CS209917B2 - Method of preparation of the /omega-aminoalkoxy/bibenzyles - Google Patents

Description

The present invention relates to a process for the preparation of (meth-R 3 gaaminoalkoxy) bibenzyls of the general formula I —C—, wherein R3 is alkyl of one to 5 atoms wherein R is

Ri /

-N \

R 2 wherein R 1 and R 2, which are the same or different, represent hydrogen, alkyl of 1 to 8 carbon atoms and hydroxy-alkyl of 1 to 8 carbon atoms, not bio

wherein A is a bivalent radical consisting of two or more groups, such as methylene —CH2— and myosubstituted methylene carbon or hydroxyl, and none or one or more groups, such as oxy-O—, has a weight of

H —S—, imino —N— and substituted amino

R 8 —N—, wherein R 8 is alkyl of one to 5 carbon atoms or hydroxyalkyl of one to 5 carbon atoms that combine in any arrangement, the number of combined groups is up to 9, the substituent Y and Y 'is hydrogen, n is an integer 2 to 8, m is an integer of 1 and m is an integer of 1, or an acid addition salt thereof.

(Omega-aminoalkoxy) bibenzyls are pharmacologically effective as platelet aggregation inhibitors.

As mentioned above, the invention relates to a group of compounds useful as pharmaceutically active substances, the structure and numbering of which are as follows:

(I) wherein R is represented by the formula (1) R1

Z —N \

R 2 or (2) which will be described in more detail below.

1. Where R is

Ri

Z —N \

R 2 is R 1 and R 2, which are the same or different, hydrogen, alkyl of 1 to 8 (preferably 1 to 5) carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl or alike; and hydroxyalkyl having 1 to 8 (preferably 1 to 5) carbon atoms such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 5-hydroxypentyl and the like.

2. In the case where R is 'M', J is A a divalent radical consisting of two or more groups such as methylene (CH 2), methylan-substituted methylene (R 3)

-C-

H and disubstituted methylene

R4 'I

AND

-C-,

R 5 wherein R 3, R 6 and R 5 are independently alkyl of 1 to 5 (preferably 1 to 3) carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl or the like; carboxyl; alkoxycarbonyl of 2 to 6 (preferably 2 to 4) carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or the like; hydroxyl; or·

Re

Z-CON wherein R 6 and R 7 is hydrogen or alkyl of 1 to 5 (preferably 1 to 3) carbon atoms such as carbamoyl, methylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, butylcarbamoyl; and none or one or more groups such as oxy-0, thioi-S,

H Re

Imino-N- and substituted imino-N-, wherein R 5 is alkyl of 1 to 5 (preferably 1 to 3) carbon atoms such as methyl, ethyl, propyl, butyl or the like; or. hydroxyalkyl having 1 to 5 (preferably 1 to 3) carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or the like, which are combined in any arrangement, the number of combined groups is up to 9 (preferably 7).

Examples of typical R groups are:

1. Where it is

Ri

OF

R — N \

R 2 amino, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino, N-methyl-N-butylamino, dibutylamino, dipentylamino, dihexylamino, 2-hydroxyethylamino, bis (2-hydroxyethyl) amino-, N- (2-hydroxyethyl) -N-methylamino.

2. In case R is

-ON

1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidine O ', 1-hexamethyleniminyl, 1-heptamethyleniminyl, 1-piperazinyl, morpholino-, thiazolidinyl, thiomorpholino,

3-methyl-1-pyrrolidinyl,

2,5-dimethyl-1-pyrrolidinyl,

2-Ethyl-pyrrolidinyl

2-methylpiperidino,

3-methylpiperidino,

4-methylpiiperidino,

4-ethylpiperidino,

2,4-dimethylpiperidino,

4-Methyl-1-piperazinyl

4- (2-hydroxyethyl) -1-piperazinyl, 4-propyl-1-plperazinyl,

4- (2-hydroxyethyl) -1-piperazinyl,

4- (3-Hydroxypropyl) -1-piperazinyl,

4- (2-hydroxyethyl) piperidino, carboxyaziridinyl,

3-methoxycarbonyl-1-pyrrolidinyl,

2-carboxy-1-pyrrolidinyl,

3-dimethylcarbamoyl-1-pyrrolidinyl, .1-carboxypiperidino,

Rz

WITH

4-methoxycarbo, nylpiperidine-o,

4-Diimethylcarbamoylpiperidino

3-carboxypiperidino,

3-carbamoyl-1-pyrrolidinyl,

3-carbamoylpiperidino,

4-carboxy-1-hexamethyleniminyl, 4-carbamoyl piperidino, 4-hydroxypiperidino, 3-hydroxypiiperidino,

1-imidazolidinyl,

3-Methyl-1-imidazolidinyl

4-methylhexahydro-1,4-diazepinyl, 4- (2-hydroxyethyl) hexahydro-1,4-diazepinyl.

A preferred group may be represented by Formula II:

(II) wherein Z is —CH2—, —O—, —NH—, —N — alkyl wherein alkyl contains 1 to 5 (preferably 1 to 3) carbon atoms, and —N — hydroxyalkyl wherein hydroxyalkyl contains 1 R 5 and R 10 are alkyl of 1 to 5 (preferably 1 to 3) carbon atoms, carboxyl, alkoxycarbonyl of 2 to 6 (preferably 2 to 4) carbon atoms, hydroxy] and

R6 /

—CON \

R?

wherein R 5 and R 7 is hydrogen or alkyl of 1 to 5 (preferably 1 to 3) carbon atoms; and -r and r ‘is an integer of 1, 2 or 3 (preferably r + r * is 3 or-4j.

The most preferred R groups are as follows: 1. In the case where R is

Rl

Z —N \

R 2 is C 1 -C 5 alkylamino, C 2 -C 6 dialkylamino, C 1 -C 5 -alkylalkylainino, N- (C 1 -hydroxyalkyl) -C 2 -C 6 -alkylamino and bis ( n-hydroxyalkyl) amino having 2 to 6 carbon atoms.

(B)

2. In case R is - · Aj A

1-pyrrolidinyl, piperidino, morpholino, 4-alkyl, 1-piperazinyl of 6 to 8 carbon atoms and 4-hydroxy-1-piperazinyl of 6 to 8 carbon atoms, each of which is unsubstituted or substituted by one or two carboxy, C 2 -C 4 alkoxycarbonyl, C 3 -C 6 -carbamoyl, C 3 -C 6 -alkylcarbarooyl, C 2 -C 4 -alkylcarbamoyl, C 1 -C 13 alkyl and hydroxyl .

In the above formula I, the residue Y and Y is hydrogen; halogen such as fluorine, chlorine and bromine; alkyl of 1 to 5 (preferably 1 to 3) carbon atoms such as methyl, ethyl, propyl, butyl or the like; hydroxyl; alkoxy of 1 to 5 (preferably 1 to 3) carbon atoms such as methoxy, ethoxy, propoxy butoxy or the like; carboxyl; alkoxycarbonyl of 2 to 6 (preferably 2 to 4) carbon atoms such as methoxycarbonyl, ethoxycarbonyl or the like; amino; alkylamino of 1 to 5 (preferably 1 to 3) carbon atoms such as methylamino, ethylamino, propylamino, butylamino or the like, or dialkylamino of 2 to 10 (preferably 2 to 6, most preferably 2 to 4) carbon atoms, such as dimethylamino, diethylamino, dipropylamino or polymers. -d.

Preferred Y and Y 'radicals are hydrogen, fluoro, chloro, (C 1 -C 3) alkyl, hydroxyl, (C 1 -C 3) alkoxy, carboxyl, (C 2 -C 4) alkoxycarbonyl, and C 2 -C 4 dialkylamino. carbon atoms.

The omega-aminoalkoxy group shown in Formula I may be located at the 2-4 position of the benzene ring; preferably it is located at the 2 or 4 position and most preferably it is located at the 2 position.

In formula I above, n is an integer from 2 to 8, preferably from 2 to 6, and most preferably from 2 to 4; m is an integer from 1 to 4, preferably 1 or 2; and m ‘is an integer of 1 to 5, preferably 1 or 2.

Specific compounds of the invention are:

2- (4-methylaminobutoxy) bibenzyl 1,

2- (2-dimethylaminoethoxy) bibenzyl,

2- (3-dimethylaminopropoxy) bibenzyl,

2- (4-dimethylaminobutoxy) bibenzyl,

2- (5-dimethylaminopentyloxy) bibenzyl,

2- (6-dimethylaminochexyloxy) bibenzyl,

2- (2-diethylaminoethoxy) bibenzyl,

2- (3-dimethylaminopropyloxy) bibenzyl,

2- (4-diethylaminobutoxy) bibenzyl,

2- (5-diethylaminopolyloxy) bibenzyl,

2- (8-diethylamino-hexyloxy) bibenzyl,

2- (4- (N-m-ethyl-N-butylamino) butoxy] bibenzyl,

2- (4- (N-methyl-N- (2-hydroxyethyl) amino-butoxy) bibenzyl),

2- [4-bis (2-hydroxyelhyl) aminobutoxy] bibenzyl,

4- (3-dimethylaminopropoxy) bibenzyl,

4- (4-dimethylaminobutoxy) bibenzyl,

2- [4- (1-pyrrolidinyl) butoxy] bibenzyl,

2- (4-piperidinobutoxy) bibenzyl,

2- (4-moi’f olinobutoxy) bibenzyl

2- [4- (4-Hydroxypiperidino) butoxy] bibenzyl,

2- [4- (1-piperazinyl) butoxy] bibenzyl, 2- {4- [4- (2-hydroxyethyl) -1-piperazinyl] butoxy] bibenzyl,

2- [2- (1-aziridinyl-ethoxy) -bibenzyl,

2- [3- (1-azetidinyl) propoxy] bibenzyl,

2- (3-thiomorpholinoipropoxy) bibenzyl,

- [3- (4-Methyl-1-piperazinyl) propoxy] bibenzyl,

- [3- (4-Methylpiperidino), propoxy] bibenzyl,

2- [3- (4-hydroxypiperidino) propoxy] bibenzyl,

2- [2- [N-methyl-N- (2-hydroxyethyl) amino] ethoxy] bibenzyl,

2- (2-piperidinoethoxy) bibenzyl,

2- (7-dimethylaminoheptyloxy) bibenzyl,

2- (8-diethylamino-octyloxy) bibenzyl,

3- (2-dimethylaminoethoxy) bibenzyl,

3- (3-dimethylaminopropoxy) bibenzyl,

3- [4-bis (2-hydroxyethyl) aminobutoxy] bibenzyl,

- [4- (1-pyrrolidinyl-butoxy) bibenzyl],

3- (4-dimethylaminobutoxy) bibenzyl,

4- (2-dimethylaminoethoxy) bibenzyl,

4- (3-dimethylamino-propoxy) bibenzyl,

4- [4-bis (2-hydroxyethyl) aminobutoxy] bibenzyl,

4- (4- (1-pyrrolidinyl) butoxy] bibenzyl,

4- (4-diethylamino-butoxy) bibenzyl, 2- (4- (4-carboxypiperidino butoxy) bibenzyl,

2- [4- (4-Inethoxycarbonylpiperidino) butoxy] bibenzyl,

2- [4- (4-ethoxycarbonylpiperidino) butoxy] bibenzyl,

2- [4- (4-propoxycarbonylpiperidino) butoxy] bibenzyl,

2- (4- (4-carbamoylpiperidino) butoxy] bibenzyl,

2- (4- (4-methylcarbamoylpiperidino) butoxy) bibenzyl,

2- [4- (4-dimethylcarbamoylpiperidinoybutoxy) bibenzyl,

2- (4- (4-ethylcarbamoylpiperidino) butoxy) bibenzyl,

2- j 4- (4-Diethylcarbamoylpiperidino) butoxy] bibenzyl,

2- [4- (4-propylcarbamoylpiperidino) butoxy] bibenzyl,

2- [4- (4-dipropylcarbamoylpiperidino) butoxy] bibenzyl,

2- [4- (3-carbamoylpiperidino) butoxy] bibenzyl,

2- (4- (2-carboxy-1-pyrrolidinyl) butoxy] bibenzyl,

2- [3- (4-carbainoylpiperidino) propoxy] bibenzyl,

2- (3- (3-carbamoylpiperidino) propoxy) bibenzyl,

2- [3- (4-ethoxycarbonylpiperidino) propoxy] bibenzyl,

2- [3- (2-carboxy-1-pyrrolidinyl) propoxy] bibenzyl,

2- (3- (3-carbamoyl-1-pyrrolidinyl) propoxy) bibenzyl,

2- [2- (4-carbamoylpiperidino) ethoxy] bibenzyl,

2- [2- (4-carboxypiperidino) ethoxy] bibenzyl,

2- (2- (2-carboxy-1-pyrrolidinyl) ethoxy] bibenzyl,

2- (2-dimethylaminoethoxy) -4‘-chlorobibenzyl,

2- (3-dimethylaminopropoxy) -4‘-chlorobibenzyl,

2- (4- [4- (2-hydroxyethyl) -1-piperazinyl] butoxy} -4‘-chlorobibenzyl,

2- (4-diethylaminobutoxy) -4‘-chlorobenzyl,

2- (4-dimethylaminobutoxy) -4‘-chlorobenzyl,

2- (4-piperidinobutoxy) -4'-chloroblbenzyl, 2- (4- (1-pyrrolidinyl) butoxy] -4'-chlorobenzyl,

2- (4- (4-methylpiperidino) butoxy) -4‘-chlorobibenzyl,

2- (4- (4-carboxypiperidino) butoxy] -4'-chlorobibenzyl,

2- [4- (4-carbamoylpiperidino) butoxy] -4‘-chlorobibenzyl,

2- (8-dimethylaminohexyloxy) -4'-chlorobibenzyl,

2- (2-dimethylaminomethoxy-2'-chlorobibenzyl),

2- (4-dimethylaminobutoxy) -2'-chlorobenzyl,

2- {4- [4- (2-hydroxyethyl) -1-piperazinyl] butoxy} -2'-chlorobrobenzyl,

2- (4-piperidinobutoxy) -2‘-chlorobenzyl, 2- (4- (4-methylpiperidino) butoxy) -2‘-chlorobibenzyl,

2- (4- (1-pyrrolidinyl) butoxy) -2'-chlorobenzyl,

2- (4- (4-carboxypiperidino) butoxy] -2'-chlorobibenzyl,

2- (4- (4-carbamoylpiperidino) butoxy] -2'-chlorobibenzyl,

2- (6-dimethylaminohexyloxy) -2'-chlorobibenzyl,

2- (3-dimethylaminopropyloxy) -3‘-chlorobibenzyl,

2- (4-diethylaminobutoxy) -3‘-chlorobibenzyl,

2- (4- (4-carboxypiperidino) butoxy] -3‘-chlorobibenzyl,

2- [4- (4-carbamoylpiperidino) butoxy] -3‘-chlorobibenzyl,

2- (4- (1-pyrrolidinyl) butoxy] -3‘-chlorobibenzyl,

2- (2-dimethylaminoethoxy) -3 ‘, 4‘ -dichlorobibenzyl,

2- (3-dimethylaminopropoxy) -3,3,4,4-dichlorobibenzyl,

2- [4- (4-carboxypiperidino) butoxy] -3,4,4-dichlorobibenzyl,

2- [4- (4-carbamoylpiperidino) butoxy] -3,4,4-dichlorobibenzyl,

2- (2-dimethylaminoethoxy) -2,4,4-dichlorobibenzyl,

2- (4-dimethylaminobutoxy) -2,4,4-dichlorobibenzyl,

2- [4- (4-carboxypiperidino) butoxy] -2,4,4-dichlorobibenzyl,

2- [4- (4-carbamoylpiperidino) butoxy] -4- (2-chlorobenzyl)

2- (3-dimethylaminopropoxy) -4‘-fluorobibenzyl,

2- (4-dimethylaminobutoxy) -4'-fluorobibenzyl,

2- (4-diethylaminobutoxy) -4‘-fluorobibenzyl,

2- (4-piperidinobutoxy) -4‘-fluorobibenzyl, 2- (4- (4-methylpiperidino) butoxy] -4‘-fluorobibenzyl,

2- (4- (1-pyrrolidinyl) butoxy] -4-fluorobibenzyl,

2- [4- (4-carboxypiperidino) butoxy] -4‘-fluorobibenzyl,

2- (4- (4-carbamoylpiperidino) butoxy] -4‘-fluorobibenzyl,

2- (4- (4-dimethylcarbamoylpiperidino) butoxy] -4‘-fluorobibenzyl,

2- [4- (4-ethoxycarbonylpiperidino) butoxy] -4‘-fluorobibenzyl,

2- (4- (4-Hydroxypiperidino) butoxy] -4'-fluorobibenzyl,

2- (6-dimethylaminohexyloxy) -4'-fluorobibenzyl,

2- (2-dimethylaminoethoxy) -2'-fluorobibenzyl,

2- (4-dimethylaminobutoxy) -2'-fluorobibenzyl,

2- (4-dipropylaminobutoxy) -2'-fluorobibenzyl,

2- (4- (4-carboxypiperidino) butoxy] -2'-fluorobibenzyl,

2- (4- (4-carbamoylpiperidino) butoxy] -2'-fluorobibenzyl,

2- (4- (1-pyrrolidinyl) butoxy] -2'-fluorobibenzyl,

2- [4-4- (2-hydroxyethyl) -1-piperazinyl] butoxy-2H-fluorobibenzyl,

2- (3-dimethylaminopropoxy) -3‘-fluorobibenzyl,

2- [4-4- (2-hydroxyethyl) -1-piperazinyl] butoxy-3'-fluorobibenzyl,

2- (4- (4-carboxypiperidino) butoxy] -3‘-fluorobibenzyl.

2- (4- (4-carbamoylpiperidino) butoxy] -3‘-fluorobibenzyl.

2- (2-dimethylaminoethoxy) -2‘-me, thoxybibenzyl,

2- (4-dimethylaminobutoxy) -2-methoxy. bibenzyl,

2- (4-piperidinobutoxy) -2'-methoxybibenzyl,

2- (4- (1-pyrrolidinyl) butoxy] -2'-ethoxybibenzyl,

2- (4- (4- (2-hydroxy-oxy)) -1-piperazinyl] butoxy] -2'-inethoxybibenzyl,

2- (4-dimethylaminobutoxy) -3‘-methoxybibenzyl,

2- {4- [4- (2-hydroxyethyl) -1-piperazinyl] butoxy] -3'-methoxybibenzyl,

2- (3-dimethylaminopropoxy) -2‘-ethoxybibenzyl,

2- (4-dimethylaminobutoxy) -2'-ethoxybibenzyl,

2- (4-diethylaminobutoxy) -2'-ethoxybibenzyl,

2- (2-dimethylaminoethoxy) -2'-hydroxybibenzyl,

2- (4-dimethylaminobutoxy) -2'-hydroxybibenzyl,

2- (2-dimethylaminoethoxy) -2'-carboxybibenzyl,

2- (4-dimethylaminobutoxy) -2'-carboxybibenzyl,

2- {4- [4- (2-hydroxyethyl) -1-piperazinyl] butoxy (-2'-carboxybibenzyl),

2- (2-dimethylaminoethoxy) -2‘-methoxycarbonylbibenzyl,

2- (4-dimethylaminobutoxy) -2‘-methoxycarbonylbibenzyl,

2- (4-dimethylaminobutoxy) -3‘-methoxycarbonylbibenzyl,

2- (3-dimethylaminopropoxy) -3‘-carboxybibenzyl,

2- (4-dimethylaminobutoxy) -4'-carboxybibenzyl,

2- (4-dimethylaminobutoxy) -4‘-methoxycarbonylbibenzyl,

2- (4-dimethylaminobutoxy) -2'-methylbibenzyl,

2- (4-piperidinobutoxy) -2'-methylbibenzyl, 2- (4- (1-pyrrolidinyl) butoxy] -2'-ethylbibenzyl,

2- [4- (4-carbamoylpiperidino) butoxy] -2'-methylbibenzyl,

2- (4- (4-methyl-1-piperazinyl) butoxy] -2'-methylbibenzyl,

2- (4-diethylaminobutoxy) -2'-propylbibenzyl,

2- (3-dimethylaminopropoxy) -3‘-methylbibenzyl,

2- [4- (4-carboxypiperidino) butoxy] -3‘-ethylbibenzyl,

2- (4-dimethylaminobutoxy) -4'-methylbibenzyl,

2- (3-dimethylaminopropoxy) -4'-dimethyl • aminobibenzyl,

2- (4- (4-carbamoylpiperidino) butoxy] -4'-dimethylaminobibenzyl,

2- [4-4- (2-hydroxyethyl) -1-piperazinyl] butoxy-4'-dimethylaminobibenzyl,

2- (3-dimethylaminopropoxy) -5-chlorobibenzyl,

2- {4-piperidinobutoxy} -5-chlorobibenzyl, 2-4- (4-methylpiperidino) butoxy-5-chlorohibenzyl,

2- (3-dimethylaminopropoxy) -5-fluorobibenzyl,

2- (4- (4-carbamoylpiperidino) butoxy] -5-fluorobibenzyl,

2- (4-dimethylaminobutoxy) -3-methoxybibenzyl,

2- (4-diethylamino-butoxy) -3-e, thoxybibenzyl,

2- (4- (4-carboxypiperidino) butoxy] -3-propoxybibenzyl,

2- [4-bis (2-hydroxyethyl) aminobutoxy] -3-methoxybibenzyl; and 2- [4-dimethylaminobutoxy) -5-methoxybibenzyl.

Pharmaceutically acceptable acid addition salts of the above compounds are also included within the scope of the invention.

It is understood that the term "pharmaceutically acceptable acid addition salts" includes non-toxic anionic salts of the compounds of the invention.

Examples of such salts are hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, acetates, fumarates, succinates, adipanes, proipinates, tartrates, maleic acids, citrates, benzoates, toluenesulfonates and methanesulfonates.

The following compounds are most preferred of the compounds of the invention for inhibiting platelet aggregation.

2- (2-dimethylaminoethoxy) bibenzyl,

2- (4-dimethylaminobutoxy) bibenzyl,

2- (4- (4- (2-hydroxyethyl) -1-piperazinyl) butoxy) bibenzyl,

2- (4-diethylaminobutoxy (bibenzyl, 2- [4- (4-carbamoylpiperidylbutoxy) bibenzyl),

2- (4-dimethylaminobutoxy) -3‘-methoxybibenzyl,

2- (4-Piperidino-butoxy) -2'-chlorobenzyl,

2- (4- (4-carbamoylpiperidino) butoxy] -4‘-fluorobibenzyl,

2- (3-dimethylaminopropoxy) -4‘-dimethylaminobibenzyl; and 2- (3-dimethylaminopropoxy) -5‘-chlorobibenzyl.

The foregoing compounds serve only to illustrate typical compounds of the invention without limiting the scope of the invention.

A process for the preparation of compounds of formula I is characterized by reacting an alkali metal salt of hydroxybibenzyl of formula III "OM wherein M is an alkali metal and Y and Y‘, m and m ‘are as defined above with ω-haloalkyl amine IV

X - (CH 2) _n - R wherein X is halogen and R and _n are as defined above.

The reaction may be carried out in a hydrocarbon solvent such as toluene, xylene or the like, or an aprotic solvent such as idimethylformamide at a temperature up to the boiling point of the solvent.

The amount of omega-haloalkylamine (IV) used is in the range of 1 to 5 moles per mole of hydroxybibenzyl (III). The reaction time varies according to the reaction temperature, but is normally in the range of 5 to 120 min.

The (dega-aminoalkoxy) bibenzyl formed or the acid addition salt thereof can be purified by recrystallization from a suitable solvent as the alcohol-ether.

(Omega-aminoalkoxy (bibenzyl where R 3, R 6 or R 8 is alkoxycarbonyl) is prepared by esterifying the corresponding (omega-aminoalkoxy) biphenyl wherein R 3, R 6 or R 8 is carboxyl, at a temperature ranging from 50 to 150 ° C for 1 to Iv alcohol (R 3 OH, R 5 OH or R 5 OH) using an acid catalyst.

(Omega-aminoalkoxy (bibenzyl, where R 3, R 6 or R 5 is carboxyl) is converted to the corresponding acid halide by treatment with a halogenating agent such as thionyl chloride or phosphorus pentachloride in the absence or presence of a solvent such as phosphorus oxychloride at 20 to 100 DEG C. Amidation of the acid halide with an amine of formula V,

Re

OF

Η — N \

R 7 (V), wherein R e and R 7 are as defined above, is carried out in a solvent such as water, tetrahydrofuran, dioxane, or chloroform in the presence of a basic catalyst at -20 to 50 ° C for 0.5 to 5 hours .

Pharmacological tests (omega-aminoalkoxy (bibenzyls of the invention) demonstrate their anticoagulant activity, especially anti-platelet aggregation activity, and these compounds are useful in the treatment and prevention of thrombosis. according to the invention to rabbits.

Evaluation of the compounds of the invention for their anti-platelet aggregation activity is performed according to the tribidometric method described by G.V. Born, Nature 194, 927 (1962).

Platelet aggregation is measured using platelet-rich plasma prepared from a mixture of sodium citrate and blood collected from the carotid artery of male Japanese white rabbits. A suspension of bovine collagen in physiological is used

IV of the solution to cause platelet aggregation. Platelet aggregation in the rabbit is induced by the addition of a collagen suspension to obtain 10-15 μξ collagen per milliliter. At the same time, tests are performed at 37 ° C at 4 x 10 ⁵ / mm ³ platelets. A solution of the compounds of the invention in saline is added to the platelet-rich plasma. After a 3 minute platelet-rich plasma preincubation, collagen is added to cause platelet aggregation. Percent inhibition is calculated by comparison with the control.

Using the above procedure, the compounds of the invention are compared with aspirin.

The concentration of the compound in micromoles causing 50% inhibition of platelet aggregation (Iso) and LD 50, as calculated by the ¹ Litchfield-Wilcoxon method, is shown in Table I.

The compounds of the invention may be administered by any means to inhibit platelet aggregation in warm-blooded animals.

E.g. the compounds may be administered parenterally, subcutaneously, intravenously, intramuscularly, or intraperitoneally. Alternatively or concurrently, administration of the compounds may also be effected orally. The dose to be administered depends on the age, health and weight of the patient, the type of concomitant treatment, the repeated dose and the nature of the effect desired. In general, the daily dose of the active ingredient is in the range of 0.5 to 50 mg / kg body weight. An amount of 1 to 30 mg / kg per day, in one or more doses per day, is normally effective to achieve the desired result.

The compound of the invention may be used in dosage forms such as ¹ tablets, capsules, packaged powders, or liquid solutions or elixirs for oral administration, or sterile liquid preparations as solutions or suspensions for parenteral use. These compositions contain, in addition to the active ingredient of the invention, a solid or liquid non-toxic pharmaceutical carrier for the active ingredient. The solid carrier may also be a capsule of the conventional gelatin type. Alternatively, the active ingredient may be tableted with or without an adjuvant, or it may be used as a packaged powder. These capsules, tablets and powders generally contain 5 to 95% w / w. % and preferably 25 to 90 wt. active substance. These doses preferably contain 5 to 500 mg of active ingredient, most preferably 25 to 250 mg.

The pharmaceutical carrier may be a sterile liquid such as water and oils, including those derived from petroleum, animal, vegetable * or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.

In general, saline, aqueous solutions, dextrose and related sugars, and glycols such as propylene glycol and polyethylene glycol are preferred liquid carriers, especially for injectable solutions containing physiological saline typically 0.5 to 20% by weight. % and preferably 1 to 10 wt. active substance.

As mentioned above, a suspension or syrup in which 0.5 to 10% by weight is normally contained is suitable for oral administration. active substance. The pharmaceutical carrier in this formulation may be an aqueous vehicle, such as aromatic water, syrup, or pharmaceutical slime.

The invention will be further elucidated in the following examples without limiting the scope of the invention.

Example 1

A solution of 3.96 g of 2-hydroxybibenzyl in 30 ml of toluene was added dropwise at room temperature to the suspension of 1.0 g of lithium hydride in 30 ml of toluene over 5 minutes. The mixture was heated under reflux for 30 minutes, a solution of 6.45 g of 2-chloro-N, N-dimethylethylamine in 20 ml of toluene was added dropwise over 5 minutes, and then refluxed for a further 2 hours. The reaction mixture was cooled to room temperature and water (50 ml) was added. The toluene layer was separated, washed twice with water, dried over anhydrous sodium sulfate, and then the toluene was distilled off in vacuo. The residue was dissolved in ethyl ether and then a 20% ethanolic hydrogen chloride solution was added. The resulting precipitate was filtered and recrystallized from -ethanol-ether to give 5.81 g (95% yield) of 2- (2-dim ^and ethylaminoethoxyjbibenzylhydrochloridu, mp 172-173 ° C.

For C18H23NO. HCl calculated:

% C, 70.69;% H, 7.91;% N, 4.58; found:

% C, 70.49;% H, 7.68;% N, 4.62.

Example 2

To a solution of 2.5 g of 2-hydroxy-3 ', 4 ' -dichlorobibenzyl in 10 ml of dimethylformamide was added with cooling 0.23 g of sodium hydride. The mixture was stirred for 30 minutes and then added dropwise to a mixture of 2.2 g of 3-dimethylaminopropyl chloride. The reaction mixture is heated to about 60 ° C and then stirred for 5 hours. After completion of the reaction, 2N aqueous sodium hydroxide solution was added and the product was extracted with ether. The ether extract was washed well with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and then distilled under vacuum to sufficiently remove the ether and a small amount of the remaining 3-dimethylaminopropyl chloride. The residue was dissolved in ether and 20% ethanolic HCl solution was added to form a precipitate. Recrystallization from ethanol-ether gave 2.6 g (71% yield) of 2- (3209917)

-dimethylaminopropoxy) -3,4,4-dichlorobibenzyl hydrochloride, m.p. 136-137 ° C.

For C19H23NCl2O. HCl calculated:

58.70% C 6.22 _0/0 H Found:

% C, 58.65;% H, 6.11;

3.60% N; 3.53% N.

Various other (omega-aminoalkoxy) bibenzyls are prepared according to the methods set forth in the previous examples. The results, including the examples, are summarized in Table 1.

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Claims (3)

SUBJECT A method of preparation (omega-aminoalkoxy) wherein R is Ri OF -N R2 wherein R1 and R2, which are the same or different, are hydrogen, alkyl of 1 to 8 carbon atoms and hydroxyalkyl of 1 to 8 carbon atoms, or wherein A is a bivalent radical consisting of two or more groups such as methylene- CH2- and monosubstituted methylene R 3 -C, wherein R 3 is alkyl of one to 5 atoms AND Carbon or hydroxyl, and none or one or more groups such as oxy-O-, thio-S-, H Rs II imino-N- and substituted imino-N-, wherein R 5 is alkyl of 1 to 5 carbon atoms, or hydroxyalkyl of 1 to 5 carbon atoms, which are combined in any arrangement, the number of combined groups is up to 9, the substituents Y and Y 'is hydrogen, · n is an integer of 2 to 8, m is an integer of 1 and m' is an integer of 1, or an acid addition salt thereof, characterized in that an alkali metal salt of hydroxybibenzyl of formula III is reacted YNÁLEZU X - (CH ₂ ) n -R IV wherein X is halogen and R and n are as defined above. 2. A process according to item 1 of a compound of formula I -N A where A is a divalent radical consisting of two or more groups such as methylene —CH2 — and monosubstituted methylene R 3 -C, wherein R 3 is carboxyl, alkoxycarbonyl H having two to six carbon atoms, or Re From —CON \ R 7 wherein R 6 and R 7 is hydrogen or C 1 -C 5 alkyl which combine in any configuration, the number of combined groups is in the range of 2 to 7, the substituent Y and Y 'is hydrogen, n is an integer · 2 to 6, m is an integer · 1, and m is an integer · 1, or an acid addition salt thereof, characterized in that an alkali metal salt of the hydroxybibenzyl of formula III is reacted wherein M is an alkali metal and Y and Y ', mam * are as defined above, with an omega-haloalkylamine of formula IV wherein M is an alkali metal and Y and Y ', mam' are as defined above with an omega-haloalkylamine of formula IV X - (CH 2) _n -R IV wherein X is halogen and R and n are as defined above. 3. A process according to item 1 wherein R is Ri -N R 2 wherein R 1 and R 2, which are the same or different, represent hydrogen, C 1 -C 5 alkyl and C 1 -C 5 hydroxyalkyl, or wherein A is a bivalent radical consisting of two or more groups such as methylene —CH2—, monosubstituted methylene R3 R1 C - and disubstituted methylene - C, H R 8 wherein R 3, R 7 and R 8 is alkyl of 1 to 5 carbon atoms, carboxyl, alkoxycarbonyl of 2 to 6 carbon atoms, hydroxyl or Re — CON R 7 wherein R 8 and R 7 is hydrogen or alkyl of 1 to 5 carbon atoms, and no or one or more H groups such as imino-N- and substituted R aminino-N-, wherein R a is C 1 -C 5 alkyl or C 1 -C 5 hydroxyalkyl, which combine in any arrangement, the number of combined groups is up to 2 to 5 7, Y and Y 'are hydrogen, halogen, alkyl of 1 to 5 carbon atoms, hydroxyl, alkoxy of 1 to 5 carbon atoms, carboxyl, alkoxycarbonyl of 2 to 6 carbon atoms, or R9 / -N Wherein R 9 and R 10 is hydrogen or (C 1 -C 5) alkyl, n is an integer of 2 to 8, m is an integer of 1 to 4, and m is an integer of 1 to 5 or an acid addition salt thereof; by reacting an alkali metal salt of the hydroxybibenzyl of the general formula III wherein M is an alkali metal and Y a _; Y ', m and m' are as defined above, with the omega-haloalkylamine of formula IV X - (CH 2) _n - R IV wherein X is halogen, and R and n are as defined above.