JPH03502103A - Prostanoic acid compound having antiplatelet and antithrombotic activity, method for its preparation, and pharmaceutical composition containing the same - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Brostanic acid compound having antiplatelet and antithrombotic activity, method for its preparation and containing the same The present invention relates to the activity and use of compounds having a prostaglandin-like structure. The invention also relates to a pharmaceutical composition of the compound having platelet antiaggregation and antithrombotic activity.

Substances such as ADP, collagen, thrombin, and arachidonic acid are found in - and major cause of cerebral disease, atherosclerotic peripheral arterial disease and venous thrombosis It is known to assist in the platelet aggregation phenomenon that causes the formation of certain blood clots. follow Therefore, substances that can neutralize these effects are suitable therapeutic targets.

IT 1.190,400 filed on October 4, 1985 and June 1987 IT 1,205,183 filed on February 25, 1988 (P. CT Patent Application IT88100010) In research conducted by the applicant on prostaglandin-like compounds that is disclosed therein, and some of the compounds corresponding to formula (1) of the present application are It was discovered that it has antiplatelet activity and antithrombotic activity.

[In the formula, n=2, 3; m=4, 5, 6, 7; X=NIIR.

CHzNHR, NHNHz (where R=H1 linear or branched (C.

=C,)alkyl, linear or branched (C,-C,)acyl)7Y =C)I Jilz, C0OH, C0NHz (however, n=2, m,=5, X=N tlR (R=H1 linear or branched (C+ to C4) alkyl, linear or branched (C+~C4) acyl); Y=COOH, CON! ＋□ except for compounds )] has three asymmetric atoms, identified by asterisks, and therefore Eight stereoisomers are possible.

Therefore, unless otherwise specified, the above formula (1) represents all possible stereoisomerisms. all possible combinations of multiple stereoisomers, all possible enantiomers and mixtures of enantiomers in any proportion.

Code number 1. BI-P-(1) A, , IBI-P-(1) B.

Four possible sets indicated by IBI-P-(1)C and IBI-P-(1)D Enantiomers are designated as: (trans-trans) (trans-trans (trans-cis) (trough 1-' piece) (trans-cis) Here, in the chemical literature, As is customary in Considering that the dotted line indicates that a particular substituent exists below the molecular plane, and A solid line in the shape of a square indicates that a particular substituent is present on the molecular plane. system and to Lances are used to indicate the relative position of substituents with respect to each other.

More specifically, the present invention provides a method for preparing a pharmaceutical composition having antiplatelet activity and antithrombotic activity. The present invention relates to a compound of the above formula (1) useful for.

The compound of formula (1) is TT 1.190,40 filed on October 4, 1985. 0 and the main substance of IT 1,205.183 filed on June 25, 1987 are again of interest, and here their activity as mine canker agents and Their use for preparing pharmaceutical compositions is described and therefore they are Here, it is not claimed as such, but the applicant claims that the platelet It is desirable to protect their use as inhibitors of aggregation and antithrombotic agents.

n=2, m=5, X=NHR (R=H1 linear or branched (C1-C ,)alkyl, linear or branched (C+-C4) acyl), Y=COOH , C0NII2 2 (1) is owned by the applicant, 1974 8 lies within the claims of IT 1.060,366 filed on May 7, and This discloses their activity as inhibitors of platelet aggregation and therefore Therefore, such compounds are excluded from this invention.

The present invention also provides pharmaceutically acceptable cations of compounds of formula (1) where Y=COOK Also included are salts and generally pharmaceutically acceptable anionic salts.

When used in the present invention, "pharmaceutically acceptable cationic salts" refer to alkali and and alkaline earth metal salts, such as sodium, potassium, calcium, and magnesium. or salts of aluminum 1, ammonium, zinc and organic amines, and For example, amino acids such as lysine, arginine, phenylalanine and proline, Triella 2-nolamine salt, internal salt and basic resin salt are added to the mushroom.

As used in the present invention, "pharmaceutically acceptable anionic salts" include hydrochloric acid, hydrochloric acid, , nitric acid, phosphoric acid, sulfuric acid, benzenesulfonic acid, benzoic acid, citric acid, lauryl Sulfonic acid, fumaric acid, oxalic acid, malic acid, methanesulfonic acid, tartaric acid, asco obtained by adding rubic acid, p-toluenesulfonic acid, salicylic acid and succinic acid. Regarding salt.

For polybasic acids, the salt can contain one or more moles of base per mole of acid.

However, preference is given to salts obtained from 1 mol of acid per mol of compound according to the invention. .

Finally, 1. The present invention provides a pharmaceutical composition or a pharmaceutically acceptable compound containing the compound of 1.2 (1). and its anionic or cationic salts.

Some preparation methods of compound 2 (1) are described in IT 1 filed on October 4, 1985. , 190,400 and IT 1,205,183 filed June 25, 1987. Already listed.

For example, the above patent describes a method for preparing a compound of formula (1) with the following components: are: n=2, m=5, X=CH, NL.

Y - COOH (IBI P 01.058) n = 2, m, = 5, X = NtlNHz, Y = C0OH (IBI-P-01062) n = 2, m = 5, X = N) I2. Y=C)12NH.

(IBI P-01068) n=3, m=5, X=NH i, Y=COOH(iBI P 05006) n=3, rn = 5, X = C) IzNHi, Y = C0OH (IBN -05011 ) n = 3, m = 5, X = NH2, Y = CHzNHz (IBI -P-05012) n=2, m=6, X=NHz, Y=COOH( IBI-P-12004).

For illustrative purposes only, a method for preparing a compound of formula (1) of the following components is shown below: : n=2, m=4, X=NHz, Y=COOH (IBI P 12003) n = 2, m = 7, X = N) It, Y = C0 OH (1B!-P-12005) n=3, m=5, X=NH, Y=CO OH (IBj-05006), where the compound is prepared according to Reaction Scheme I below. Prepared by: Here, Y'''=CHJHz, C0NII□, C0OR' and R'=linear or branched H(C1-C,)alkyl.

The cycloalkenone of formula (II) in case n-2 is owned by the applicant, IT Patent No. 19043^184 filed on January 5, 1984 (June 1, 1985) US application S, N, 744406 filed on November 5, 1987 Partial continuation application L1. S, S, N, 117669). It can be done.

Cycloalke of formula (II) when n = 3, Y' = COOCL Non can be prepared according to the following reaction scheme H: (Vllll　　　　　　　　　　　　　　+l +XN where n=3; Y=COOCIIz ;HaJ2=cz, Br, T.

Monochloride of 8-carbomethoxy-octanoic acid (X) (IT patent application 1904 3A184) in an inert polar solvent, e.g. Tetrahydrofuran, ethyl Special Table Hei 3-502103 (4) In ether, butyl ether, dioxane, dimethylformamide, Notation (■): Grignardization of [where Hal=C1, Br, I; P=2.3] It is condensed as a compound.

Acetate of 1,5-dicarbonyl compound (XI) prepared by Grignard condensation Tar is cyclized by an acid that catalyzes intermolecular croton condensation in a suitable solvent. , the desired compound of formula (n) is obtained.

Compounds of formula (IX) can be prepared by known methods from the literature, e.g. Suk-ku-kan G, 5ynthesis, 116H1985). Monohalogenation of 1,4-butanediol (V) carried out, P, L, Anal li+ C, B1ff1. F, Montanari, J, Org, Chen +.

52, 2559 (1987) as the oxidizing agent. Sodium oxate and the free radical 2.2.6.6-thitramethyl-viberi as a catalyst Preparation of ω-halobutanol (Vl) by catalytic method using diny-1-oxyl Oxidation of aldehyde (■) and ethylene glycol or 1,3-propanediol Subsequent protection of the carbonyl group of the compound of formula (■) by and Grignard reagent, e.g. i.e. by subsequent transformation to a compound of formula (IX).

As described in IT No. 1,205,183 filed on June 25, 1987. Uni, the cycloalkenone of formula (II) is a copper salt, for example CuC/! , C In the presence of u(OAc)z, CuCN, Cnr, CuC42g, Grignard reagent such as CHs(CHz)-MgHaJ2 CHal = C11 ,,B.

cycloalkanone of formula (■) [where m = 4, 5, 6 and 7] using can be converted into polar and inert solvents such as tetrahydrofuran, dimethyl - Formamide, ethyl ether, butyl ether are commonly used.

Compounds of formula (IV) can be prepared according to Reaction Scheme I or by any method known from the technical literature. That is, according to the following scheme ■, a reaction known per se, for example in an alcoholic solvent hydrogen and gold at a temperature of 30@~100°C and a pressure of 1~20 atm. The corresponding cycloalkali Prepared from non(III): Schem■ Here, lithium aluminum chloride, sodium borohydride, lithium tri-5e c-butylhydrogen boride, lithium dicyclohexyl-tert-butylhydrogen boride, Lithium di-5ec-butyl-\xylborohydride, lithium diisobutyl-te Alcohol (XII) with selected hydrides from rt-butylhydroboride Reduction of cycloalkenone of formula (III); Preparation of mesylate (XI[[), 2( Replacement of its mesylate with sodium azide to obtain the compound of XIV), and subsequent reduction with metal catalyst and hydrogen. Filed on June 25, 1987 As disclosed in IT 1.205.183, the compound of formula (IV) can be and a base capable of hydrolyzing the carbalkoxy group, such as Na0)1 ゜KoH, K2CO2 aqueous solution or alcohol aqueous solution or in alcohol solution , converted to the compound of Ni(I) [wherein Y=COOH and X=NH, Ru.

Unless otherwise specified, the compound 2(1) prepared according to the method of the present invention is In general, mixing of stereoisomers is possible, depending on the synthetic route, reagents used, and experimental conditions. Consists of compounds.

The desired set of enantiomers is obtained by separating the stereoisomeric mixture by methods known to those skilled in the art. It can be prepared by:

A set of compounds from a mixture containing all stereoisomers of a compound of formula (I) or formula (IV) Enantiomers can be isolated by chromatographic treatment; stationary phase For example, acidic alumina, neutral alumina, basic alumina, cellulose, Charcoal, silica, Amberlite XAD2 (Fluka), Amberl ite IRC50 (Fluka) can be used; and as eluent , such as ethanol, methanol, ethyl acetate, acetone, ethyl ether, selected from methylene chloride, chloroform, hexane, betrol ether itself solvents or solvent mixtures, or bases such as diethylamine, isopropylamine It is possible to use a mixture with triethylamine, triethylamine and ammonium hydroxide. be. The set of enantiomers of the compound of formula (IV) thus separated is By saponification with a suitable base in a alcoholic or hydroalcoholic solvent , producing its corresponding set of enantiomers of formula (I).

At temperatures between -20"C and +40C, e.g. isopropanol, ethanol, meth Nor, ethyl ether, diisopropyl ether, dioxane, tetrahydro Solvent selected from furan, chloroform, methylene chloride, benzene, toluene or into a solvent mixture, such as the following acids: hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, Methanesulfonic acid, P-)luenesulfonic acid, methanesulfonic acid, acetic acid, triphenate Addition of inorganic or organic acid selected from fluoroacetic acid, oxalic acid, maleic acid, benzoic acid and by subsequent reaction with a base to obtain the desired enantiomeric rod set in their free form. Fractional condensation of salts of stereoisomeric mixtures of compounds of formula (1) or formula (IV) prepared by It is possible to prepare enantiomeric rod sets of formula (1) by crystallization.

C, H, Brown, S, Kirishnamurthy, J, As+, C Stereoselective reduction as described by Hem, Soc, 7159 (1972) or by reduction with a low steric demand of the compound of formula (III) (Scheme ■) of stereoisomeric alcohol (XII) prepared by reduction with a reducing agent having Chromatographic separation of the mixture and subsequent conversion to the corresponding mesylate , substitution with sodium azide and reduction with hydrogen and a metal catalyst gives formula (I) It is further possible to prepare enantiomeric rod sets of each of the compounds of the present invention. further exemplifies the preparation of compounds of formula (I), intermediates of formula (1) and enantiomeric rod sets. This will be illustrated by the following example.

Group-1 2-6'-carbomethoxy-n-hexyl-2-cyclohexen-1-one n=3 and Y’-COOCH ■p11”ri- a) Suspension of magnesium (19.6 g) in tetrahydrofuran (220 m) 2-(4-bromobutyl)- in tetrahydrofuran (1600d) In a solution of 1,3-dioxolane (prepared according to reaction scheme ①), 20 to 2 was added while maintaining a temperature of 5°C, and at the end of this addition the reaction mixture was further added. Maintain under stirring for 60 minutes. The reaction mixture was cooled to -45°C and -40°C. 8-Carbomethoxy-octanoic acid ( The method disclosed in IT patent application 19043A184 filed on January 5, 1984 Add the monochloride (prepared accordingly). The reaction mixture was heated to -15°C. Stir for 5 hours, at the end of which sodium chloride (120d) and ethyl ether A 15% solution of (120d) is added thereto.

The organic phase is separated and washed neutral with aqueous sodium chloride solution; then it is soaked in sulfuric acid. For any further purification, anhydride over sodium chloride and evaporation of the solvent under reduced pressure Crude 2-(11-carbomethoxy)4-oxo-n-un used without 125 g of decyl-1,3-dioxolane are obtained.

b) prepared in step (a) above dissolved in tetrahydrofuran (1000d) A solution of the compound (125 g) was reacted with 6N hydrochloric acid (300 d) at room temperature for 16 hours. I will respond.

Finally, the reaction mixture was extracted with methylene chloride (2X300d) and The organic phase is washed with a 10% brine solution to make it neutral.

Then it is anhydrified over Na, SO, and the solvent is distilled off under reduced pressure. this The crude material thus obtained was reacted with methanol and P-1 luenesulfonic acid. 2-(6'-cyboxy-n-hexyl)-cycloconverted to the title compound by Contains lohexen-2-one as a major by-product. Compounds prepared in this way The product is distilled at 0.3 mmHg, thereby reducing the temperature between 140° and 142°C. , to obtain 60 g of the title compound.

・ B, p, : 0.3 mm) 1g is 140”~142° C1, R, (ν+aa x) = 1740CI+-', 1675C1-'NMR(δ)-6-75 (m, IH): 3.7 (s, 3H); 2.2 (m.

8 H) ; 1.5 (m, l0H) Calculated value: C = 70.56% H ==9.30% Actual value: C=70.47% H=9.21%-6'-carbo Mex-n-hexyl --n-hexyl-cyclohexanone n = 3 , Eyu J Yu Jko 11th grade student at Y'-COOCH This derivative is disclosed in IT patent application No. 19043A18 filed on January 5, 1984. 2-(6'-carbomethoxy-hexyl)-2 -cyclohexen-1-one) (41 g), bromohexane (52 g) and Cu Prepared by reacting with I (3.3 g); title compound 48.3 g is obtained.

minute 1] Shinikyu 1, R, (νwaax): 1740cm-', 1710c111- 'NMR (δ) = 3.1 (s, 3H); 3.6 to 1.1 (m , 30H); 0.95 (s, 3H) 劃-”- 2-6'-carbomethoxy-hexyl-3-pentyl-cyclopene non This derivative was prepared as described in Example 2. xyl)-2-cyclopenten-1-one (67g) and Mg, (14.4g) , bromopentane (96.6g) and Cur (5.7g) were reacted. 73 g of the labeled compound are obtained.

1. R, (νehmx): 1740cm-'Ban-Sat 2-(6'-carboxyhexyl-3-pentyl-cyclopentanone The compound of Example 3 was dissolved in methanol (300d) and in water (300m). Treat with a solution of NaOH (24 g).

The reaction mixture is refluxed under stirring until the reaction is complete, then cooled and heated to Acidified in H2, extracted with methylene chloride (25oId) and washed with water. Purify and neutralize. The reaction mixture is anhydrified and the solvent is distilled; the title compound 68g 2-6'-carboxyhexyl-3-pentyl-cyclopentylamide n = 2, m = 4, X = NH2”, Y = COOH The compound (68 g) of Example 4 (IBI-P・-12003) , at a temperature of 40-60°C in an autoclave (1000 d ), 77moni7 (200g), and Pt0z (3g), and The mixture was left under hydrogen pressure for 3 days to obtain 42 g of a white solid compound.　　　　　　　　　　　　　　　　　　　 Eni fork ..., p, = 166"~168°C 1, R, (+'smx): 3300cm-', 1560ca+-' N? lR(δL=4.6 (s, 3H); 2.8 (m, LH); 1.2 (m.

26H) ; 0.9 (mu+'3H)' titration (as base) = 9 6% Calculated value: C=72.08% H=11.66% N=4.95% Actual value: C = 71.92% H = 11.72% N = 4.98% Group once 2-6'-carboxyxy-hexyl-3-octyl-This derivative was used as the starting material 2-(6'-carbomethoxy-hexyl)-2-cyclopentene-1 as a material -one (67 g) by a method similar to that described in Example 3. Yield: 78 g of the title compound.

1, R-(v sa, l): 1740CII+-1■-1 2-6'-Lupoxyhexyl-3-octyl-cyclopentylamine n= 2, m='1; X-Nllz, Y=COOH output I '(IBI)-P-12005)) This derivative was used as a starting material for 2''-( Using 6'-carboxyhexyl)-3-octyl-cyclopentanone (75 g) and is prepared by a method analogous to that described in Example 5.

Finally, 34 g of white solid material are obtained.

(1) shi: kyu Lightning, p, = 152' ~ 154 °CT, R, (v + asx) : 3300aa-', 1560C1-'NMR (δ) = 4.6 (s , 3H); 2.8 (m, IH); 1.2 (m.

32H); 0.9 (t, 3H) titration (as base) = 98% ■Once 2-6'-Carbomethoxy-hexyl-3-n-hexyl-cyclohexyl min 2-(6'-carboxyhexyl)=3-n-hexyl in methanol (IOM) Xyl-cyclohexylamine (200g) (IBI-P-05006,1 Compounds disclosed in IT 1,205.183 filed June 25, 987 p-)Toluensulfonic acid is added to the suspension of ).

The reaction mixture was refluxed for 3 hours, cooled to room temperature, then the solvent was concentrated under reduced pressure and Then, an aqueous IN NaOH solution (1000 II dl) was added to the reaction mixture. and extracted with ethyl ether (2x300d).

The organic phase was washed with 20% brine, made neutral, and dried over Na25O. The solvent is distilled off under reduced pressure to obtain 203 g of a colorless oil.

light hill fork IR, (ν 1IlaX) 1745a口1-', 1670 c11-' Calculated value: C = 73.85% H = 12.00% N = 4.31 % actual measurements: C = 73.90% H = 12.11% N = 4.27% − R,S-cis-2-6'-carbomethoxy-hexyl-cis-3-n-hexy -cyclohexylamine 1.2-(6'-ka) in methanol (50.0g) ruboxymethoxy-hexyl-3-=n-hexy-cyclohexylamine (1 P-toluenesulfonic acid (61.4 g) was added to a solution of Stir at room temperature for 15 minutes, then distill the solvent under reduced pressure; a white solid material is obtained.

The material thus obtained was suspended in ethyl ether (50(ld)) and and stir at room temperature for 60 minutes.

The reaction mixture was filtered through a Buchner funnel and the solid material was dried, R,S -cis-2-(6'-carbomethoxy-hexyl)-cis-3-n-hexyl- 104 g of cyclohexylamine p-)luenesulfonate are obtained.

The solid thus obtained was mixed with water (250 d) and aqueous IN NaOH solution (2 d). 50d), stirred for 10 minutes and dissolved in ethyl ether (500d). Extracted from: the organic phase was washed with 20% brine, neutralized and washed with Na, SO, and the solvent is distilled off under reduced pressure. Yield: 43.5 g colorless oil .

Separation of the two forks 1, R, (!’saw): 1745aa-’, 1675cm-’N ? lR (δ): 3.6 (s, 3H); 2.69 (m, IH); 2.27 (t .

2H); 1.6-0.9 (wide, 30H); 0.85 (t).

3H) Calculated value: C = 73.85% H = 12.00% N = 4.31% Actual value: C = 73.79% H = 11.95% N = 4.37% Voice L'' R,S-cis-2-6'-carboxyhexyl-cis-compound of Example 9 (40 g ) in methanol (400d) and potassium carbonate in water (60d). Add a solution of (34.2 g). The reaction mixture was refluxed for 3 hours and then is cooled and the solvent is distilled off under reduced pressure. The reaction mixture was then added with water (250 acidified to pH=5.6-5.8 with 3N HC2 solution and filtered. , washed with water and acetone, and dried under reduced pressure to obtain 36 g of a white solid compound. obtain.

Min' L Otsuji! − m, p, = 208° ~ 210°C Titration (as base) = 98.67% Calculated value: C-73, 31% H = 1 1.90% N=4.50% Actual value: C=73.41% H=12.00 %N=4.61% Direct weight S-cis-2-6'-carbomethoxy-hexyl-cis-3-n-hexy -cyclohexanol a) 2-(6'-cyclohexyl) -3-n- Hexyl-cyclohexanol (125 g) and H, C, Brown, etc., J , Am.

T according to the method described by Che++, Soc, 7159 (1972) IN glue tri5ec-butylhydrogen boride solution in HF (80M!) R,S-cis-2-(6'-carboxyhexyl)-cis-3 -n-hexyl-cyclohexanol and R,S-cis-2-(6'-carboxy from a mixture of cyhexyl)-trans-3-n-hexyl-cyclohexanol 130 g of an oil consisting essentially of 130 g of oil are obtained.

Oka Goeni Fork 1, R, (v ssx): 3400C1-', 1710cm-'b ) The compound thus obtained was dissolved in methanol (750d) and Then P-1-luenesulfonic acid (12.5 g) is added. The reaction mixture was Reflux for 0 min, cool, and concentrate the methanol under reduced pressure; then the reaction mixture Water (600d) and ethyl ether (400111) were added to the mixture.

The organic phase was washed with 20% brine, dried over Na2SO2, and the solvent was distilled under reduced pressure to obtain R,S-cis-2-(6'-carbomethoxyhexyl)- cis-3-n-hexyl-cyclohexanol and R,S-cis-2-(6'- Carbomethoxyhexyl)-trans-3-n-hexyl-cyclohexanol A yellow oil (124.3 g) consisting of a mixture of .

silica T, L, C using a 7:3 hexane:ethyl acetate mixture as eluent. , the stereoisomer mixture is chromatographed and the result is cissis The enantiomeric pair gives R,f,=0.50, whereas the cis-trans enantiomerism Body composition is R, f.

=0.59 is given.

The stereoisomer mixture was analysed, using a 7:3 hexane:ethyl acetate mixture as eluent. chromatographed on a silica gel column with R,f = 0.50. Collect the enantiomeric rod set.

Yield: title compound 70° Eniku Bunkaji 1, R, (v 1m1lK): 3450cm-', 1742cm- 'NMR (δ): 3.70 (m, IH); 3.68 (s, 3H); 2.3 ( t.

2H); 1.8-1 (wide, 29H); 0.87 (t).

3H).

Calculation (!: C=73.61% H=11..66% Actual value: C=7 3.55% H=i1.71% basis -■ -R,S-1trans-''-carbomethoxyhexyl-cis-3-〇- Hexylcyclohexylamide R,S-cyclohexylamide in methylene chloride (350I11) -2-(6'-carbomethoxyhexyl)-cis-3-hexyl-cyclohexyl Add triethylamine (51,,7d) to a solution of xanol (70g), Then, methanesulfonyl chloride (34.3 g) was added dropwise at a temperature of 0° to 5°C. ; the reaction mixture was allowed to react for 30 minutes at the same temperature, and finally it was poured with water. (600d) Pour inside. Separate the various phases; wash the organic phase with 10% brine. neutralized, anhydrified over NazSOa, and the solvent was distilled under reduced pressure. 93.9 g of a clear oil are obtained. (1, R, (ν@IIX): 1 740C11-', 1340CI-', 11.70C11-'), The residue was taken in water (850d), NaNz (37.4g), hexabromide Decyltributylphosphonium (12,22g) was added and the Stir for an hour.

Finally, the reaction mixture was cooled and extracted with ethyl ether (500d). put out The organic phase was washed with 20% brine, dried over Na25O, and The solvent is distilled under reduced pressure to obtain 96 g of an orange oil. The substance, 9 Silica gel chromatography using a 5:5 hexane:ethyl acetate mixture as eluent. Purify by chromatography. Yield: 42 g of the title compound.

Tachiori Eniku 1,, R, (νasx): 2100CI-', 1745cm-'■ −And R,S-) Lance-2-6'-Kurazomememethoxyhexyl-Y-cis-3-n-he xyl-cyclohexyl-amine methanol (400a!), ethyl ether (200d), R,S-trans-2-(6'-carbomethoxyhexyl) - In a solution of cis-3-n-hexyl-cyclohexylamide (42 g), 5% P Add d/C (4g).

The reaction mixture was then shaken under an atmosphere of hydrogen for 5 hours, then the catalyst was filtered and the soluble The medium was distilled under reduced pressure; the residue was diluted with 80:20:0.5 hexane:acetone. :Chromatography on silica gel using ammonia mixture as eluent Process. Yield: 9.6 g of oil consisting essentially of the title compound.

1 minute: 叉 1.9- (νsaw): 1745cm-', 1675cm-' IJMR (δ): 3.65 (s, 3H); 2.65 (m, IH); 2.25N .

2H); 1.7-1 (wide, 30H); 0.82 (t).

3H) Example 2”1 R,S-tones-2-61-carboxy to 2-carboxy-3-n-hexyl -Cyclohexylamine (IBI-P-R,S-trans-2-(6'- Carbomethoxyhexyl)-cis-3-n-hexyl-cyclohexylamine 9 ．． 6 g are treated in the same manner as described in Example 10. Yield: as a white solid 5.2 g of the title compound.

Stand up and grab m, p, -1,54' ~ 156°C ','-(L'nmx): 1580cm-'Calculated value: C=73. 31% N (= 11.90% N = 4.5% Actual value: C = 73.28 % H = 11.97% N = 4.45% Titration (as base) 99.3% The activity of the compound of the present invention as a platelet aggregation inhibitor and antithrombotic agent was determined by , R. Born: Nature 194, 927-929 (1962) and G, V, R, Born and M, J, Gross: Physiol, 168. 178-195 (1963), mammalian platelet-rich plasma (hereinafter P ADP, collagen, arachidonic acid and thrombi The percentage inhibition of platelet aggregation induced by the 47-day trial was determined and investigated.

1) By the simulated ADP The test was performed on rats P P P (500,000 platelets/1lII113). A compound of formula (I) or a pharmaceutically acceptable salt thereof, which is carried out as follows: , so that the plasma concentration was 10-’M, and incubated at room temperature for 9 minutes. then add ADP (3 μM) as an aggregating agent and inhibit platelet aggregation. The % inhibition is determined using the Born and Cross turbidimetry (Table 1).

2) Silkworm ■ Direct Collagen Guyo (1u” This test used collagen (3mcg/In1l) as a coagulant, Inhibition of platelet aggregation by added ADP as described in sub 1) harm) is carried out (Table 1).

3) Addition A: Addition of acid mushrooms to the blood clots. =Gosarahama- This test was performed using arachidonic acid (200 μM) as a coagulant, as described in sub 1). (Inhibition of platelet aggregation by added ADP) (Table 1).

4) IL ki "Yu dog" Σ town ↓ 衾 ◇ ζ & article 10 "E lock Hayabusa - he cause on ヱ" - En ni O ”■1 This test is performed as described in subl) using thrombin (0, IU/d) as the flocculant. (Inhibition of platelet aggregation by added ADP) (Table 1). The transmittance measurement is Chromo-Log or E1νi 8 40 aggregometer.

Turtle” - table Application filed on August 7, 1974 owned by the applicant (7) IT 1,060,366 Disclosed formula (I) [wherein n=2, m=5, X=NHR (where R= H1 linear or branched (C+ to C4) alkyl, linear or branched ((C +=C4)7sil), Y=COO8, C0NHz T: is a compound , showed very low inhibition of platelet function, ie antithrombotic activity.

Table 2 shows the % inhibition of platelet function by rat PPP, which under the same conditions and at the same compound concentration (10-''M) as used in the above test of and at the same flocculant concentration, e.g. for the preferred compounds of formula (I) above. As for the following ingredients: n=2, m=5, X=NHz, Y=COOH (181-P-0100 9) n = 2, m = 5, X = NHCOCH+, Y = C0O ) 1 (IBI P 01012) n = 2, m = 5, X = NHC)13. Y=C0OH(IBI-P-01013)n,=2, m=5, X=NHCH(CHa)z, Y=COOH(IBI P 01015) n = 2, m = 5, X = NHZ, Y = CON) It (I BI-P-013036).

Accordingly, the compounds of the present invention are disclosed in ITl, No. 060.366, filed Aug. 7, 1984. Surprisingly higher (more than 10 times) antiplatelet, antithrombotic activity than that of the compounds disclosed in It is found to exhibit activity.

The compounds of the invention preferably contain one or more pharmaceutically acceptable diluents and/or is mixed with a carrier and administered as a pharmaceutical composition.

According to the scope of the invention, “pharmaceutically acceptable diluent and/or carrier” ° means the following substances, such as starch and its derivatives (corn starch, It is a trademark of Co1acon Ltd, Orping-ton, Kent. STA l? χ15000, rice starch, carboxymethyl starch); Lulose and its derivatives (e.g. FMC Corporation, Ph1 ladlphia, IJ, S, A, trademarks of Avice19 and Hymethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose); silica cate and silica oxides (e.g. talc, hydrated calcium silicate, magnesium silicate) Munich and Aluminum, Wacker-Chemie Gn+bH, Munich , Fed.

Aerosil @ lll1, a trademark of Repub, of Germany ．． R, Grace & Co.

5yloid, a trademark of New York, IJ, S, A); Ionic solid surfactants (e.g. sodium lauryl sulfate) and nonionic interfaces Activators (e.g. fatty acid esters of saccharose); acrylic acid conductors and their Polymers; alkali and alkaline earth metal sulfates, carbonates and phosphates; Mention is made of vinylpyrrolidone and its derivatives. Preferably, the compounds of the invention are administered orally. Oral administration (e.g. tablets, capsules, granules, syrups) or parenteral administration (j, v, or i, m, ). The dosage depends on the patient's symptoms, gender, weight and symptoms, as well as the dosage. Depending on the frequency of the given route, the compounds of the invention may be administered in 1 to 2 doses per dose. 000 ■, preferably in a daily dosage of 10 to 1000 ■ or over a 24 hour period. It can be administered orally to adults in divided doses.

international search report international search report IT 13900061

Claims (8)

[Claims] 1. Preparation of pharmaceutical compositions with antiplatelet, antithrombotic activity in human and veterinary medicine The formula below, including all possible optical and/or geometrical isomers, (I): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, n = 2, 3; m = 4 , 5, 6, 7; X=NHR, CH2NHR, NHNH2 (where R=H, linear or is branched (Cl-C4) alkyl, linear or branched (C1-C4) acyl Y=CH2NH2,COOH,CONH2] compound [however, n=2, m=5, X=NHR (R=H, linear or branched (C1 ~C4) alkyl, linear or branched (C1-C4) acyl), Y=COOH , CONH2] or a pharmaceutically acceptable salt thereof; use. 2. R,S-cis-2-(6'-carboxyhexyl)-cis-3-n-hexy A method for preparing 2-(6'-carbomethoxyhexylamine) (xyl)-3-n-hexyl-cyclohexylamine. The compound obtained by addition of 1 equivalent of p-toluenesulfonic acid to the mixture containing Crystallized from thyl ether, thereby the R,S- cis-2-(6'-carbomethoxyhexyl)-cis-3-n-hexyl-cyc Treatment of lohexylamine p-toluenesulfonate with a base thereby R,S-cis-2-(6'-carboxyhexyl)-cis-3-n-hexyl- A process characterized in that it obtains cyclohexylamine. 3. R,S-trans-2-(6'-carboxyhexyl)-cis-3-n-he A method for preparing xyl-cyclohexylamine, comprising: 2-(6'-carboxyhexylamine) xyl)-3-n-hexyl-cyclohexanone in THF at -70°C. to react with lithium tri-sec-butylhydrogen boride, thereby forming R, S-cis-2-(6'-carboxyhexyl)-cis-3-n-hexyl-cyc Lohexanol and R,S-cis-2-(6'-carboxyhexyl)-tran A mixture of su-3-n-hexyl-cyclohexanol was then obtained in this way. The resulting mixture was treated with methanol and p-toluenesulfonic acid, and Chromatography on silica gel using a 7:3 mixture of hexane:ethyl acetate as eluent. chromatographic treatment, whereby R,S-cis-2-(6'-carbomethoxy cyhexyl)-cis-3-n-hexyl-cyclohexanol and its pair. After subsequent conversion to the corresponding mysylate and substitution with sodium azide and metal catalytic After reduction with solvent and hydrogen, subsequent saponification yields R,S-trans-2-(6'-carboxylic acid). (xyhexyl)-cis-3-n-hexyl-cyclohexylamine. A method characterized by: 4. Preparation of pharmaceutical compositions with antiplatelet, antithrombotic activity in human and veterinary medicine A compound of formula (I) according to claim 1 or a pharmaceutically acceptable Use of a salt thereof, in the formula: n=2, m=5, X=CH2NH2, Y=COOH; n=2, m=5, X=NH NH2, Y=COOH; n=2, m=5, X=NH2, Y=CH2NH2; n= 3, m=5, X=NH2, Y=COOH; n=3, m=5, X=CH2NH2, Y=COOH;n=3,m=5,X=NH2,Y=CH2NH2;n=2,m= 4, X=NH2, Y=COOH; n=2, m=6, X=NH2, Y=COOH; Use characterized in that n=2, m=7, X=NH2, Y=COOH. 5. R,S-cis-2-(6'-carboxyhexyl) has antiplatelet and antithrombotic activity. sil)-cis-3-n-hexyl-cyclohexylamine, i.e. the claims Human and veterinary medicine of compounds of formula (I) according to paragraph 1 and pharmaceutically acceptable salts thereof Use in. 6. R,S-trans-2-(6'-carboxy), which has antiplatelet and antithrombotic activity. hexyl)-cis-3-n-hexyl-cyclohexylamine, i.e. Human and veterinary compounds of formula (I) and pharmaceutically acceptable salts thereof according to scope 1 Use in medicine. 7. A pharmaceutical composition having antiplatelet, antithrombotic activity, claimed as an active ingredient. Contains the compound of formula (I) described in item 1 or a pharmaceutically acceptable salt thereof. A composition characterized by: 8. As an active ingredient, a compound or a drug according to any one of claims 4 to 6. A pharmaceutical composition having antiplatelet, antithrombotic activity, comprising a pharmaceutically acceptable salt thereof.