R ¹ · N

_R 2 _R 4 '''

(IV) (VII)

0 (CH ₂ ) _m -O COO

/ WWWW

Base H ₂ C HC CCC

-HX H ₂ C CH ₂ HC CC

V / WWV ₁

[Step Bl] N CC R ¹

A «- A A *

(VIII)

0 (CH ₂ ) _m -O COO

I \ I \ I \ IV /

Deprotection H ₂ C HC CCC

I

[Step B2] H ₂ C CH ₂ HC CC

V / WWV ₁

N CCR ¹

I II

H HR ²

(Ia ')

ι.

O O φ OH

WWW

IIH. + X-CH-CH- (CH ₂ ) _m -N-R 5

/ \ / \ / R ⁸ R ⁷ R ⁶

R ¹ · ·

I (IX)

(IV)

base

-HX [Step Cl]

R ⁵ COO

\ I \ I \ I

N-CH-CH- (CH ₂ ) _m -OC CC

L I ₇ L ι H ι

R ⁵ R ⁷ R ⁸ HC CC

I L

HR ² (Ib ')

Reaction Scheme D:

O O · OH

IIH +. X-CH-CH- (CH ₂ ) _m -N-R 5

• · · Il I

, / WW R ⁸ R ⁷

R ¹ ·

L (IXa)

R ²

(IV)

-HX [Step Dl]

5 COO

WW

N-CH-CH- (CH ₂ ) _m -O-CCC

/ Il I Il I Deprotection

6a r ~

_R 6a _R 7 _R 8 _H _c CC

W W \ C C Rl

(X)

RS COO

N-CH-CH- (CH ₂ ) _m -OC CC

/ Il I II

HR ⁷ R ⁸ HC CC

WWX ₁ CCR ¹

HR ² (Ib ")

Reaction Scheme E:

I [Step D2]

HR ²

O O · OH

II II - + HO-CH-CH- (CH ₂ ) _m -NR ⁵

I II

/ \ / \ / R ⁸ R ⁷ R ⁶ '

R ¹ ·.

I (XI)

R ²

(IV)

Dehydrating agent

- * -H ₂ O

[Step El]

i.5 COO

N-CH-CH- (CH ₂ ) _m -O-CCC

UL I II

r7 r8 H-C C C

W N / N,

CCR ¹

HR ²

In the above version of the formulas R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁶ , R ⁷ , R ⁸ , m and R ⁶ 'are as explained above; R ⁴ "represents an alkyl group of 1 to 4 carbon atoms, said alkyl group being unsubstituted or having at least one substituent selected from the group consisting of aryl groups of 6 to 10 carbon atoms, said aryl group being unsubstituted or having at least one substituent selected from the group which consists of the substituents (a) as explained above; R ⁴ "represents an amino-protecting group; R ⁶ "is an alkyl group; R ^6a is an amino-protecting group; and X represents a halogen atom or a sulphonyloxy group.

Examples of halogen atoms which can be represented by X or Y are chlorine, bromine or iodine atoms. Examples of sulfonyloxy groups represented by X or Y are alkylsulfonyloxy groups such as methylsulfonyloxy and ethylsulfonyloxy groups, and arylsulfonyloxy groups such as phenylsulfonyloxy, ^ methylphenylsulfonyloxy and ^ nitrophenylsulfonyloxy groups.

There are no particular restrictions on the nature of the amino-protecting groups that can be used in the above reactions because the group is eliminated during the reaction and thus has no effect on the final product, as each group prevents the amino group from being undesired Participation in the reaction can protect. Examples of amino-protecting groups which may be used in the reaction are: aralkyl groups such as benzyl, p-methoxybenzyl and triphenylmethyl groups; Trialkylsilyl groups such as the trimethylsilyl and t-butylmethylsilyl groups; Acyl groups such as the formyl, acetyl and trifluoroacetyl groups; and alkoxycarbonyl-ralkyloxycarbonyl groups such as the benzyloxycarbonyl, the p-nitrobenzyloxycarbonyl, the methoxycarbonyl, the ethoxycarbonyl and the T-butoxycarbonyl groups, of which the acyl, alkoxycarbonyl and aralkyloxycarbonyl groups are preferred.

Steps A1, B1, C1 and D1 of Schemes A, B, C and D basically involve the same reaction in which a hydroxy compound of formula (IV) is reacted with a halide or sulfonate of formula (VI), (VII), ( IX) or (IXa) or in the presence of a base and an inert solvent.

There are no particular limitations on the type of solvent to be used, provided that it has no adverse effect on the reaction or on the reactants. Examples of suitable solvents are:

Hydrocarbons, especially aromatic hydrocarbons such as benzene or toluene, ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol, ethanol and t-butanol, amides such as N, IM-dimethylformamide, Ν, Ν-dimethylacetamide and N-methyl 2-pyrrolidone, and sulfoxide such as dimethylsulfoxide. Preferred are ketones and amides.

Again, there are no limitations on the nature of the base to be used so that any base common to reactions can be used equally provided it has no deleterious effect on other parts of the molecule.

Examples of such bases are: alkali metal hydrides such as lithium hydride and sodium hydride, alkali metal alcoholates such as sodium methylate, sodium ethylate and potassium t-butylate and alkali hydrogen carbonates such as sodium bicarbonate and potassium bicarbonate and alkali metal carbonates such as sodium carbonate and potassium carbonate. Preferred alkali metal hydrides are the alkali metal carbonates.

The reaction can proceed in a wide temperature range, the exact reaction temperature is not critical. The reaction should be carried out best between 0 ⁰ C and 12O ⁰ C (preferably between 20 ⁰ C and 80 ° C). Also, the reaction time may vary widely and depends on many factors, especially the reaction temperature and the nature of the reactants. Provided that the reaction proceeds under the conditions listed above, a reaction time of 1 to 24 hours is sufficient.

The resulting compound of formula (Ia '), (VIII), (Ib') or (X) may be optionally separated from the reaction mixture in any manner. This can e.g. in the following stages: extraction with an organic solvent such as ethyl acetate, rinsing of the extract with water, drying, e.g. over anhydrous sodium or magnesium sulfate and then distilling off the solvent. If necessary, the compound may be further purified by various conventional methods, e.g. B. by recrystallization or with various chromatographic methods, especially by column chromatography or preparative thin layer chromatography. The compound can also be used in each subsequent stage without special intermediate cleaning.

The starting compound of the formula (IV) used in this step is either a known compound or easily prepared by known methods, for example, as described in Journal of Organic Chemistry 27,3703 (1962).

In step B 2 and D 2, the amino-protecting groups are removed if necessary. This separation reaction can be carried out in any known manner, but the exact method depends on the nature of the protecting group to be removed. For example, aralkyl and aralkyloxycarbonyl groups such as benzyl and benzyloxycarbonyl groups can be removed by catalytic reduction using a palladium catalyst; Triphenylmethyl groups, trialkylsilyl groups (such as the trimethylsilyl group) and t-butoxycarbonyl groups can be removed with the aid of an acid such as aqueous acetic acid, hydrochloric acid dioxane or hydrogen chloride acetate, and acyl groups (such as formyl, acetyl and trifluoroacetyl groups) and alkoxycarbonyl groups.

and aralkyloxycarbonyl groups (such as the benzyloxycarbonyl group) can be removed using an alkali such as sodium methylate, sodium ethylate, sodium hydroxide or potassium hydroxide; Trialkylsilyl groups such as the t-butylmethylsilyl group can be removed using a compound that can generate fluorine ions. There are no particular limitations on the type of solvent used to remove the protecting groups in the reaction, provided it does not adversely affect the reactions or the reactants. Examples of suitable solvents are: water, alcohols such as methanol and ethanol, lower fatty acids such as acetic acid, ethers such as tetrahydrofuran and dioxane, esters such as ethyl acetate and halogenated hydrocarbons, in particular aliphatic halogenated hydrocarbons such as methylene chloride. The reactions can take place over a wide range of temperatures, and it is not the exact reaction temperature that is crucial to the invention. The reactions should be carried out best between O ⁰ C and 100 ⁰ C (preferably at room temperature to 80 ⁰ C). Also, the reaction time can vary widely and depends on many factors, especially the reaction temperature and the nature of the reactants. Provided that the reactions proceed under the above-mentioned preferential conditions, a reaction time of 30 minutes to 24 hours (preferably 1 to 16 hours) is normally sufficient.

After completion of the reaction, the reaction product may be separated in an organic solvent such as ethyl acetate or diethyl ether in the form of a salt of the compound of the formula (I) by adding an acid such as hydrochloric acid. Also, the reaction product can be separated by making the reaction solution alkaline and then extracting the free compound of the formula (I) with an organic solvent such as ethyl acetate. If necessary, the compound can be further purified by various conventional methods, e.g. B. by recrystallization or by various chromatography methods, especially by column chromatography or preparative thin layer chromatography. In level E; of Reaction Scheme E, a hydroxy compound of the formula (IV) reacts with an α-amino-o-hydroxy compound of the formula (XI) in the presence of a dehydrating agent. There are no particular restrictions on the nature of the solvent to be used, provided it does not adversely affect the reaction or the reactants. Examples of suitable solvents are: hydrocarbons, in particular aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons, in particular aliphatic halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane, ketones such as acetone and methyl ethyl ketone and amides, especially fatty acid amides such as Ν, Ν-dimethylformamide, Ν, Ν- Dimethylacetamide and N-methyl-2-pyrrolidone; Of all, the halogenated hydrocarbons and the amides are particularly preferred.

The reaction can be carried out in a wide temperature range, the exact reaction temperature is not critical to the invention. It is best to the reaction between 0 ⁰ C and 60 ⁰ C, preferably run between 10 ° C and 30 ° C. Also, the reaction time depends on many factors and can vary widely, provided that the reaction proceeds under the above-mentioned preferential conditions, a reaction time of 1 to 24 hours is normally sufficient. When R ⁶ 'is an amino-protecting group, it can be removed by conventional reactions as described above with respect to stages B 2 and D 2.

The desired product can be obtained in a conventional manner from the reaction mixture, for. B. simply by increasing the concentration of the reaction mixture. The resulting compound can be cleaned if necessary by various conventional methods such. B. by recrystallization or by different chromatographies, especially by column chromatography, or preparative thin-layer chromatography.

As already stated, the compounds according to the invention can exist as different optical isomers because of the asymmetric carbon atom in the 2-morpholinylmethoxy group of the compound of formula (Ia) or of the asymmetric carbon atom (s) when R ⁷ and / or R ^{8 represents} an alkyl group in the compounds of formula (I b). When the compound of the present invention is obtained as a mixture of optical isomers, the resolving power is achieved by reacting an optically active compound of the formula (VI), (VII) or (IX) with the compound of the formula (IV) in the step A1, BI or C1 or by optical resolution after conversion of the compound of formula (I) to a salt by reaction with an optically active acid, especially a sulfonic acid or carboxylic acid such as L- or D-camphorsulfonic acid, L- or D-tartaric acid or with an acylated L- or D- -Amino acid.

The compounds of formula (I) may be converted into their pharmaceutically acceptable salts by treatment in a conventional manner with an acid. For example, the compound of formula (I) can be dissolved in an organic solvent such as ethyl acetate or methylene chloride, and then an equimolar amount or an extract of an acid such as hydrogen chloride dioxane is added. The solvent can then be distilled off, and the resulting compound of formula (I) is obtained in the form of a salt by crystallization or solidification in an organic solvent such as diethyl ester or diisopropyl ether.

A compound of the formula (Ib) in which one group of R ⁵ and R ^{6 is} a hydrogen atom and the other is an alkyl group can be prepared from the corresponding compound in which both groups, R ⁵ and R ⁶ , are hydrogen atoms, so to speak a compound of the formula (Ic):

I H COO

WW

N-CH-CH- (CH ₂ ) _m -OC CC

/ I, I ₀ I Il I

H r7 r8 H-C C C

HR ²

(in the R ¹ , R ² , R ³ , R ⁷ , R ⁸ and m as explained above), by alkylation of this compound. Suitable alkylation processes include a reduction reaction with a carbonyl compound of the formula R ⁹ R ¹⁰ C = O (XII) wherein R ⁹ and R ^{10 are the} same or different and each represents a hydrogen atom or an alkyl group of 1 to 3 carbon atoms, and by alkylation with a Compound of the formula R ⁶ "-X (XIII), wherein R ⁶ " and X are as explained above.

In the alkylation-reduction reaction, a Schiff base is formed by reaction of the aminoalkoxycumarin derivative of formula (Ic) with the carbonyl compound of formula (XII), and this Schiff base is then reduced with a reducing agent (eg, with sodium cynoborohydride) or treated in catalytic reduction in a hydrogen atmosphere and in the presence of a reduction catalyst such as Raney nickel or palladium, preferably all in a single step. Therefore, the reaction is preferably carried out in a suitable solvent (e.g., an alcohol such as methanol or ethanol) and in the presence of hydrogen (preferably at atmospheric or superatmospheric pressure, eg at 1 to 5 at) for catalytic reduction or in the presence of a reducing agent , The reaction can take place in a wide temperature range and the exact reaction temperature is not critical to the invention. Most preferably, the reaction between 0 ° C and 50 ⁰ C (preferably between 0 ⁰ C and room temperature) should be performed. The reaction time also has a large range and depends on many factors, especially the reaction temperature and the nature of the reactants. Nevertheless, in most cases, a reaction time of 30 minutes to 24 hours is usually sufficient.

After completion of the reaction, the desired compound of the formula (I b ') in which R ^{5 is} a hydrogen atom can be separated from the reaction mixture by a plurality of known and conventional methods. If z. B. the reaction proceeds with a catalytic reduction, this is achieved by filtering off the catalyst and then condensing the filtrate; when using a reducing agent, the appropriate separation method is to condense the reaction solution under reduced pressure and then extract the residue with an organic solvent such as methylene chloride or ethyl acetate.

The alkylation reaction involves the reaction of the compound of formula (Ic) with a compound of the formula R ^e "-X (XIII), wherein R ⁶ " and X are as explained above, ie an alkyl halide or alkyl sulfonate. This reaction is preferably carried out in the presence of an inert solvent and a base; the reaction conditions are similar to those in the reaction of the compound of formula (IV) with a compound of formula (XI) or (XIa). For preparing a compound of formula (Ib) in which only one of R ⁶ and R ^{6 is} an alkyl group and the other is a hydrogen atom, should be about

1 equivalent of the compound of formula (XIII) per equivalent of the compound of formula (Ic) or, in any event, less than

2 equivalents are used; when using 2 or more equivalents of the compound of formula (XIII) per equivalent of the compound of formula (Ic), the product will predominantly be a compound of formula (I b) in which both groups, R ⁶ and R ⁶ , are alkyl groups are.

Biological effectiveness

The compounds of the invention can inhibit the increase in blood viscosity, which, on the other hand, occurs as a result of cerebral ischemia; they may also have a strong antirespheric effect. Therefore, the compounds of the invention are intended to activate brain metabolism as well as to stimulate circulation because of their monoamine activating activity and the ability to improve microcirculation.

In the following experiments, the compounds according to the invention are characterized by the number of the example in which the compound was prepared.

(1) anti-reserpine action

As experimental animals were ddY mouse male, age 4 weeks, mass per 22 to 27 g, in question. The animals were divided into two groups of three mice each. The compound to be tested was dissolved or suspended in a physiological saline solution, ie, in a 0.5% CMC solution (carboxymethylcellulose solution) or in a 1% dimethylsulfoxide solution, and 100 mg / kg of sample solution were orally administered to each mouse in the treated group administered. The mice in the other group received only the solution without any drug (control group). Immediately following administration, each mouse received 2 mg / kg reserpine subcutaneously. After 90 minutes, it was determined how far the eyelids were closed (Lidptosis). For evaluation of the results, a mouse without ptosis received 0 points, while a mouse with V2 to V3 ptosis received a dot and a mouse with ^2/3 ptosis and 2 points until slightly opened eyes and 3 points with a mouse completely closed. The reserpine inhibition rate of the test sample was calculated using the following equation.

, ,,,,. Points of the control group - points of the treated group ".

Reserpine inhibition rate (%) = - --- ^ - χ 100

Points of the control group

Table 4 shows the results.

Table 4

Test compound

Reserpine-inhibitory rate (%)

CompoundofExamplei 86

CompoundofExample2 100

Compound of Example 3 100

CompoundofExample4 100

Compound of Example8 100

Compoundof Example9 71

Compoundof Example 10 77

CompoundofExample11 100

Compound Example 15 100

CompoundofExample16 100

CompoundofExample17 100

Compoundof Example 18 100

Compoundof Example19 100

Compound of Example 22 100

CompoundofExample23 100

Compound of Example 25 100

CompoundofExample26 100

CompoundofExample27 100

Compound Example 28 100

Compoundof Example 29 100

CompoundofExample30 100

Compound of Example 31 100

CompoundofExample32 100

test compound

Reserpine inhibition (%)

Compound Example 33 100

Compound Example 34 100

Compound Example 35 100

Compound Example 36 100

Compound Example 37 100

Connection Example 40 100

Connection Example41 100

Compound Example42 100

Compound Example 43 100

(2) inhibitory activity against increase in blood viscosity after cerebral ischemia

Adult Wistar rat male were divided into 2 groups, each group containing six animals. The test sample was dissolved or suspended in a physiological saline solution or 0.5% CMC solution, respectively, then 100 mg / kg of the sample was orally administered to each animal in a group (treated group). The rats in the other group received only the solution without any drug (control group). Immediately after administration, the rats were each given 40 mg / kg of pentobarbital intraperitoneally for anesthesia. The rat was kept lying on its back. Then 0.6 ml of blood sample was withdrawn from one side of the jugular vein. With a blood viscometer (Biorheolyzer, Tokyo Keiki) the blood viscosity was measured with shear values of 37.5 / s, 75 / s, 150 / s and 375 / s. The common carotid artery was suppressed on both sides for 1 h to induce incomplete cerebral ischemia; then, 0.5 ml of blood was taken from the jugular vein on each side to allow the blood viscosity to be measured as mentioned above. The inhibition of the increase in blood viscosity by the experimental medicine was calculated by the following equation for each thrust value. In carrying out the experiments, various compounds of the invention as well as known compounds such as indeloxazine hydrochloride were used.

Inhibition of increase in blood viscosity (%)

(Increase in blood viscosity triggered

through ligature

in the control group [%])

(Increased blood viscosity triggered - by ligation into

in the treated group [%])

(Increase in blood viscosity by inhibition in the control group [%])

Table 5 shows the results.

Table 5

test compound

Increase in blood viscosity (%) Threshold / sec

37.5 75 150

Example 1 compound Example 2 compound Example 3 compound Example 4 compound Example 8 compound Example 15 compound Example 16 compound Example 17 compound Example 18 compound Example 22 compound Example 29 compound Example 31 compound Example 34 compound Example 36 compound Example 37 compound Example 41 compound Example 43

57 47 59 79 57 42 35 19 65 63 76 71 80 83 100 100 72 70 81 100 100 79 87 100 97 75 79 95 78 67 74 80 69 55 71 91 66 61 55 75 96 88 90 98 67 60 82 84 76 79 86 100 62 58 53 97 77 85 77 100 68 57 47 71 72 53 64 83

Indeloxazine hydrochloride (control drug)

47

52

The above results show that the compounds of formula (I) and their pharmaceutically acceptable salts can be used to improve blood flow and brain metabolism. For this purpose, they may be administered orally or parenterally in forms suitable for administration. For oral administration, for. For example, it is possible to use preparations as powders, granules, tablets or capsules and for parenteral administration forms such as injections, suppositories and patches. The compound itself may be used alone or in admixture with any other suitable pharmaceutically acceptable carrier, carrier or solvent. The preferred dosage may vary depending on the nature of the disorder to be treated, the age, physical condition and mass of the patient, and the manner of administration; however, a daily dose of from 1 to 1,000 mg, and more preferably from 1 to 100 mg, is preferred for oral administration; a dose of from 0.1 to 100 mg, and more preferably from 0.5 to 30 mg, is preferred when administered intravenously. The compounds may be administered singly or in divided doses one to three times daily depending on the symptoms.

embodiments

The invention is further illustrated by the following examples, which demonstrate the preparation of certain compounds of the invention. The following formulations show the preparation of certain starting materials used in these examples while the following formulations illustrate the compositions of the invention.

example 1

7- (2-morpholinyl) methoxycoumarin

1 (a) 7- (4-t-Butoxycarbonyl-2-morpholinyl) methoxycoumarin

1.6% potassium carbonate was added to 25 ml of an acetone solution containing 0.32 g of 7-hydroxycoumarin and 0.80 g of 4-t-butoxycarbonyl-2 - [(4-nitrophenylsulfonyloxy) methyl] morpholine (prepared as in Preparation 2). The reaction mixture was then stirred for 16 hours while heating to reflux. Towards the end of this time, the acetone was evaporated under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with water. Subsequently, the extract was dried over anhydrous magnesium sulfate and then the solvent was removed. The result was the above-named compound in the form of crystals. These crystals were purified by silica gel column chromatography, the volume ratio of the mixture of ethyl acetate and methylene chloride as the eluent was 1: 4. Result: 0.62 g of the named compound in the form of crystals, mp at 146 ° C

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), ppm:

1.46 (9H, singlet);

2.5-4.3 (9H, multiplet); 6.25 (1H, doublet, J = 9Hz); 6.8-7.0 (2H, multiple); 7.42 (1H, doublet, J = 9Hz); 7.68 (1H, doublet, J = 9Hz).

1 (b) 7- (2-morpholinyl) methoxycoumarin hydrochloride

A mixture of 0.62 g of 7- (4-t-butoxycarbonyl-2-morpholinyl) methoxycoumarin (prepared as described in step [a] above) and 1.5 ml of a 4N solution of hydrogen chloride in dioxane was stirred for 2 hours at room temperature. Toward the end of this time, the reaction solution was evaporated under reduced pressure and ethyl acetate was added. The hydrochloride of the named compound was separated in the form of crystals (mp 185-187 "C), which were then filtered off to yield 0.53 g of the named compound.

2.6-4.4 (9H, multiples); 6.27 (1H, doublet, J = 9Hz); 6.88-7.02 (2H, multiple); 7.66 (1H, doublet, J = 9Hz); 8.02 (1H, doublet, J = 9Hz); 9.95 (2 H, broad-legulett).

Example 2

4-Methyl-7- (2-morpholinyl) methoxycoumarin 2 (a) 7- (4-t-Butoxycarbonyl-2-morpholinyl) methoxy-4-methylcoumarin 0.35 g 7-hydroxy-4-methylcoumarin, 0.80 g 4-t Butoxycarbonyl-2 - [(4-nitrophenylsulfonyloxy) methyl] morpholine (prepared as described in Preparation 2) and 1.6 g of potassium carbonate were added to 19 ml of methyl ethyl ketone, then the reaction mixture was stirred for 23 hours and heated to reflux. Subsequently, the evaporation was carried out under reduced pressure. To the residue was added ethyl acetate and water. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate. Then the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography at a volume ratio of 1: 5 of ethyl acetate and methylene chloride as the eluent. Result: 0.75 g of the named compound in the form of crystals, m.p. 124-125 ° C. Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), ppm:

1.48 (9H, singlet); 2.37 (3H, singlet); 2.5-7.3 (9H, multiple); 6,12 (1 H, broad innlet); 6.8-7.0 (2H, multiple); 7.52 (1H, doublet, J = 9Hz).

2 (b) 4-methyl-7- (2-morpholiny!) Methoxycumarin hydrochloride

0.70 g of 7- (4-t-butoxycarbonyl-2-morpholinyl) -methoxy-4-methylcoumarin (prepared as described in step [a] above) were treated in a procedure similar to that in Example 1 (b). Result: 0.61 g of crystalline hydrochloride of the named compound in the form of hygroscopic crystals, mp 169-171 "C. Nuclear Magnetic Resonance Spectrum (hexadecrane-labeled dimethylsulfoxide), ppm:

2.39 (3H, singlet); 2.7-4.3 (9H, multiples); 6.21 (1H, broad innlet); 6.9-7.1 (2H, multiples); 7.72 (1H, doublet, J = 10Hz); 9.92 (2 H, broad-legulett).

Example 3

4,8-Dimethyl-7- (2-morpholinyl) methoxycoumarin 3 (a) 7- (4-t-Butoxycarbonyl-2-morpholinyl) methoxy-4,8-dimethylcoumarin. A procedure similar to that described in Example 2 (a) was repeated with the exception that 0.57 g of 7-hydroxy-4,8-dimethy! coumarin and 0.74 g 4-t-butoxycarbonyl-2 - [(4-nitrophenylsulfonyloxy) methyl] morpholine (prepared as described in Preparation 2) were used were. Result: 0.84 g of the named compounds in the form of crystals, mp. 145-147 ° C.

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), ppm:

1.46 (9H, singlet); 2.26 (3H, singlet); 2.34 (3H, broad innlet); 2.5-4.3 (9H, multiples); 6.08 (1H, broad innlet); 6.81 (1H, Dublet, J = 9Hz); 7.40 (1H, doublet.J = 9Hz).

3 (b) 4,8-Dimethyl-7- (2-morpholinyl) methoxycoumarin hydrochloride Repeatedly, a procedure similar to that described in Example Kb) was repeated, except that 0.84 g of 7- (4-t-butoxycarbonyl-morpholinylmethoxy) Result: 0.75 g of the named compound in the form of its crystalline hydrochloride, mp. 256-259 ° C.

Nuclear magnetic resonance spectrum (hexadecrane-labeled dimethyl sulfoxide), ppm: 2.17 (3H, singlet); 2.36 (3H, broad innlet); 2,7-4,3 (9H, multiple); 6.17 (1H, broad innlet); 7.00 (1H, doublet, J = 9Hz); 7.56 (1H, doublet, J = 9Hz); 9.80 (2 H, broad-legulett).

Example 4

3,4,8-trimethyl-7- (2-morpholinyl) methoxycoumarin

4 (a) 7 (4-t-butoxycarbonyl-2-morpholinyl) methoxy-3,4,8-

4.84 g of 7-hydroxy-3,4,8-trimethylcoumarin, 9.6 g of 4-t-butoxycarbonyl-2 - [(4-nitrophenylsulfonyloxy) methyl] morpholine (prepared as described in Preparation 2) and 12 g of potassium carbonate were dissolved in 200 ml of dimethylformamide mixed, then the mixture was stirred at 60 ⁰ C for 8 hours. Towards the end of this time, ethyl acetate and water were added to the mixture. Then, the methyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the named compound in the form of crystals.

These crystals were washed with small amounts of ethyl acetate and diethyl ether and then filtered off. Result: 7,35g of the titled compound as crystals, melting at 124-128 ⁰ C..

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), ppm:

1.51 (9H, singlet);

2.10 (3H, singlet);

2.25 (6H, singlet);

2.5-4.3 (9H, multiple ");

6.71 (1H, Düble, J = 9Hz);

7.27 (1 H, Düble ", J = 9Hz).

4 (b) 3,4,8-trimethyl-7- (2-morpholinyl) methoxycoumarin hydrochloride

40 ml of a 4N solution of hydrogen chloride in ethyl acetate was added to 6.87 g of 7- (4-t-butoxycarbonyl-2-morpholinyl) methoxy-3,4,8-trimethylcoumarin (prepared as described in step [a] above). The reaction mixture was stirred at room temperature for 1 hour, then the ethyl acetate was distilled off under reduced pressure. Diethyl ether was added to the residue so that the named compound was formed by filtering off in the form of its crystalline hydrochloride (mp

The yield after recrystallization from ethanol was 5.53 g.

Nuclear resonance spectrum (hexadecrane-labeled dimethyl sulfoxide), ppm:

2.05 (3H, singlet);

2.18 (3H, singlet);

2.32 (3H, singlet);

2,7-4,3 (9H, multiple);

7.03 (1 H, Düble ", J = 9Hz);

7.61 (1H, doublet, J = 9Hz);

9.8 (2 H, broad-legulett).

Example 5 3-Isopropyl-4,8-dimethyl-7- (2-morpholinyl) methoxycoumarin

A procedure similar to that described in Example 4 (a) was repeated except that 0.93 g of 3-isopropyl-7-hydroxy-3,8-dimethylcoumarin and 1.60 g of 4-t-butoxycarbonyl-2- [4 -nitrophenylsulfonyloxy) methyl] morpholine (prepared as described in Preparation 2).

Result: 1.20 g of the named compound in the form of crystals, mp 106-108 ⁰ C.

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), ppm:

1.33 (6H, doublet, J = 8Hz);

1.46 (9H, singlet);

2.27 (3H, singlet);

2.36 (3H, singlet);

2.5-4.3 (1OH, multiple);

6.78 (1H, dowel ", J = 9.5Hz);

7.41 (1H, dowel ", J = 9.5Hz).

5 (b) 3-Isopropyl-4,8-dimethyl-7- (2-morpholinyl) methoxycoumarine fumarate

A procedure similar to that described in Example 4 (b) was repeated except that 1.1 g of 7- (4-butoxycarbonyl-2-morpholinyl) methoxy-3-isopropyl-4,8-dimethylcoumarin (prepared as described in Step [a] above) were used and that after the reaction, the reaction solution was evaporated under reduced pressure. The residue was dissolved in water and this aqueous solution was washed with diethyl ether. Then enough potassium carbonate was added to make the solution alkaline. The named compound was separated and extracted with ethyl acetate. For salting out, the aqueous residual layer of sodium chloride was added and the remaining compound remaining in the aqueous layer was extracted with ethyl acetate. The two ethyl acetate extracts were combined and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to leave 0.86 g of the named compound as a resin. This mass was dissolved in about 3 ml of ethyl acetate, then 5 ml of methanol with 280 mg of fumaric acid to the resulting solution

added. The named compound was separated as crystals in the form of its fumarate. After the addition of diethyl ether, the separated compound was filtered off. Result: 0.98 g of the named compound as crystals, mp 188 ° C. Nuclear resonance spectrum (hexane-labeled sulfoxide), ppm:

1.25 (6H, doublet, J = 6.5Hz); 2.17 (3H, singlet); 2.37 (3H, singlet); 2.7-4.2 (1OH, multiple); 5.40 (3H, broad innlet); 6.52 (2H, singlet); 7.00 (1H, doublet, J = 9.5Hz); 7.62 (1H, doublet, J = 9.5H7).

Example 6

6-chloro-3,4-dimethyl-7- (2-morpholinyl) methoxycoumarin 6 (a) 7- (4-t-Butoxycarbonyl-2-morpholinyl) methoxy-6-chloro-3,4-dimethylcoumarin. A procedure similar to that of the same was repeated as described in Example 4 (a), except that 0.85 g of 6-chloro-7-hydroxy-3,4-dimethylcoumarin and 1.60 g of 4-t-butoxycarbonyl-2 - [(4-nitrophenylsulfonyloxy) - methyl] morpholine (prepared as described in Preparation 2). Result: 1.16 g of the named compound in the form of crystals, mp at 164 ° C

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), ppm:

1.45 (9H, singlet); 2.15 (3H, singlet); 2.30 (3H, singlet); 2,7-4,3 (9H, multiple); 6.82 (1H, singlet); 7.54 (1H, singlet);

6 (b) 6-Chloro-3,4-dimethyl-7- (2-morpholinyl) methoxycoumarin hydrochloride. A procedure similar to that described in Example 4 (b) was repeated except that 1.00 g of 7- (4-t Butoxycarbonyl-morpholine-methoxy-e-chloro-S, -dimethylcoumarin (prepared as described in step [a] above), yielding 0.88 g of the named compound as its crystalline hydrochloride, the compound gradually decays from 250 ° C, Mp at 278 ° C (with decay). Nuclear Magnetic Resonance Spectrum (hexane-labeled dimethyl sulfoxide), ppm:

2.06 (3H, singlet); 2.32 (3H, singlet); 2,7-4,3 (9H, multiple); 7.15 (1H, singlet); 7.76 (1H, singlet); 9.80 (2 H, broad-legulett).

Example 7

7- (2-Morpholinyl) methoxy-4-propylcoumarin7 (a) 7- (4-t-Butoxycarbonyl-2-morpholinyl) methoxy-4-propylcoumarin. A procedure similar to that described in Example 4 (a) was repeated with the exception that 0.50 g of 7-hydroxy-4-propylcoumarin and 0.91 g of 4-t-butoxycarbonyl-2 - [(4-methylphenylsulfonyloxy) methyl] morpholine (prepared as described in Preparation 1) were used. Result: 0.89 g of the named compound as a resin.

7 (b) 7- (2-Morpholinyl) methoxy-4-propylcoumarin maleate. A procedure similar to that described in Example 5 (b) was repeated except that 0.89 g of 7- (4-t-butoxycarbonyl-2-morpholinyl ) methoxy-4-propylcoumarin (prepared as described in step [a] above). Result: 0.64 g of the named compound in the form of its free amine as a resin. This free amine was converted to crystalline maleate by reaction with 0.24 g of maleic acid. Yield: 0.86 g maleate, mp 170-171 ° C. Nuclear resonance spectrum (hexadecrane-labeled dimethyl sulfoxide), ppm:

1.00 (3H, triplet, J = 6.5Hz); 1.66 (2H, multiple); 2.7-4.3 (11H, multiples); 6,10 (2H, singlet); 6,12 (1 H, broad innlet); 6.9-7.1 (2H, multiples); 7.74 (1H, doublet, J = 9Hz).

Example 8 7- {3-N-Methylaminopropoxy) -3,4,8-trimethylcoumarin hydrochloride 9 g of potassium carbonate were added to 50 ml of a dimethylformamide solution containing 3.0 g of 7-hydroxy-3,4,8-trimethylcoumarin and 6.73 g of 3- (m.p. Nt-butoxycarbonyl-N-methylamino) propyl p-toluenesulfonate. The reaction mixture was stirred at 65 ° C for 5 hours, then ethyl acetate and water were added. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The crystalline residue was purified by silica gel column chromatography. The volume ratio of the mixture of ethyl acetate and methylene chloride as the eluent was 1: 9. Result: 4.04 g of the named compound as crystals, mp. At 110 ° C.

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), δρριτι: 1.46 (9H, singlet); 1.85-2.25 (2H, multiples); 2.17 (3H, singlet); 2.30 (3H, singlet); 2.34 (3H, singlet); 2.90 (3H, singlet); 3.45 (2H, triplet, J = 7Hz); 4.06 (2H, triplet, J = 7Hz); 6.77 (1H, doublet, J = 8.5Hz); 7.37 (1H, doublet, J = 8.5Hz).

8 (b) 7- (3-N-Methylaminopropoxy) -3,4,8-Trirnoethylcoumarin hydrochloride 30 ml of a 4 N solution of hydrogen chloride in ethyl acetate were added to 3.9 g of 7- [3- (Nt-butoxycarbonyl-N-methylamino) - propoxy] -3,4,8-trimethylcoumarin (prepared as described in step [a] above). Then, the mixture was stirred at room temperature for 4 hours. Towards the end of this time, the gelatinous reaction mixture was evaporated under reduced pressure. To the residue was added about 20 ml of ethanol, and this mixture was refluxed and then cooled. Then, 40 ml of ethyl acetate was added and the precipitate filtered off. Result: 2.99 g of the named compound which softens at about 215 ° C and melts at 253 ° C. Nuclear resonance spectrum (hexadecrane-labeled dimethyl sulfoxide), ppm:

2.08 (3H, singlet); 2.21 (3H, singlet); 2.05-2.25 (2H, multiple);

2.36 (3H, singlet); 2.59 (3H, singlet); 3.08 (2H, triplet, J = 7.5Hz); 4.21 (2H, triplet, J = 7.5Hz); 7.04 (1H, doublet, J = 8.5Hz); 7.63 (1H, doublet, J = 8.5Hz).

Example 9

7- (4-N-Methylaminobutoxy) -3,4,8-trimethylcoumarin hydrochloride 9 (a) 7- [4-Nt-butoxycarbonyl-N-methylamino) butoxy] -3,4,8-trimethylcoumarin. Repeatedly, a procedure similar to that described in Example 8 (a), except that 0.96 g of 7-hydroxy-3,4,8-trimethylcoumarin, 2.19 g of 4- (Nt-butoxycarbonyl-N-methylamino) -butyl-p-nitrobenzenesulfonate and 2, 6g of potassium carbonate were used. Then, the product was purified by silica gel column chromatography. The volume ratio of the mixture of ethyl acetate and hexane as the eluent was 1: 4. Result: 1.80 g of the named compound as crystals, mp at 86 ° C

 Nuclear Magnetic Resonance Spectrum (CDCI3), δρρην.

1.48 (9H, singlet); 1.65-1.95 (4H, multiple); 2.16 (3H, singlet); 2.29 (3H, singlet); 2.33 (3H, singlet); 2.86 (3H, singlet); 3,15-3,45 (2 H, multiple "); 3.95-4.15 (2H, multiple); 6.76 (1H, doublet, J = 8.5Hz);

7.37 (1H, doublet, J = 8.5Hz).

9 (b) 7- (4-IM-methylaminobutoxy) -3,4,8-trimethylcoumarin hydrochloride. Repeatedly, a procedure similar to that described in Example 8 (b) was used, except that 1.70 g of 7- [4-l] 1-t-butoxycarbonyl-N-methylaminolbutoxyl-SAS-trimethylcoumarin (prepared as described in step [a] above): Result: 1.30 g of the named compound as crystals, mp at 197 ° C. Nuclear Magnetic Resonance Spectrum (hexadecrane-labeled dimethylsulfoxide) , öppm:

3.75-1.95 (4H, multiple); 2.09 (3H, singlet); 2.22 (3H, singlet); 2.36 (3H, singlet); 2.55 (3H, singlet); 2.85-3.10 (2H, multiple); 4,00-4,20 (2H, multiple); 7.03 (1H, doublet, J = 8.5Hz); 7.59 (1H, doublet, J = 8.5Hz).

Example 10

S-ChloM.S-dimethyl-TpN-methylaminopropoxy-cumarin hydrochloride 10 (a) 7- [3- (Nt-butoxycarbonyl-N-methylamino) -propoxy] -3-chloro-8-dimethylcoumarin. A procedure similar to that described in Example 8 (a) was repeated with the exception that 0.65 g of 3-chloro-7-hydroxy-4,8-dimethylcoumarin, 1.44 g of S-fN-t-butoxycarbonyl-N-methylamino propyl p-toluenesulfonate and 2.0 g of potassium carbonate were used. After purification by silica gel column chromatography using a volume ratio of 1: 9 in the mixture of ethyl acetate and methylene chloride as the eluent, 0.93 g of the title compound was obtained as crystals (mp. 161 ° C).

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), ppm:

1.41 (9H, singlet); 2.06 (2H, quintet, J = 7Hz); 2.27 (3H, singlet); 2.50 (3H, singlet); 2.87 (3H, singlet); 3.44 (2H, triplet, J = 7Hz); 4.08 (2H, triplet, J = 8.5Hz); 6.86 (1H, doublet, J = 8.5Hz); 7.44 (1H, doublet, J = 8.5Hz).

10 (b) S-Chloro-e-dimethyl-IL-N-methylaminopropoxy-cumarin hydrochloride. A procedure similar to that described in Example 8 (b) was repeated except that 0.90 g of 7- [3-Nt- Butoxycarbonyl-N-methylaminolpropoxyl-S-chloro-e-methylcoumarin (prepared as described in step [a] above). Result: 0.73 g of the named compound as crystals which soften at about 245 ° C and melt at 273 ° C (with coloration). Nuclear resonance spectrum (hexadecrane-labeled dimethyl sulfoxide), ppm:

2.0-2.35 (2H, multiple); 2.21 (3H, singlet); 2.54 (6H, singlet); 2.95-3.2 (2H, multiple); 4.24 (2H, triplet, J = 7.5Hz); 7.10 (1H, doublet, J = 8.5Hz); 7.68 (1H, doublet, J = 8.5Hz).

Example 11

3,4-Dimethyl-7- (4-N-methylaminobutoxy) coumarin hydrochloride 11 (a) 7- [4- (N-Butoxycarbonyl-N-methylamino) butoxy] -3,4-dimethylcoumarin. A procedure similar to that in Example was repeated 8 (a), except that 1.00 g of 3,4-dimethyl-7-hydroxyxarin, 2.4 g of 4- (Nt-butoxycarbonyl-N-methylamino) -butyl-p-nitrobenzenesulfonate and 2.83 g of potassium carbonate were used were. Result: 2.06 g of the title compound as a syrup after purification by silica gel column chromatography at a volume ratio of 1: 2 with respect to ethyl acetate and hexane as the eluent. Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), ppm:

1.44 (9H, singlet); 1.65-1.85 (4H, multiple); 2.17 (3H, singlet);

2.36 (3H, singlet); 2.86 (3H, singlet); 3,18-3,14 (2 H, multiple); 3.92-4.13 (2H, multiple); 6.78-6.96 (2H, multiple); 7.42-7.60 (1H, multiple).

11 (b) 3,4-dimethyl-7- (4-N-methylaminobutoxy) coumarin hydrochloride

A procedure similar to that described in Example 8 (b) was repeated except that 2.00 g of 7- [4- (N-t-butoxycarbonyl-N-methylamino-Jbutoxyl-S, -dimethylcoumarin (prepared as described in Step [a] above Result: 1.24 g of the named compound as crystals, mp at 196-198 ° C. Nuclear Magnetic Resonance Spectrum (hexadecrane-labeled dimethyl sulfoxide), ppm:

1.8-1.9 (4H, multiple); 2.08 (3H, singlet);

2.37 (3H, singlet); 2.54 (3H, singlet); 2.8-3.05 (2H, multiple); 4.0-4.2 (2H, multiple); 7.65-7.76 (1 H, multiple).

Example 12 7- (3-N-ethylaminopropoxy) -3,4,8-trirnethylcurnarin hydrochloride

12 (a) 7- [3- (N-t-butoxycarbonyl-N-ethylamino) propoxy] -3,4,8-trimethylcoumarin

Repeatedly, a procedure similar to that described in Example 8 (a) was followed except that 2.3 g of 3- (Nt-butoxycarbonyl-N-ethylamino) propyl p-toluenesulfonate and 3.0 g of potassium carbonate were used. Result: 1.20 g of the titled compound as crystals, melting at 107 ⁰ C, after purification by silica gel column in the volume ratio 1:. 2 with ethyl acetate and hexane as the eluent.

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), δ ppm:

1.11 (3H, triplet, J = 7Hz); 1.43 {9H, singlet); 1.85-2.25 (2H, multiplet); 2.17 (3H, singlet); 2.34 (3H, singlet); 3.25 (2H, quartet, J = 7Hz); 3.41 (2H, triplet, J = 7Hz); 4.06 (2H, triplet, J = 7Hz); 6.81 (1H, doublet, J = 10Hz); 7.42 (1H, doublet, J = 10Hz).

12 (b) 7- (3-N-ethylaminopropoxy) -3,4,8-trimethylcoumarin hydrochloride. A procedure similar to that described in Example 8 (b) was repeated except that 0.90 g of [3- (Nt-butoxycarbonyl N-ethyl-amino-propoxyl-SAS-trimethyl-coumarin (prepared as described in step (a) above) Result: 0.74 g of designated compound as crystals, mp at 245 ° C. Nuclear Magnetic Resonance Spectrum (hexane-labeled dimethylsulfoxide), δ ppm:

1.27 (3H, triplet, J = 7Hz); 1.9-2.4 (2H, multiplet); 2.08 (3H, singlet); 2.20 (3H, singlet); 2.33 (3H, multiplet); 2.7-3.3 (4H, multiplet); 4.20 (2H, triplet, J = 6Hz); 6.98 (1H, doublet, J = 9.5Hz); 7.55 (1H, doublet, J = 9.5Hz);

9.30 (2H, broad-pitched).

Example 13

7- (3-N-isopropylaminopropoxy) -3,4,8-trimethylcoumarin hydrochloride 13 (a) 7- [3- (Nt-Butoxycarbonyl-N-isopropylamino) -propoxy] -3,4,8-trimethylcoumarin 0.23 ml acetone and 0.30 ml of acetic acid were added to 15 ml of a methanolic solution containing 642 mg of 7- (3-aminopropoxy) -3,4,8-trimethylcoumarin (prepared as described in Example 17 below). To the mixture kept in the ice bath was then added 157 mg of sodium cyanoboronate. The mixture was stirred for 2 hours at room temperature and then evaporated under reduced pressure. Then a saturated sodium bicarbonate solution was added to precipitate the desired free amino compound. The precipitate was filtered off and suspended in ethyl acetate. 0.42 ml of triethylamine and 643 mg of di-t-butylpyrocarbonate were added to the suspension, and then the reaction mixture was stirred for three hours. Towards the end of this time, the mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, the volume ratio was 1: 9 for ethyl acetate and methylene chloride as the eluent. Result: 0.57 g of 7- [3- (N-butoxycarbonyl-N-isopropylamino) propoxy] -3,4,8-trimethylcoumarin as crystals, melting at 132 ⁰ C.

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), δ ppm:

1.17 (6H, doublet, J = 7Hz); 1.50 (9H, singlet); 1.95-2.25 (2H, multiplet); 2.20 (3H, singlet); 2.33 (3H, singlet); 2.36 (3H, singlet);

3.31 (2H, double doublet, J = 6 & 7.5 Hz); 4.08 (2H, triplet, J = 7Hz); 4.0-4.8 (1H, multiplet); 6.81 (1H, doublet, J = 8.5Hz); 7.42 (1H, doublet, J = 8.5Hz).

13 (b) 7- (3-N-isopropylpropoxy) -3,4,8-trimethylcoumarin hydrochloride. A procedure similar to that described in Example 8 (b) was repeated except that 0.52 g of 7- [3 (Nt-butoxycarbonyl-N-isopropylaminolpropoxyl-S, J-trimethylcoumarin (prepared as described in step (a) above), resulting in 0.44 g of the title compound as crystals, mp at 286 ° C, softening at 27O ⁰ C. Nuclear magnetic resonance spectrum (D ₂ O), δ ppm:

1.89 (6H, doublet, J = 6.5Hz); 2.19 (3H, singlet); 2.05-2.4 (2H, multiplet); 2.33 (6H, singlet); 3.7-3.9 (2H, multiplet); 3.85-4.2 (1H, multiplet); 4.45-4.6 (2H, multiplet); 7.07 (1H, doublet, J = 8.5Hz); 7.43 (1H, doublet, J = 8.5Hz).

Example 14 7- (3-N-methylaminopropoxy) coumarin fumarate. Repeated procedures were repeated as described in Example 8 (a) and 8 (b), except that 1.3 g of 7-hydroxycoumarin was used. Result 2.1 g of the hydrochloride of the named compound in the form of highly hygroscopic crystals. The hydrochloride was dissolved in 10 ml of water. The resulting solution was neutralized by adding a saturated aqueous solution of sodium bicarbonate followed by extraction with methylene chloride. The methylene chloride extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Result: 1.66g of free coumarin derivative as a resin corresponding to the named compound. This resin was treated with 0.83 g fumaric acid and the product with diethyl ether and then washed with ethyl acetate to give 2.30 g of the titled compound in the form of crystals emerged, mp. At 108 ⁰ C (with softening). Nuclear Magnetic Resonance Spectrum (hexane-labeled dimethylsulfoxide), δ ppm:

1.9-2.35 (2H, multiple); 2.56 (3H, singlet);

3.05 (2H, triplet, J = 8Hz); 4.18 (2H, triplet, J = 6Hz); 6.28 (1H, doublet, J = 9.5Hz); 6.50 (2H, singlet); 6.8-7.05 (2H, multiples); 7.64 (1H, doublet, J = 9.5Hz); 7.98 (1H, doublet, J = 9.5Hz).

Example 15 SADimethyl-N-methylaminopropoxycoumarin hydrochloride Repeated procedures were repeated as described in Example 8 (a) and 8 (b), except that 2.88 g of 3- (Nt-butoxycarbonyl-N-methylamino) propyl p-toluenesulfonate and 1.2g of 7-hydroxy-3,4-dimethylcoumarin were used. Result: 1.69 g of the titled compound in the form of crystals, mp 180-182 ⁰ C. for nuclear magnetic resonance spectrum (hexadeuteriummarkiertes dimethyl sulphoxide), δ ppm.:

1.95-2.3 (2H, multiples); 2.09 (3H, singlet); 2.37 (3H, singlet); 2.57 (3H, singlet);

3.06 (2H, triplet, J = 7.5Hz);

4.20 (2H, triplet, J = 6Hz); 6.9-7.05 (2H, multiples); 7.71 (1H, doublet, J = 9.5Hz); 9.23 (2 H, broad-pitched).

Example 16

7- (3-N, N-Dimethylaminopropoxy) -3,4,8-trimethylcholine and its hydrochlorides 1.2 g of 7-hydroxy-3,4,8-trimethylcoumarin, 1.0 g of 3- (dimethylamino) propyl chloride hydrochloride and 1 5 g of sodium carbonate were added to 30 ml of methyl ethyl ketone. The mixture was stirred for 9 hours while refluxing. Towards the end of this time, the reaction solution was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The crystals were separated and washed with diethyl ether. Result: 0.98 g of the named compound in the form of crystals, mp at 86 ° C. Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), δ ppm:

1.8-2.6 (4H, multiples); 2.16 (3H, singlet); 2.27 (3H, singlet); 2.30 (3H, singlet); 2.33 (3H, singlet); 4.09 (2H, triplet, J = 6Hz); 6.79 (1H, doublet, J = 9Hz); 7.36 (1H, doublet, J = 9Hz).

0.90 g of these crystals were reacted with a 4N solution of hydrogen chloride in ethyl acetate. Yield: 1.05 g of the hydrochloride of the titled compound, soft becoming at about 220 ⁰ C and melting at 252 ° C. Nuclear Magnetic Resonance Spectrum (hexane-labeled dimethylsulfoxide), δ ppm:

2.09 (3H, singlet); 2.05-2.35 (2H, multiple); 2.23 (3H, singlet); 2.37 (3H, singlet); 2.77 (3H, singlet); 2.83 (3H, singlet); 3,1-3,4 (2H, multiple);

4.21 (2H, triplet, J = 6Hz); 7.05 (1H, doublet, J = 9Hz); 7.62 (1H, doublet, J = 9Hz).

Example 17 7- (3-Aminopropoxy) -3,4,8-trimethylcoumarin hydrochloride 4 g of potassium carbonate were added to a solution of 2,7g7-hydroxy-3,4,8-trimethylcoumarin and 3.8 g of 3- (Nt-butoxycarbonylamino) propyl bromide Added 50 ml of dimethylformamide. The mixture was stirred at 65 ° C for 5 hours, then ethyl acetate and water were added.

The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and then evaporated in vacuo. The remaining residue was recrystallized from ethanol. Result: 3.80 g of the named compound in the form of crystals, m.p .: 137 ° C.

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), δ ppm:

1.45 (9H, singlet); 1.8-2.3 (2H, multiple); 2.15 (3H, singlet); 2.29 (3H, singlet); 2.32 (3H, singlet); 3.35 (2H, quartet, J = 6Hz); 4.10 (2H, triplet, J = 6Hz); 4.95 (1H, broad innlet); 6.78 (1H, doublet, J = 9Hz); 7.35 (1H, doublet, J = 9Hz).

17 (b) 7- (3-Aminopropoxy) -3,4,8-trimethylcoumarin hydrochloride. 30ml of a 4N solution of hydrogen chloride in ethyl acetate were added to a hot solution of 7- [3- (Nt-butoxycarbonylamino-propoxyl-SAe-trimethylcoumarin (prepared as described in step (p. The mixture was stirred at room temperature for 4 hours at the end of which time the reaction mixture was evaporated under vacuum to give the title compound as crystals. aqueous ethanol recrystallized, giving 2.88 g of the title compound as crystals, m.p.

Resonance spectrum (hexadecrane-labeled dimethyl sulphoxide), δ ppm:

1.95-2.35 (2H, multiple "); 2.08 (3H, singlet);

2.21 (3H, singlet); 2.37 (3H, singlet); 2.8-3.15 (2H, multiple);

4.22 (2H, triplet, J = 6Hz); 7.03 (1H, doublet, J = 9Hz); 7.62 (1H, doublet, J = 9Hz); 8.27 (3H, broad-pitched).

Example 18 7- (4-Aminobutoxy) -3,4-dimethylcoumarin hydrochloride Repeated procedures were repeated as described in Examples 8 (a) and 8 (b), except that 3.12 g of 4- (Nt-butoxycarbonylamino) butyl p-toluenesulfonate and 1,3g7-hydroxy-3,4-dimethylcoumarin were used. Result: 1.87 g of the named compound, which softens at 19O ⁰ C and melts at 215 ⁰ C. Resonance spectrum (hexadecrane-labeled dimethyl sulphoxide), δ ppm:

1.65-1.95 (4H, multiples); 2.08 (3H, singlet); 2.36 {3H, singlet); 2.7-3.0 (2H, multiple); 4.0-4.25 (2H, multiple); 6.85-7.05 (2H, multiples); 7.68 (1H, doublet, J = 9Hz); 8.22 (3H, broad-pitched).

Example 19 7- (4-Aminobutoxy) -3,4,8-trimethylcoumarin hydrochloride Repeated procedures were repeated as described in Example 8 (a) and 8 (b), except that 2.91 g of 4- (Nt-butoxycarbonylamino) butyl p-toluenesulfonate and 1.3 g of 7-hydroxy-3,4,8-trimethylcoumarin were used. Result: 1.71 g of the named compound, m.p. at 245-247 ° C. Resonance spectrum (hexadecrane-labeled dimethyl sulphoxide), δ ppm:

1.65-2.05 (4H, multiple); 2.06 (3H, singlet); 2.20 (3H, singlet); 2.34 (3H, singlet); 2.7-3.1 (2H, multiple); 4.0-4.3 (2H, multiples); 7.02 (1H, doublet. J = 9Hz); 7.59 (1H, doublet, J = 9Hz); 8.20 (3H, broad-pitched).

Example 20 to 24

By a method as described in Example 4 (a) and 4 (b), the following compounds were prepared.

Example 20 4-Ethyl-7- (2-morpholinyl) methoxycoumarin hydrochloride mp. At 115 ° C (with decomposition).

Nuclear Magnetic Resonance Spectrum (hexane-labeled dimethylsulfoxide), δ ppm:

1.23 (3H, triplet, J = 7.5Hz); 2.80 (2H, quartet, J = 7.5Hz); 2,90-4,37 (9 H, multiple); 6.17 (1H, singlet); 6.97-7.02 (2H, multiple); 7.74 (1H, doublet, J = 9Hz); 9.74 (2 H, broad-legulett).

Example 21

7- (Morpholinyl) methoxy-3,4,5-trimethylcoumarin hydrochloride mp. At 250 ° C (color), 265 ° C (with decomposition). Nuclear resonance spectrum (D ₂ O), δ ppm:

2.23 (3H, singlet); 2.57 (3H, singlet); 2.66 (3H, singlet); 3.5-4.8 (9H, multiple); 6.73 (2H, broad-legulett).

Example 22 3-Chloro-4,8-dimethyl-7- (2-morpholinyl) methoxycoumarin hydrochloride M.p. at 265 ° C (color), 275 ° C (with decomposition). Nuclear Magnetic Resonance Spectrum (D2O), δ ppm:

1.88 (3H, singlet); 2.08 (3H, singlet); 6.76 (1H, doublet, J = 8Hz); 7.12 (1H, doublet.J = 8Hz).

Example 23 3,4-Dimethyl-7- (2-morpholinyl) methoxycoumarin hydrochloride M.p. at 255-226 ° C (with decomposition).

Nuclear Magnetic Resonance Spectrum (hexane-labeled dimethylsulfoxide), δ ppm:

2.04 (3H, singlet); 2.32 (3H, singlet); 2,7-4,4 (9 H, multiple); 6.8-7.1 (2H, multiple); 7.67 (1H, doublet, J = 9Hz); 9.90 (2 H, broad-legulett).

Example 24 8-methyl-7- (2-morpholinyl) methoxycumarinhydrochlorid mp. At 233 ⁰ C (coloration), 244-246 ⁰ C (with decomposition). Nuclear resonance spectrum (D ₂ O), δ ppm:

2.43 (3H, singlet); 3.6-4.9 (9H, multiplet); 6.52 (1H, doublet. J = 9Hz); 7.22 (1 H, Düble, J = 9Hz); 8.11 (1H, doublet, J = 9.5Hz).

Example 25 3,4,8-Trimethyl-7- (4-methyl-2-morpholinyl) methoxycumarin hydrochloride 2 ml of a 35% aqueous formaldehyde solution was added to 20 ml of a methanolic solution containing 1.1 g of 3,4,8-trimethyl -7- (2-morpholinyl) -methoxycumarin hydrochloride (prepared as described in Example 4). Then, 0.21 g of sodium cyanoboronate was added to the mixture in an ice bath, and the mixture was stirred for 4 hours. Towards the end of this time, the reaction mixture was evaporated at reduced pressure. The resulting residue was dissolved in methylene chloride and in a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography in a volume ratio of 1: 9 of methanol and methylene chloride as the eluent, after which the latter was treated with a 4N solution of hydrogen chloride in ethyl acetate. Result: 0.85 g of the named compound, mp 248-250 ⁰ C.

Nuclear magnetic resonance spectrum (hexadecrane-labeled dimethylsulfoxide), δ ppm: 2.06 (3H, singlet); 2.20 (3H, singlet); 2.33 (3H, singlet); 2.85 (3H, singlet); 2.7-4.4 (9H, multiple); 6.98 (1H, doublet, J = 9Hz); 7.54 (1H, doublet, J = 9Hz).

Example 26 3,4,8-trimethyl-7 - [(S) - {2-morpholinyl) methoxy] coumarin hydrochloride. A procedure was repeated as described in Example 4 (a) except that 0.63 g of 7-hydroxy -3,4,8-trimethylcoumarin and 1,25g (S) -4-t-butoxycarbonyl-2- [(4-nitrophenylsulfonyloxy) methyl] morpholine (prepared as described in Preparation 2). Result: 1.11 g of the named compound in the form of crystals, mp. 137-139 ° C. '

Rotation of polarization plane [α] "+ 23.7 °, (c = 1, dimethylformamide) The nuclear magnetic resonance spectrum of this compound was the same as in the product of Example 4 (a).

26 (b) 3,4,8-trimethyl-7 - [(S) - (2-morpholinyl) methoxy] coumarin hydrochloride. A procedure was repeated as described in Example 4 (b), except that 1.0Og of 7 - [(S) -4-t-Butoxycarbonyl- (2-morpholinyl) methoxy] -3,4,8-trimethylcurnarin (prepared as in step [a] above). Result: 0.70 g of the named compound in the form of crystals, mp 226-228 ° C.

Rotation of the polarization plane [α] "+ 2.0 °, (c = H ₂ O).

The nuclear magnetic resonance spectrum was the same as the product of Example 4 (b).

Example 27 7 - [(S) - (2-morpholinyl) methoxy] coumarin hydrochloride The procedure was repeated as described in Example 26 except that 0.65 g of 7-hydrocoumarin and 1.6Og of (S) -4-t Butoxycarbonyl-2 - [(4-nitrophenylsulfonyloxy) methyl] morpholine (prepared as described in Preparation 5). Result: 1.05 g of the named compound in the form of crystals, mp 186-188 ⁰ C.

Rotation of the polarization plane [α] "+ 23.6 °, (c = 1, dimethylformamide).

The nuclear magnetic resonance spectrum of this compound was the same as the product of Example 1 (b).

Example 28 3,4-Dimethyl-7 [(S) - (2-morpholinyl) methoxy] coumarin hydrochloride The procedure was repeated as described in Example 26, except that 0.90 g of 7-hydroxy-3,4-dimethylcoumarin and 1.90 g of (S) -4-t-butoxycarbonyl-2 - [(4-nitrophenylsulfonyloxy) methyl] morpholine (prepared as in Preparation 5). Result: 1.37 g of the titled compound in the form of crystals, mp 226-228 ⁰ C. with rotation of the plane of polarization [α] "+ 9.8 °, (c = 1, dimethylformamide) The nuclear magnetic resonance spectrum was the same as the product.. from example

Example 29 SAe-trimethyl-1-fluoro-morpholino-osmioxio-cumarine hydrochloride. A procedure was repeated as described in Example 26 except that 2.54 g of 7-hydroxy-3,4,8-trimethylcoumarin and 5.0 g of (R) -4-t- Butoxycarbonyl-2 - [(4-nitrophenylsulfonyloxy) methyl] morpholine (prepared as described in Preparation 3) were used.

Result: 3.40 g of the named compound in the form of crystals, mp 225-226 ° C.

Rotation of the plane of rotation [a] § ⁶ - 1,8 °, (c = 1, H ₂ O).

The nuclear magnetic resonance spectrum was the same as the product of Example 4 (b).

Example 30 7 [(R) - (2-Morpholinyl) -methoxy] coumarin hydrochloride The procedure was repeated as described in Example 26, except that 0.81 g of 7-hydrocoumarin and 1.86 g of (R) -4-t Butoxycarbonyl-2 - [(4-methylphenylsulfojyloxy) methyl] morpholine (prepared as described in Preparation 4). Result: 1.05 g of the named compound in the form of crystals, mp 187-189 ° C.

Rotation of the plane of rotation [α] "- 22,4 °, (c = 1, dimethylformamide).

The nuclear resonance spectrum of this compound was the same as for the product of Example 1 (b).

Example 31 3,4-Dimethyl-7 [(R) - (2-morpholinyl) methoxy] coumarin hydrochloride The procedure was repeated as described in Example 26, except that 0.90 g of 3,4-dimethyl-7-hydroxycoumarin and 1.80 g of (R) -4-t-butoxycarbonyl-2 - [(4-methylsulfonyloxy) methyl] morpholine (prepared as described in Preparation 4). Result: 1.40 g of the named compound in the form of crystals, mp 225-228 ° C.

Rotation of the polarization plane [α] "- 8,8 °, (c = 1, H ₂ O).

The nuclear resonance spectrum of this compound was the same as for the product of Example

Example 32

7 - [(RS) -3-Aminobutoxy] -3,4,8-trimethylcoumarin hydrochloride 32 (a) 7 - [(RS) -3- (t-Butoxycarbonylamino) butoxy] -3,4,8-trimethylcoumarin 4.02g Potassium carbonate was added to 20 ml of a dimethylformamide solution containing 1.32 g of γ-hydroxy-SAS-trimethylcoumarin and 2.67 g of S-lt-butoxycarbonylaminol-butyl-p-toluenesulfonate. The reaction mixture was stirred at 80 ^° C. for 5 hours, then ethyl acetate and water were added. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The crystalline residue was purified by silica gel column chromatography in the volume ratio of 2: 5 with ethyl acetate and hexane as the eluent. Result:. 1.87 g of the titled compound in the form of crystals, mp 132-134 ⁰ C. Nuclear Magnetic Resonance Spectrum (CDCI _3), δ ppm:

1.23 (3H, doublet, J = 7Hz); 1.43 (9H, singlet); 1.8-2.3 (2H, multiples); 2.16 (3H, singlet); 2.30 (3H, singlet); 2.34 (3H, singlet); 3,55-4,3 (3 H, multiple); 4.65 (1H, doublet, J = 7 Hz); 6.77 (1H, doublet, J = 8.5Hz); 7.36 (1H, doublet, J = 8.5Hz).

32 (b) / - [(RSl-S-aminobutoxyl-SAe-trimethylcoumarin hydrochloride 20 ml of a 4N solution of hydrogen chloride in ethyl acetate were added to 1.87 g of 7 - [(RS) -3- (t-butoxycarbonylamino) butoxy] -3,4 The reaction mixture was then stirred at room temperature for 4 hours The known compound was separated from the reaction mixture, filtered and washed with a mixture of ethyl acetate and diethyl ether. After recrystallization from 90VoI .-% aqueous ethanol formed 1.26 g of the named compound, mp. 226-227 ⁰ C. Nuclear magnetic resonance spectrum (hexadecrane-labeled dimethyl sulfoxide), δ ppm:

1.31 (3H, doublet, J = 6Hz); 1.9-2.3 (2H, multiple); 2.06 (3H, singlet); 2.18 (3H, singlet); 2.34 (3H, singlet); 3.3-3.65 (1 H, multiple); 4.21 (2H, triplet, J = 6Hz); 7.03 (1H, doublet, J = 9Hz); 7.61 (1H, doublet, J = 9Hz); 8.30 (3H, broad-pitched).

Example 33

y-KRSI-S-aminopentoxyl-SAe-trimethylcoumarin hydrochloride 33 (a) 7 - [(RS) -3- (t-butoxycarbonylamino) pentoxy] -3,4,8-trimethylcoumarin 2 ml of a solution of diethyl 2,26 g of diethyl azodicarboxylate Methylene chloride was added dropwise to 30 ml of an ice-cooled solution of 2.04 g of 7-hydroxy-3,4,8-trimethylcoumarin, 2.58 g of 3- (t-butoxycarbonylamino) pentanol and 3.40 g of triphenylphosphine in methylene chloride. The reaction mixture was then stirred for 2 hours at room temperature. Thereafter, the solvent was separated by distillation under reduced pressure. The residue was purified by column chromatography on a silica gel column, eluting with a 2: 3 mixture of ethyl acetate and hexane. There were obtained 3.65 g of the title compound in crystal form with a melting point of 143 ° C. Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ ppm 0.95 (3H, triplet, J = 7Hz); 1.39 (9H, singlet); 1,4-2,1 (4H, multiple); 2.14 (3H, singlet); 2.28 (3H, singlet); 2.32 (3H, singlet); 3.5-3.9 (1H, multiple); 4.12 (2H, triplet, J = 6Hz); 6.80 (1H, doublet, J = 9Hz); 7.38 (1H, doublet, J = 9Hz);

33 (b) 7 - [(RS) -3-Aminopentoxy] -3,4,8-trimethylcoumarin hydrochloride The procedure as described in Example 32 (b) was repeated except that 3.30 g of 7,3 ((RS) -3- (t-butoxycarbonylaminolpentoxyl-SAS-trimethylcurnarin] prepared as described in step (a) above.) Result: 2.04 g of the named compound in the form of crystals, mp at 242-245 ° C.

Nuclear Magnetic Resonance Spectrum (D ₂ O), δ ppm: 1.54 (3H, triplet, J = 7 Hz); 2.13 (3H, singlet); 2.25 (3H, singlet); 2.30 (3H, singlet); 2.25-2.45 (2H, multiples); 2.5-2.8 (2H, multiples); 3.85-4.1 (1H, multiples); 4.4-4.7 (2H, multiple); 7.08 (1H, doublet, J = 9Hz); 7.41 (1H, doublet, J = 9Hz).

Example 34 to 43

Following a procedure as described in Example 33, the following compounds were obtained.

Example 34 7 - [(S) -3-aminobutoxy] -3,4,8-trimethylcumarinhydrochlorid melting point of 232-234 ⁰ C.

Rotation of the polarization plane [a] o ⁵ -5,8 ° (c = H ₂ O).

The nuclear magnetic resonance spectrum of this compound corresponded to the values of the compound as described in Example 32 (b).

Example 35 7 - [(R) -3-Aminobutoxyl · 3,4,8-trimethylcumarinhydrochlorid Fp at 232-234 ⁰ C..

Rotation of the polarization plane [a] o ^B - 5.5 ° (c = H ₂ O). The nuclear magnetic resonance spectrum of this compound was that of the compound as described in Example (32b).

Example 36 7 - [(RS) -3-amino-2-methylpropoxy] -3,4 _/ 8-trimethylcumarinhydroch ORID compound softens at 230 ⁰ C, decomposes at 238-241 ⁰ C. Nuclear Magnetic Resonance Spectrum (hexadeuteriummarkiertes dimethyl sulphoxide), δ ppm :

1.12 (3H, doublet, J = 7Hz); 2.0-2.4 (1H, multiples);

2.08 (3H, singlet); 2.21 (3H, singlet); 2.36 (3H, singlet); 2.7-3.15 (2H, multiplet); 4.07 (2H, doublet, J = 6Hz); 7.02 (1H, doublet, J = 9Hz); 7.61 (1H, doublet, J = 9Hz); 8.30 (3H, broad-legulett).

Example 37 7 - [(RS) -3-Amino-4-methylpentoxy] -3 _/ 4,8-trimethylcumarinhydrochlorid compound softens at 240 ⁰ C, decomposes at 243-245 ° C. Nuclear Magnetic Resonance Spectrum (hexane-labeled dimethylsulfoxide), δ ppm:

1.00 (6H, doublet, J = 6.5Hz); 1.85-2.20 (3H, multiple);

2.09 (3H, singlet); 2.21 (3H, singlet); 2.36 (3H, singlet); 3.05-3.40 (1 H, multiple "); 4.28 (2H, triplet, J = 6Hz); 7.05 (1H, doublet, J = 9Hz); 7.62 (1H, doublet, J = 9Hz); 8.23 (3H, broad-pitched).

Example 38 7 - [(RS) -trans- (2-aminocyclohexyl) methoxy] -3,4,8-trimethylcoumarin hydrochloride Melting point at 293-296 ° C (with decomposition).

Nuclear Magnetic Resonance Spectrum (hexane-labeled dimethylsulfoxide), δ ppm:

1.0-2.3 (9H, multiple); 2.06 (3H, singlet); 2.21 (3H, singlet); 2.35 (3H, singlet); 2.7-3.3 (1 H, multiple "); 4.0-4.3 (2H, multiple "); 7.05 (1H, doublet, J = 9Hz); 7.61 (1H, doublet, J = 9Hz); 8.38 (3H, broad-pitched).

Example 39 7 - [(RS) -cis- (2-Aminocyclohexyl) methoxy] -3,4,8-trimethylcumarinhydrochlorid melting point at 261-265 ⁰ C (with decomposition).

Nuclear Magnetic Resonance Spectrum (hexane-labeled dimethylsulfoxide), δ ppm:

1,1-2,1 (9H, multiples); 2.09 (3H, singlet); 2.22 (3H, singlet);

2.36 (3H, singlet); 3.2-3.6 (1H, multiple); 4.0-4.2 (2H, multiples); 7.05 (1H, doublet, J = 9Hz); 7.58 (1H, doublet, J = 9Hz); 8.30 (3H, broad-pitched).

Example 40 7 - [(RS) -trans- or -cis- (2-aminocyclopentyl) methoxy] -3,4,8-trimethylcoumarin hydrochloride mp. At 264 ° C (color), 265-269 ° C (with decomposition). Nuclear resonance spectrum (D ₂ O), δ ppm:

2.16 (3H, singlet); 2.28 (3H, singlet); 2.33 (3H, singlet); 2.1-3.2 (7H, multiples); 4.0-4.25 (1H, multiples); 4.46 (2H, doublet, J = 6Hz); 7.08 (1H, doublet, J = 9Hz); 7.44 (1H, doublet, J = 9Hz).

Example 41 7 - [(RS) -trans or -cis- (2-aminocyclopentyl) methoxy-3,4,8-trimethylcoumarin hydrochloride This is the diastereomer of the compound as described in Example Fp. At 260 ° C (with decomposition ). Nuclear resonance spectrum (D ₂ O), δ ppm:

2.1-2.8 (6H, multiples); 2.20 (3H, singlet);

2.37 (3H, singlet); 2.40 (3H, singlet); 3.0-3.3 (1H, multiple "); 4,3-4,45 (1 H, multiple); 4.60 (2H, doublet, J = 6Hz); 7.22 (1H, doublet, J = 9Hz); 7.58 (1H, doublet, J = 9Hz).

Example 42 7-t (RS) -3- (Methylamino) pentoxy] -3,4,8-trimethylcumarinhydrochlorid mp. 218-220 ⁰ C in

Nuclear resonance spectrum (D ₂ O), δ ppm:

1.52 (3H, triplet, J = 7Hz); 2.15 (3H, singlet); 2.2-2.45 (2H, multiples); 2.26 (3H, singlet);

2.32 (3H, singlet); 2.55-2.8 (2H, multiples); 3.7-3.95 (1H, multiple); 4.4-4.65 (2H, multiples); 7.09 (1H, doublet, J = 9Hz); 7.42 (1H, doublet, J = 9Hz).

Example 43 7-t (RS) -3- (Dimethylamino) butoxy] -3,4,8-trimethylcumarinhydrochlorid mp. At 220-222 ⁰ C.

Nuclear Magnetic Resonance Spectrum (hexane-labeled dimethylsulfoxide), δ ppm:

1.34 (3H, doublet, J = 7Hz); 1.8-2.5 (3H, multiple); 2.06 (3H, singlet); 2.20 (3H, singlet);

2.33 (3H, singlet); 2.66 (3H, singlet); 2.73 (3H, singlet);

3,1-3,7 (1 H, multiple ");

4.20 (2H, triplet, J = 6Hz); 7.04 (iH, doublet, J = 9Hz); 7.60 (iH, doublet, J = 9Hz); 11.10 (1H, broad-pitched).

PREPARATION 1 4-t-Butoxycarbonyl-2- (4-methylphenylsulfonyloxymethylmorpholine

68 ml of triethylamine, followed by 100 ml of methylene chloride with 102 g of di-t-butylpyrocarbonate, were added to a mixture of 100 ml of methanol and 200 ml of methylene chloride containing 52 g of 2-hydroxymethylmorpholine (described in Chem. Pharm. Bull. 33 [9], 3766 [1985]) and stirred in an ice bath. The reaction mixture was then stirred for a further hour at room temperature. Towards the end of this time, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and water, and the ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. Result: 82.9 g of oily 4-t-butoxycarbonyl-2-hydroxymethylmorpholine.

This entire oil was dissolved in a mixture of 150 ml of methylene chloride and 70 ml of triethylamine, then, while the mixture was in the ice bath, 150 ml of methylene chloride containing 73 g of p-toluenesulfonyl chloride was added dropwise. The reaction mixture was stirred at room temperature for 16 hours and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate and evaporated under reduced pressure. Hexane was added to the syrupy residue to aid in crystal formation for the named compound. Then the resulting crystals were filtered off. Yield: 56,8g of the titled compound, mp 85-87 at ⁰ C.

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), δ ppm:

1.43 (9H, singlet);

2.42 (3H, singlet);

2.6-4.2 (7H, multiplet);

4.00 (2H, doublet, J = 8Hz);

7.36 (2H, doublet, J = 8Hz);

7.82 (2H, doublet, J = 8Hz).

Preparation 2 4-t-Butoxycarbonyl-2 - [(4-nitrophenylsulfonyloxy) methyl] morpholine

By a method as described in Preparation 1, 40.7 g of 4-t-butoxycarbonyl-2-hydroxymethylmorpholine (recovered as an intermediate in Preparation 1) was sulfonylated with 47 g of p-nitrobenzenesulfonyl chloride. Yield: 61 g of the named compound in the form of crystals, mp. At 112-113 ⁰ C.

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), δ ppm:

1.44 (9H, singlet);

2.5-4.1 (7H, multiplet);

4.17 (2H, doublet, J = 5Hz);

8.16 (2H, doublet, J = 8Hz);

8.45 (2H, doublet, J = 8Hz).

Preparation 3

(R) -4-t-Butoxycarbonyl-2 - [(4-nitrophenyl-sulfonyloxy) -methyl] -morpholine 3 (a) (R) -2- (benzyloxymethyl) -morpholine

48 g of 2-aminoethyl hydrogen sulfate was added to 18 ml of water containing 13.6 g of sodium hydroxide and then 10 ml of isopropanol containing 13.9 g of (S) -benzyl-2,3-epoxypropyl ether (described in J. Chem. Soc. [C] 1021 [1967] and Heterocycles 16, 381 [1981]) were added dropwise at 50 ° C to this solution. The resulting mixture wure stirred for 1 hour at 50 ⁰ C. Towards the end of this time, 60 ml of water with 27 g of sodium hydroxide were added to the reaction mixture, and the mixture was stirred at 55 ° C. for 20 hours. Then, toluene and a small amount of water were added to the reaction mixture. The toluene layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by 9: 1 by volume silica gel column chromatography for methylene chloride and methanol as eluent. Result: 10.9g of the named compound as a syrup. Rotation of polarization plane [α] "+ 4.5 ° (pure)

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), δ ppm:

2.11 (1H, singlet);

2.55-3.1 (4H, multiplet);

3.55-4.05 (5H, multiplet);

4.51 (2H, singlet);

7.30 (5H, singlet).

3 (b) (R) -2- (benzyloxymethyl) -4-t-butoxycarbonylmorpholine

7.3 ml of triethylamine were added to 100 ml of methylene chloride containing 10.9 g of (R) -2- (benzyloxymethyl) morpholine (prepared as described in step [a] above) and then 20 ml of methylene chloride with 12.1 g of di-t-butylpyrocarbonate added dropwise to the mixture in an ice bath. The mixture was stirred for 2 hours at room temperature, then the reaction mixture was evaporated under reduced pressure. The residue was purified by 1: 4 by volume silica gel column chromatography for ethyl acetate and hexane as the eluent.

Result: 14.2g of the named compound as a syrup.

Rotation of polarization plane [α] "-17,2 ° (c = 1, trichloromethane).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ), δ ppm: 1.48 (9H, singlet); 2.5-4.05 (9H, multiple); 4.52 (2H, singlet); 7.32 (5H, singlet).

3 (c) (R) -4-t-Butoxycarbonyl-2- (hydroxymethyl) morpholine

4.1 g of 5% palladium on carbon was added to 140 ml of an ethanolic solution containing 14.2 g of (R) -2- (benzyloxymethyl) -4-t-butoxycarbonylmorpholine (prepared as described in step [b] above). The mixture was stirred at 70 ° C in hydrogen gas at normal pressure for 9 hours. Towards the end of this time, the catalyst was filtered off. Then, the solvent was distilled off under reduced pressure. Result: 10.0 g of the named compound in the form of crystals, mp. 61-62 ° C.

Rotation of the polarization plane [aJo ⁶ -8.1 ° (c = 1, dimethylformamide).

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), δ ppm:

1.43 (9H, singlet);

2.6 (1H, broad innlet);

2,5-4,1 (9H, multiple).

3 (d) (R) -4-t-Butoxycarbonyl-2 - [(4-nitrophenylsulfonyloxy) methyl] morpholine. A procedure was repeated as described in Preparation 1 except that 5.6 g of (R) -4-t -butoxycarbonyl-2- (hydroxymethyl) morpholine (prepared as described in step [d] above) and 6.0 g of p-nitrobenzenesulfonyl chloride were used. Result: 10.1 g of the titled compound in the form of crystals, mp 106-107 ⁰ C. with.

Rotation of the polarization plane [a] o ⁶ -19.7 ° (c = 1, dimethylformamide).

The nuclear magnetic resonance spectrum of this compound corresponded to that of the product of preparation 2.

Preparation 4 (R) -4-t-Butoxycarbonyl-2 - [(4-methylphenylsulfonyloxy) methyl] morpholine

A procedure was repeated as described in Preparation 1, except that 9.2 g of (R) -4-t-butoxycarbonyl-2- (hydroxymethyl) morpholine (prepared as described in Preparation 3 [c] above) and 8, 5 gp toluenesulfonyl chloride were used. Result: 15.1 g of the named compound in the form of crystals, mp 105.5-107 ° C (after recrystallization from ethanol).

Rotation of the polarization plane [α] "-19.3 (c = 1, dimethylformamide).

The nuclear magnetic resonance spectrum of this compound corresponded to that of the product of preparation 1.

Preparation 5

(S) -4-t-Butoxycarbonyl-2 - [(4-nitrophenylsulfonyloxy) methyl] morpholine 5 (a) (S) -N-Benzyl-3-chloroacetamidopropane-1,2-dio!

39.5 g of 1,2,5,6-di-O-isopropylidene-D-mannitol was added to 240 ml of water containing 35 g of sodium periodate in an ice bath, then the reaction mixture was stirred at 5-10 ° C for 1 hour. Towards the end of this time, 240 ml of ethanol were added to the reaction mixture, and the mixture was stirred at 5-10 ° C. for a further hour. Then another 240 ml of ethanol were added. The resulting precipitate was filtered off, then 35 g of benzylamine and about 15 ml of Raney nickel were added to the filtrate, which was then stirred for 1.5 hours at 5-10 ° C under hydrogen gas and at normal pressure. Further, the mixture was stirred at room temperature for 4.5 hours. Towards the end of this time, the catalyst was filtered off. Then 180 ml of triethylamine were added to the filtrate and then 70 ml of chloroacetyl chloride in an ice bath at 10-15 ⁰ C was added. The reaction mixture was stirred for 1 hour at room temperature and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate and water. The ethyl acetate layer was separated, washed with water and re-evaporated under reduced pressure. This residue was dissolved in 300 ml of acetic acid and 100 ml of water. This solution was stirred at 100 ° C for 2 hours. Towards the end of this time, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in ethyl acetate. The resulting solution was washed with a saturated sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by 9: 1 by volume silica gel column chromatography for methylene chloride and methanol as eluent. Result: 33.1 g of the named compound as a syrup. Rotation of the polarization plane [α] -4.9 ° (c = 1, dimethylformamide)

 Nuclear Magnetic Resonance Spectrum (CDCl3), δ ppm:

3,1-3,6 (4H, multiple);

4.06 (2H, singlet);

3.6-5.1 (5H, multiple);

7.05-7.40 (5H, multiple).

5 (b) (SJ-N-benzyl-S-chloroacetamido-i-triphenylmethoxy) -propanol

39.4 g of triphenylmethyl chloride were added at room temperature to 200 ml of methylene chloride containing 33.1 g of (S) -N-benzyl-3-chloroacetamidopropane-1,2-diol (prepared as described in step [ajoben) and 25 ml of triethylamine. The mixture was stirred for 2 hours at room temperature and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate and water. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by 1: 1 by volume silica gel column chromatography for ethyl acetate and hexane as the eluent. Result: 50.0 g of the named compound as a resin.

Rotation of the polarization plane [a] § ⁵ -4.4 ° (c = 1, dimethylformamide). Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), δ ppm:

3.11 (2H, broad doublet, J = 5Hz); 3,1-5,1 (8H, multiple); 7.1-7.5 (2OH, multiple).

5 (c) (S) -4-Benzyl-3-oxo-6 (triphenylmethoxymethyl) morpholine 4.77 g of sodium hydride (as a 55% suspension in mineral oil) was added to a mixture of 200 ml of dimethylformamide and 66 ml of toluene containing 50.0 g (Sl-N-benzyl-S-chloroacetamido-i-triphenylmethoxy) -propanol (prepared as described in step [b] above) The reaction mixture was then stirred for 2.5 hours at 100 ° C in a nitrogen stream towards the end of this time The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography in a volume ratio of 1: 2 for ethyl acetate and hexane as the eluent Result: 38.6 g of the title compound as a resin.

Rotation of the polarization plane [α] "-27,1 ° (c = 1, dimethylformamide).)

Nuclear Magnetic Resonance Spectrum (CDCI ₃ ), δ ppm:

2.9-3.45 (4H, multiple); 3.6-3.95 (1H, multiple ");

4.22 (2H, AB quartet, Δδ = 0.27 ppm, J = 16Hz); *

4.53 (2H, AB quartet, Δδ = 0.29ppm, J = 15Hz); 7.1-7.5 (2OH, multiple).

5 (d) (S) -4-Benzyl-2- (triphenylmethoxymethyl) morpholine 3.15g of lithium aluminum hydride was added to 350ml of tetrahydrofuran containing 38.6 (S) -4-benzyl-3-oxo-6- (triphenylmethoxymethyl) morpholine (prepared as described in step [c] above). The reaction mixture was stirred in a water bath at 75 ° C for 3.5 hours, after which sufficient crystalline sodium sulfate decahydrate was added to decompose the excess lithium aluminum hydride. The precipitate was filtered off. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography in a volume ratio of 1: 2 for ethyl acetate and hexane as the eluent. Result: 33.6 g of the named compound as a syrup. Rotation of polarization plane [α] "+ 6.3 ° (c = 1, dimethylformamide). Nuclear Magnetic Resonance Spectrum (CDCl ₃ ), δ ppm:

1.8-3.9 (9H, multiple); 3.48 (2H, singlet); 7.1-7.5 (2OH, multiple).

5 (e) (S) -4-Benzyl-2- (hydroxymethyl) morpholine A mixture of 140 ml of acetic acid and 70 ml of water with 33.6 g of (S) -4-benzyl-2- (triphenylmethoxymethyl) morpholine (prepared as described in step [d] above) was stirred at 100 ° C for 2 hours. Towards the end of this time, the reaction solution was cooled. The separated triphenylmethanol was filtered off, then the solvent was distilled off under reduced pressure. The residual acetic acid was removed by azeotropic distillation with toluene. The residue was purified by 1: 9 by volume silica gel column chromatography for methanol and methylene chloride as the eluent. Result: 14.8 g of the named compound as an oil. Rotation of the polarization plane [α] "+ 9,9 ° (c = 1, dimethylformamide). Nuclear Magnetic Resonance Spectrum (CDCl ₃ ), δ ppm:

1.8-2.8 (5H, multiple); 3.48 (2H, singlet); 3,45-4,0 (5H, multiple); 7.31 (5H, singlet).

5 (f) (S) -4-Butoxycarbonyl-2- (hydroxymethyl) morpholine 2.3g of 10% palladium on carbon was added to 120ml of methanol containing 14.8g of (S) -4-benzyl-2-hydroxymethylmorpholine (prepared as described in step [e] above). The mixture was stirred at 60 ° C for 7 hours under hydrogen gas at atmospheric pressure. Towards the end of this time, the catalyst was filtered off. To the filtrate was added 12 ml of triethylamine, followed by dropwise addition of 20 ml of methylene chloride solution containing 15.6 g of di-t-butylpyrocarbonate to the mixture in an ice bath. The mixture was stirred for 1 hour at room temperature and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography in a volume ratio of 1: 1 of ethyl acetate and hexane as the eluent. Result: 12.2g of the named compound as a syrup. Rotation of the polarization plane [a] o ⁵ + 8,3 ° (c = 1, dimethylformamide). i

5 (g) (S) -4-t-Butoxycarbonyl-2 - [(4-nitrophenylsulfonyloxy) methyl] morpholine. A procedure was repeated as described in Preparation 1 except that 12.2 g of (S) -4- t-butoxycarbonyl-2- (hydroxymethyl), (prepared as described in step [f] above) morpholine and 13.0 g p-nitrobenzenesulfonyl chloride used \ were. Result: 19.7 g of the named compound in the form of crystals, mp. At 107 ° C.

Rotation of the polarization plane [α] "+ 23,1 ° (c = 1, dimethylformamide).

The nuclear magnetic resonance spectrum of this compound corresponded to that of the product from the preparation

recipe 1 7- [3- (methylamino) propoxy] -3,4,8- 20.0 mg capsules trimethylcumarinhydrochlorid 158.7 mg (Compound of Example 8) 70.0 mg lactose 1.3 mg corn starch magnesium stearate

250 mg

The powders of the above-mentioned components were mixed well and sieved through a 60 mesh screen. (Tyler Standardsiebskale). 250 mg of the finished powder were weighed out and covered with a gelatine capsule No. 3 for the preparation of the capsules.

Recipe 2 7- [3- (methylamino) propoxy] -3,4,8- 20.0 mg tablets trimethylcumarinhydrochlorid 154.0 mg (Connection of examples) 25.0 mg lactose 1.0 mg corn starch magnesium stearate

200 mg

The powders of the components were mixed well and pressed into tablets of 200 mg each. If necessary, these tablets can be sugar coated.

Recipe 3 7 - [(RS) -3-amino-2-methylbutoxy] -3,4,8- 20.0 mg capsules trimethylcumarinhydrochlorid 158.7 mg (Compound of Example 36) 70.0 mg lactose 1.3 mg corn starch magnesium stearate

250 mg

The powders of the components were mixed well and sieved through a 60 mesh screen. 250 mg of the finished powder were weighed out and coated with a gelatine capsule no. 3 to prepare the capsules.

Recipe 4 7 - [(RS) -3-amino-2-methylbutoxy] -3,4,8- 20.0 mg tablets trimethylcumarinhydrochlorid 154.0 mg (Compound of Example 36) 25.0 mg lactose 1.0 mg corn starch magnesium stearate

200 mg

The powders of the components were mixed well and pressed into tablets of 200 mg each. If necessary, the tablets can be sugar coated.

Claims (26)

1. Process for the preparation of a compound of the formula (I) COO / WW A- (CH ₂ , _m -OCc C H-C C C H _R 2 or their pharmaceutically acceptable salts, characterized in that
A is a group of formula (II) or (III) / \
H ₂ C CH ₂ (H) I i H ₂ C HC- N-CH-CH- (HD; R ¹ , R ² and R ^{3 are the} same or different and each of these groups is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a halogen atom, R ^{4 is} a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, this alkyl group is unsubstituted or at least one substituent from the aryl groups with 6 to 10 carbon atoms, wherein said aryl group is unsubstituted or has at least one of the substituents (a), as explained below, R ⁵ and R ^{6 are the} same or different and each of these groups is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R ⁷ and R ^{8 are the} same or different and each of these groups is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or R ⁷ and R ⁸ together represent an alkylene group having 3 or 4 carbon atoms, and m is 1 or 2, wherein the substituents (a) have the meaning of alkyl groups with 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, trifluoromethyl groups, Nitro groups, cyano groups and halogen atoms may have, and the method following Steps includes: (a) Reacting a compound of the formula (IV) r3 I
COO HO-C C C I Il I < ^IV > H-C C C WWX ₁ C.C.R. ¹ HR ² where R ¹ , R ² and R ^{3 are} as defined above,
with a compound of the formula (V) Y- (CH ₂ LA '(V) wherein m is as defined above, Y is a halogen atom, a sulfonyloxy group or a hydroxy group and A 'is a group of formula (ΙΓ) or (IH') H ₂ C CH ₂ (H ') H ₂ C HC- X /
O \
N-CH-CH- (IH ') r6 'R ⁷ R ⁸ wherein R ⁵ , R ⁷ and R ⁸ as defined above, R ^{4 is} an amino-protecting group or an alkyl group having up to 4 carbon atoms and this alkyl group is unsubstituted or at least one substituent of the aryl groups having 6 to 10 carbon atoms, wherein the aryl group is unsubstituted or at least one of substituents (a) as defined above, and R ^{6 is} an amino-protecting group or an alkyl group of 1 to 4 carbon atoms if necessary, one of the steps (b) or (c), (b) when A 'said group of formula (H') and R ^{4 is} an amino-protecting group or A 'said group of formula (HI') and R ^{6 is} an amino-protecting group, removal of the amino-protecting group, (c) when the product is a compound in which one or both of R ⁵ and R ^{6 represents} a hydrogen atom, the alkylation of the hydrogen atom and its conversion to an alkyl group of 1 to 4 carbon atoms, and optionally the formation of a salt. A method according to claim 1, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, said compound having the formula (I a) NR ³ H ₂ C CH ₂ COO Il / WW _{(| a)} H ₂ C CH- (CH ₂ ) _m -O-CCC < ^la > I Il 0 H-C C C WWX ₁ CCR ¹ HR ²
wherein R ¹ , R ² , R ³ , R ⁴ and m are as explained in claim 1. 3. The method according to claim 2, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein m is 1. 4. The method according to claim 2, characterized in that the reactants and the reaction conditions are selected so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ^{1 is} a hydrogen atom, a methyl group; is an ethyl group, a propyl group, an isopropyl group, a fluorine atom or a chlorine atom. 5. The method according to claim 2 or 4, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ^{2 is} a hydrogen atom, a methyl group, an ethyl group , a propyl group or an isopropyl group. 6. The method according to claim 2,4 and 5, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ^{3 is} a hydrogen atom, a Mehylgruppe, is an ethyl group or an isopropyl group. 7. The method according to claim 2 and 4 to 6, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ^{1 is} a hydrogen atom, a methyl group, a fluorine atom or a chlorine atom, R ² and R ^{3 are the} same or different and each is a hydrogen atom and a methyl group, and R ^{4 is} a hydrogen atom. 8. The method according to claim 1, characterized in that the reactants and the reaction conditions are selected so that a compound of formula (I) or a salt of this compound can be prepared, said compound having the following formula (I b) r3 R ⁵ COO X / X / X / N-CH-CH- (CH ₂ ) _m -OC CC / I ₇ LI Il I ( _lb) R ⁶ r7 r8 · HC CC \ / X / X,
CCR ¹ HR ² in which R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and m are as defined in claim 1. 9. The method according to claim 8, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ⁷ and R ^{8 are} both hydrogen atoms. 10. The method according to claim 8, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ⁵ and R ^{6 are} both hydrogen atoms. 11. The method according to claim 8, characterized in that the reactants and the reaction conditions are selected so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ^{5 is} a hydrogen atom and R ^{6 is} an alkyl group having 1 to 4 carbon atoms. 12. The method according to claim 8, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ^{5 is} a hydrogen atom and R ^{6 is} a methyl group. 13. The method according to claim 8, characterized in that the reactants and the reaction conditions are selected so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ⁵ and R ^{6 is the} same or different and each is a methyl or ethyl group. 14. The method according to claim 8 and 10 to 13, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ^{1 is} a hydrogen atom, a chlorine atom or is a methyl group. 15. The method according to claim 8 and 10 to 14, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ^{2 is} a hydrogen atom or a methyl group , 16. The method according to claim 8 and 10 to 15, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ^{3 is} a hydrogen atom or a methyl group , 17. The method according to claim 8, characterized in that the reactants and the reaction conditions are selected so that a compound of formula (I) or a salt of this compound can be prepared, wherein: R ^{1 is} a hydrogen atom, a chlorine atom or a methyl group, R ^{2 is} a hydrogen atom or a methyl group, R ^{3 is} a hydrogen atom or a methyl group and R ⁵ and R ^{6 are} hydrogen atoms. 18. The method according to claim 8, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ^{1 is} a hydrogen atom, a chlorine atom or a methyl group, R ^{2 is} a hydrogen atom or a methyl group, R ^{3 is} a hydrogen atom or a methyl group and R ^{5 is} a hydrogen atom and R ^{6 is} an alkyl group having 1 to 4 carbon atoms. 19. The method according to claim 8, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ^{1 is} hydrogen, chlorine or methyl, R ^{2 is} hydrogen or methyl,
R ^{3 is} a hydrogen atom or a methyl group,
R ^{5 is} a hydrogen atom and
R ^{6 is} a methyl group. 20. The method according to claim 8, characterized in that the reactants and the reaction conditions are selected so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ^{1 is} hydrogen, chlorine or methyl, R ^{2 is} hydrogen or methyl, R ^{3 is} a hydrogen atom or a methyl group and R ⁵ and R ^{6 are the} same or different and each is a methyl or ethyl group. 21. The method according to claim 8, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ¹ , R ² and R ^{3 are} methyl groups, R ⁵ and R ^{6 are} hydrogen atoms and R ⁷ and R ^{8 are the} same or different and each is hydrogen, methyl, ethyl and isopropyl. 22. The method according to claim 8, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, in which R ¹ , R ² and R ^{3 are} methyl groups, R ^{5 is} a hydrogen atom, R ^{6 is} a methyl group and R ⁷ and R ^{8 are the} same or different and each is hydrogen, methyl, ethyl and isopropyl. 23. The method according to claim 8, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ¹ , R ² and R ^{3 are} methyl groups, R ⁵ and R ^{6 are} methyl groups and R ⁷ and R ^{8 are the} same or different and each is hydrogen, methyl, ethyl and isopropyl. A process according to claim 1, wherein the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein m is 1. 25. The method according to claim 1, characterized in that the reaction conditions and the reactants are selected so that
3,4,8-trimethyl-7- (2-morpholinyl) methoxycoumarin;
3,4-dimethyl-7- (2-morpholinyl) methoxycurnarin;
3,4,8-trimethyl-7- (4-methyl-2-morpholinyl) methoxycoumarin; 7- (3-N, N-dimethylamino) -3,4,8-trimethylcurnarin; 7- (3-aminopropoxy) -3,4,8-trimethylcoumarin and
7- (3-aminobutoxy) -3,4,8-trimethylcoumarin or a pharmaceutically acceptable salt of these compounds can be prepared. Process according to any one of the preceding claims, characterized in that the reactants and the reaction conditions are chosen so that a compound of formula (I) or a salt of this compound can be prepared, wherein R ⁵ and R ^{6 are} not identical and either one A methyl group or an ethyl group when A is a group of the formula (III), R ¹ , R ³ , R ⁷ and R ^{8 are} all hydrogen atoms, R ^{2 is} a methyl group and m is 1. A process for the preparation of a pharmaceutical composition for the treatment of cardiovascular disorders by mixing a compound of formula (I) as defined in claim 26 or a pharmaceutically acceptable salt of said compound with a pharmaceutically acceptable carrier or diluent.