GB2093835A - Novel guanidinocyclohexanecarboxylic acid derivatives and a process for producing the same - Google Patents

Novel guanidinocyclohexanecarboxylic acid derivatives and a process for producing the same Download PDF

Info

Publication number
GB2093835A
GB2093835A GB8201092A GB8201092A GB2093835A GB 2093835 A GB2093835 A GB 2093835A GB 8201092 A GB8201092 A GB 8201092A GB 8201092 A GB8201092 A GB 8201092A GB 2093835 A GB2093835 A GB 2093835A
Authority
GB
United Kingdom
Prior art keywords
trans
group
formula
hydrochloride
halogen atom
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
GB8201092A
Other versions
GB2093835B (en
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Chemiphar Co Ltd
Original Assignee
Nippon Chemiphar Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP728481A external-priority patent/JPS57122061A/en
Priority claimed from JP728381A external-priority patent/JPS57122059A/en
Priority claimed from JP1083281A external-priority patent/JPS57126463A/en
Priority claimed from JP1083181A external-priority patent/JPS57126462A/en
Application filed by Nippon Chemiphar Co Ltd filed Critical Nippon Chemiphar Co Ltd
Publication of GB2093835A publication Critical patent/GB2093835A/en
Application granted granted Critical
Publication of GB2093835B publication Critical patent/GB2093835B/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C07D215/32—Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention describes compounds having the formula: <IMAGE> wherein R1 represents an indanyl, indolyl, quinolyl or chromonyl group, the group of the formula <IMAGE> (in which R2 represents a halogen atom or a nitro group), or the group of the formula <IMAGE> (in which R3 represents a halogen atom, or an alkyl, nitro, cyano, acetamino, aminosulfonyl, benzoyl, phenoxy or trifluoromethyl group, and R4 represents a hydrogen or halogen atom, or an alkyl group, and R5 represents a hydrogen or halogen atom, or an alkyl group), and pharmaceutically acceptable salts thereof. The compounds and salts exhibit strong inhibitory effects on serine proteases, and also anti-allergic effects. The compounds can be obtained by reacting 4- guanidinomethylcyclohexanecarboxylic acid or a reactive derivative thereof with a compound of the formula R1-OH wherein R1 is the same as defined above, or a reactive derivative thereof.

Description

SPECIFICATION Novel guanidinocyclohexanecarboxylic acid derivatives and a process for producing the same This invention relates to novel guanidinocyclohexanecarboxylic acid derivatives and a process for producing such derivatives.
A. Okano et al have reported that 4-guanidinomethylcyclohexanecarboxylic acid exhibits slight anti-plasmin effects [J. Med. Chem., Vol. 15, No. 3, 247(1972)]. M. Muramatsu and T. Satoh who are co-inventors of this invention, and other individuals have found that 4-guanidinomethylcyclohexanecarboxylic acid esters exhibit inhibitory effects on serine proteases and anti-ulcer effects (U.K. Patent Application No. 2,058,773A).
An object of the present invention is to provide novel guanidinocyclohexanecarboxylic acid derivatives which exhibit strong inhibitory effects on serine proteases and anti-allergic effects.
Another object of the invention is to provide a process for producing these novel guanidinocyclohexanecarboxylic acid derivatives.
According to one aspect of the invention, there are provided compounds of the formula (I):
wherein R, represents an indanyl, indolyl, quinolyl or chromonyl group. or a group of the formula
(in which R2 represents a halogen atom or a nitro group), or a group of the formula
(in which R3 represents a halogen atom, or an alkyl, nitro, cyano, acetamino, aminosulfonyl, benzoyl, phenoxy or trifluoromethyl group, R4 represents a hydrogen or halogen atom, or an alkyl group, and R5 represents a hydrogen or halogen atom, or an alkyl group), and pharmaceutically acceptable salts thereof. These derivatives and their pharmaceutically acceptable salts have been found to possess excellent inhibitory effects on serine proteases and anti-allergic effects.In particular, compounds of the formula:
wherein R3, R4 and R5 are as defined above, have been found to possess excellent anti-allergic effects.
Ester residues of the present compounds defined as R1 in the formula (I) may be indanyl, indolyl, quinolyl and chromonyl groups, or a group of the formula
(in which R2 represents a halogen atom or a nitro group), or a group of the formula
(in which R3 represents a halogen atom, or an alkyl, nitro, cyano, acetamino, aminosulfonyl, benzoyl, phenoxy or trifluoromethyl group). Suitable groups of the formula
include 4-chloro-a-naphthyl and 4-nitro-a-naphthyl groups.
Suitable groups of the formula
include chlorophenyl, bromophenyl, iodophenyl, methylphenyl, ethylphenyl, propylphenyl, butylphenyl, t-butylphenyl, nitrophenyl, cyanophenyl, acetaminophenyl, aminosulfonylphenyl, benzoylphenyl, phenoxyphenyl, trifluoromethylphenyl, 4-chloro-2-isopropyl-5-methylphenyl, 2-isopropyl-5methylphenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl groups and the like.
Compounds of the formula (I) may be either the cis- or trans-isomer. The trans-isomer is particularly preferred.
Pharmaceutically acceptable salts of the compounds are acid addition salts formed from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid and like acids.
According to a further aspect of the invention, the compounds of the formula (I) are produced by reacting 4-guanidinomethylcyclohexanecarboxylic acid or a reactive derivative thereof with a compound of the formula (ill): B1-OH (II) wherein R1 is the same as defined above or with a reactive derivative thereof.
Suitable reactive derivatives of 4-guanidinomethylcyclohexanecarboxylic acid include acid halides, such as, for example, the acid chloride, or acid bromide, and mixed anhydrides using ethylchloroformate.
Suitable reactive derivatives of the compounds of the formula (II) include disulfite compounds such as, for example, bis-(4-chlorophenyl)sulfite and bis-(4-t-butylphenyl)sulfite.
The reaction of 4-guanidinomethylcyclohexanecarboxylic acid and the disulfite derivative of the compound of the formula (II) may be carried out with stirring in a solvent at room temperature for 1-20 hours. Suitable solvents which may be used include dimethylformamide, dimethylacetamide, pyridine and the like. The reaction of a reactive derivative of 4-guanidinomethylcyclohexanecarboxylic acid and the compound of the formula (II) may be effected with stirring in a solvent at a temperature of from room temperature to the boiling point of the solvent. Suitable solvents which may be used include dimethylformamide, dimethylacetamide, pyridine, dichloromethane, dichloroethane, chloroform, acetonitrile and the like. The use of an acid-binding agent such as, for example, triethylamine, dimethylaniline or pyridine, is sometimes to be recommended.
When 4-guanidinomethylcyclohexanecarboxylic acid is reacted directly without conversion to a reactive intermediate thereof, the reaction is preferably carried out in the presence of a condensing agent, for example, a carbodiimide, such as dicyclohexylcarbodiimide, or a Lewis acid, such as phosphorusoxychloride, or borontrifluoi ide. The reaction is accomplished using a solvent, for example, toluene, xylene or dimethylformamide, one of the solvents mentioned above, or a mixture thereof, at a temperature of from room temperature to the boiling point of the solvent.
The compounds of the formula (I) thus obtained have excellent pharmacological activity, in that the compounds exhibit excellent inhibitory effects on serine proteases such as trypsin, chymotrypsin, thrombin and urokinase. The compounds also exhibit excellent anti-allergic effects and have been found to strongly inhibit histamine release from mast cells by compound 48/80. Moreover, these compounds are significantly effective for preventing anaphylactic shock and experimental asthma in guinea pigs.
Inhibition of Various Serine Proteases Inhibitory effects on the TAMe(N"-tosyl-L-arginine methyl ester) hydrolytic activity of trypsin, plasmin, plasma kallikrein and thrombin, were estimated by Hesterin's method as modified by Roberts.
Inhibition of the BAEe(N -benzoyl-L-arginine ethyl ester) hydrolytic activity of pancreas kallikrein was determined by Hesterin's method after incubation at 370C for 30 minutes in a 0.1 M borate buffer, pH 8.0. inhibitory effects on urokinase were determined by the chromotropic acid method after incubation of 60 iu of urokinase with 10 mM AGLMe(acetylglycyl-L-lysine methyl ester) at 370C for 30 minutes in a 0.06 M phosphate buffer, pH 7.5, containing 0.09 M NaCI. Inhibition of chymotrypsin was determined by Hesterin's method after incubation with 1 5 mM ATE (Na-acetyl-L-tyrosine ethyl ester) for 30 minutes at 37CC in a 0.1 M borate buffer, pH 8.0. The results are given in Table 1 below (The numbers of the test compounds in this and subsequent tables refer to the compounds of the correspondingly numbered Examples given hereinafter).
TABLE 1 inhibition of Various Serine Proteases
Concentration for 50% inhibition (1C50, M) Test Pancreas Plasma compound Trypsin Chymotry psin Plasmin kallikrein kallikrein Thrombin Urokinase Compound 2 1.7 x 10-4 9.7 x 10-5 2.6 x 10-4 6.2 x 10-5 1.5 x 10-4 2.5 x 10-4 3.6 x 10-5 3 7.0 x 10-5 3.2 x 10-4 2.6 x 10-4 5 3.9 x 10-4 1.2 x 10-5 9.0 x 10-5 3.0 x 10-4 1.6 x 10-4 1.6 x 10-4 6 2.6 x 10-4 1.5 x 10-4 1.8 x 10-4 13 4.0 x 10-4 4.0 x 10-4 3.0 x 10-5 14 1.9 x 10-4 1.0 x 10-4 4.0 x 10-4 1.3 x 10-4 2.4 x 10-4 15 9.0 x 10-5 2.8 x 10-6 2.5 x 10-5 3.0 x 10-4 9.5 x 10-5 3.1 x 10-5 21 2.0 x 10-4 3.0 x 10-5 1.1 x 10-4 24 6.0 x 10-6 2.0 x 10-5 2.3 x 10-4 5.0 x 10-5 Effects on Histamine Release from Mast Cells Induced by Compound 48/80 Released histamine was determined by the fluorometric assay as follows: 1.5 ml of a mast cell suspension (3.5 x 1 05/my) was mixed with 1 ml of a physiological solution containing each test sample, and the resulting mixture was incubated for 7 minutes at 370 C, followed by addition of 1 ml of compound 48/80 (3.5 g/ml). After incubation for 20 minutes at 370C, the suspension was cooled to 40C, and released histamine was determined as described by Shore et al. All samples examined were recognized to cause no disturbance in the fluorometric assay.
TABLE 2 Effects on Histamine Release from Mast Cells Induced by Compound 48/80
Conic. of Inhibition of Test compound test compound histamine release Compound 2 10 llg/ml 46.7% 7 10 18.4 14 10 38.8 23 10 12.7 28 10 60.9 29 10 20.6 Compound A 10 5.0 DSCG 10 10.0
(Phenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: described in U.K. Patent Application No. 80.30183).
DSCG: Disodium cromoglycate it is known that DSCG has inhibitory effects on histamine release from mast cells [Life Sciences, Vol. 10, 805-812 (1971) and Internal Medicine, Vol.42(6), 933 (1 978)j, and therefore, DSCG is used as an anti-allergic agent. However, the inhibitory effects of the present compounds on histamine release from mast cells are greater than those of DSCG.
Passive Cutaneous Anaphylaxis Diluted anti-egg albumin (rat anti-egg albumin serum) with saline (0.05 ml) was subcutaneously injected into the back of a rat. 48 hours later, egg albumin and Evans' blue dissolved in saline (egg albumin 10 mg and Evans' blue 5 mg/ml) were intravenously injected into the rat in an amount of 2.5 ml/kg. 45 minutes later, the rat was killed, bled and skinned and the permeated area (mm2) of the dye was measured. Test samples were administered per os, 1 hour prior to antigen injection.
TABLE 3 Passive Cutaneous Anaphylaxis (Dilution ratio of antigen: x32)
Test compound Dose inhibltion Compound 2 125 mg/kg, p.o. 91.16% Schultz-Dale Reaction Male guinea pigs were sensitized with bovine serum albumin by Freund's complete adjuvant method. After a lapse of 10 days, the animals were sensitized once more as described above. After two more weeks, an ileum of each sensitized guinea pig was removed and used for experiment. The ileum was provided in a magnus tube containing each test sample, and 500 g of bovine serum albumin was added. The contraction of the ileum was determined.
TABLE 4 Effects on Schlutz-Dale Reaction
Inhibition or traction (%) of Final conc.
Final conc.
Test compound 50 z9/ml compound mgrnl L Compound 2 100 64.3 3 100 83.3 10 100 100 28 100 80 Compound A O 0 Determination of Anti-acetylcholine and Anti-histamine Action Anti-acetylcholine and anti-histamine effects of the present compounds were examined using guinea pig ilea by the usual method.
Active Systemic Anaphylaxis in Mice Egg albumin (10 mg) was mixed with 10 ml Bordetella pertusis vaccine (Takeda Chemical Industries, Ltd.), and the mixture was intraperitoneally injected into mice in an amount of 10 ml/kg. 22 days later, active systemic anaphyiaxis was induced by intravenous injection of egg albumin dissolved in saline in an amount of 3 mug/10 ml/kg. A test sample suspended in 5% gum arabic was administered orally to the sensitized mice 1 hour prior to the antigen challenge. 24 hours after the antigen challenge, the number of surviving mice was counted.
TABLE 5 Anti-acetylcholine and Anti-histamine Effects
Anti-acetylcholine Anti-histamine effect inhibition effect inhibition of cony. or contraction (%) of contraction (O/o) Final conc.
compound 50,ag/ml 25 yg/ml 50,ag/ml 25 I-19/ml compoun d Compound 2 100 96 3 100 100 100 98 10 100 89.8 100 100 28 76 68 100 99.7 29 80 52 Compound A 100 100 DSCG ~ O O TABLE 6 Active Systemic Anaphylaxis in Mice
Compound Survival after 24 hr. (5 mice) 500 mg/kg 250 mg/kg 100 mg/kg Compound 4 2 2 All the animals (5 mice) of a control group died.
Experimental Asthma in Sensitized Guinea Pigs Hartley male guinea pigs each weighing 300 to 350 g were passively sensitized by intravenous injection with rabbit anti-egg albumin serum (0.5 ml/kg). 24 hours after passive sensitization, the guinea pigs were placed in a chamber for an inhalation test and then subjected to continuous spraying for 900 seconds with a mist of a 2% egg albumin solution. A test sample suspended in 5% gum arabic was orally administered 1 hour prior to the antigen challenge. The preconvulsion time was measured.
The evaluation was also performed for the experimental asthma with actively sensitized guinea pigs as follows: Hartley male guinea pigs each weighing 300 to 350 g were sensitized (by subcutaneous injection into the inguinal region) with an egg albumin solution (1 mg/ml) emulsified with an equal volume of Freund's complete adjuvant (5 mg/kg of body weight). Ten days later, the emulsion was injected subcutaneously into the axialla. On the 26th day after the first sensitization, the animals were subjected to the experiments which were conducted in the same manner as in the passively sensitized animals. The results obtained are shown in Table 7 and Table 8.
TABLE 7 Prevention of Experimental Athma with Passively Sensitized Guinea Pigs
Test compound Time to fall down (sec.) Control (12 animals) 110, 127, 135, 162, 116, 139, 153, 172, 127, 136, 194, > 900 Compound 2 (500 mg/kg) 58, 142, 191 > 900, > 900, > 900, (10 animals) > 900, > 900, > 900, > 900 - Died within 15 minutes.
---Recovered within 15 minutes after falling down.
TABLE 8 Prevention of Experimental Asthma with Actively Sensitized Guinea Pigs
Test compound Time to fall down (sec.) Control 271, 299, 349, 277, 320, 412 Compound 2 500 mg/kg 768, > 900, > 900, > 900, > 900 250 632, > 900, > 900, > 900, > 900 125 699, > 900, > 900, > 900, > 900 Died within 15 minutes.
The toxicity of a typical compound of the present compounds is described below.
Acute Toxicity Normal ICR strain mice (female: 22 g, male: 24 g) or Wister strain rats (female: 90 g, male: 95 g) were used. A test compound was orally given using a gastric sonde. The animals were observed for 7 days. The LD50 values were calculated by the Litchfield-Wilcoxon method. The results obtained are shown in Table 9.
TABLE 9 Acute Toxicity
L050 (mg/kg) Mouse | Rat Test compound Female Male Female Male Compound 2 7300 5400 10,800 11,000 The compounds of the invention are satisfactorily administered by both oral and parenteral routes.
Needless to mention, the oral mode of administration is the most preferable and can be made in the form of a capsule, a tablet, a powder or granules. In the dosage form, the active compounds are admixed with at least one inert diluent such as lactose, corn starch or crystalline cellulose; a lubricant such as magnesium stearate; a binder such as hydroxy propylcellulose; a coloring material; perfume a sweetening agent; and the like.
The dosage of the compounds according to the invention in various compositions actually utilized may be varied. However, it is necessary that the amount of the compounds be such that two suitable dosage forms are attained. Any selected dosage depends upon the desired therapeutic effect, the administration route and the treatment duration. Such dosage lies, in general, in a range from 30 to 900 mg/day.
The invention is illustrated in the following Examples, which are presented herein for purposes of illustration only and are not to be construed as in any way limiting the invention.
EXAMPLE 1 2'-Methylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 5.9 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 3.24 g of o-cresol and 6.2 g of dicyclohexylcarbodiimide was suspended in 100 ml of dry pyridine, and the suspension was reacted at room temperature for 14 days. After completion of the reaction, any insoluble materials were removed by filtration, and the filtrate was evaporated to dryness. To the residue was added ether, and the mixture was decanted for washing twice and then was washed twice with toluene.After removal of toluene, the crystals obtained were recrystallized from isopropanol to obtain 2.64 g (yield: 32%) of 2'-methylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride as colorless crystals having a melting point of 1 57-1 590 C.
IR PKaX cm : 1748 (C=O) EXAMPLE 2 4'-t-Butylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 9.4 g of trans-4-guanidinomethylcyclohexanecarboxylic acid, 7.2 g of p-t-butylphenol and 10.0 g of dicyclohexylcarbodiimide was suspended in a mixture of 61 ml of dry pyridine and 61 ml of dry dimethylformamide, and the suspension was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure. To the residue was added 240 ml of 0.1 N hydrochloric acid, and the mixture was stirred at room temperature for 1 hour. Any insoluble materials were removed by filtration and washed with ethyl acetate. The filtrate and the washings were combined and stirred to obtain an aqueous layer. After filtration of the aqueous layer, the filtrate was evaporated under reduced pressure, and the residue was cooled to give crystals. The crystals were washed with ether and recrystallized from ethanol-ether to obtain 10.3 g (yield: 70%) of 4'-t-butylphenyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride as colorless crystals having a melting point of 1 89-1 960 C. The crystals were recrystallized again from ethanol-ether to obtain colorless crystals having a melting point of 208-210 C.
IR pKBx cm-': 1750 (C=O) NMR(CD30D)S: : 0.60-2.80(10 H, m, cyclohexane protons) 1.38 (9H, s, -C(CH3)3) 3.20 (2H, d, J=8Hz, -CH2-N) 7.20-7.90 (4H, m, aromatic protons) EXAMPLE 3 4'-Methylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 8.9 g of bis(p-methylphenyl)sulfite obtained from p-methylphenol and thionylchloride, 2.0 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 1 8 ml of dry dimethylformamide and 9 ml of dry pyridine was stirred at room temperature for 1 6 hours. After completion of the reaction, the solvent was removed under reduced pressure. To the residue was added diethyl ether to give crystals.The crystals were washed with diethyl ether and then with ethyl acetate, and recrystallized from methanol-diethyl ether to obtain 1.93 g (yield: 69.9%) of 4'-methylphenyl trans4-guanidinomethylcyclohexanecarboxylate hydrochloride as colorless crystals having a melting point of 151-1 53CC.
IR p KBr cm-': 1639,1663,1742 NMR(CD3OD)#: 0.78-2.55 (1 OH, m, cyclohexane protons) 2.29 (3H, s, CH3) 3.05 (2H, d, N-CH2-) 6.72-7.46 (4H. m, aromatic protons) EXAMPLE 4 4'-Ethylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 2.35 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 2.47 g of dicyclohexylcarbodiimide and 1.46 g of p-ethylphenol was added to a mixture of 30 ml of dry pyridine and 10 ml of dry dicyclohexylcarbodiimide, and the resulting mixture was stirred at 300C for 2 days.
After being filtered, the precipitate was washed with 10 ml of pyridine. The filtrate and the washings were combined, and the solvent was evaporated. The residue was washed with ether and then with ethyl acetate, and extracted with 20 ml of acetone. To the acetone layer was added ether to give crystals. The crystals were recrystallized from methanol-ether to obtain 410 mg of 4'-ethylphenyl trans4-guanidinomethylcyclohexanecarboxylate hydrochloride as colorless crystals having a melting point of 137-1 390C.
IR#KBr max cm-: 1750 EXAMPLE 5 2'-Chlorophenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 1.18 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 1.24 g of dicyclohexylcarbodiimide, 0.77 g of o-chlorophenol and 20 ml of dry pyridine was stirred at room temperature for 4 days. The precipitate was removed from the reaction mixture by filtration. The filtrate was evaporated, and to the residue was added 10 ml of dioxane to give crystals. The crystals were recrystallized from iso-propanol to obtain 1.27 g (yield: 70%) of 2'-chlorophenyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride as colorless crystals having a melting point of 157-1 580C.
IRuKBrcm ': 1723 (C=O) EXAMPLE 6 4'-Bromophenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 1.18 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 1.24 g of dicyclohexylcarbodiimide, 1.04 g of 4-bromophenol and 20 ml of dry pyridine was stirred at room temperature for 2 days. The precipitate was removed from the reaction mixture by filtration, and the filtrate was evaporated. To the residue was added 10 ml of acetone to give crystals. The crystals were recrystallized from iso-propanol to obtain 1.06 g (yield: 52%) of 4'-bromophenyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride as colorless crystals having a melting point of 165-1 660C.
IR#KBr max cm-: 1735 (C=O) EXAMPLE 7 4'-lodophenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 10.7 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 1 0 g of p-iodophenol, 9.4 g of dicyclohexylcarbodiimide and 100 ml of dry pyridine was stirred at room temperature for 1 7 hours. After removal of any insoluble materials by filtration, pyridine was evaporated under reduced pressure. To the residue was added 300 ml of 0.1 N hydrochloric acid to give a white substance which was washed with warm ethyl acetate and dissolved in methanol.After removal of any insoluble materials by filtration with cooling, ether was added to the methanol solution to obtain 10 g (yield: 50.3%) of 4'-iodophenyl trans-4-guanidinomethylcyclohexanecarboxyate hydrochloride as colorless crystals having a melting point of 1 95-1 970C.
IR#KBr max cm-: 1740 (C=O) NMB(CD3OD, CDCI3)a: 0.96-2.70 (1 OH, m, cyclohexane protons) 3.06 (2H, d, J=7Hz, H2-) 6.80-7.80 (4H, m, aromatic protons) EXAMPLE 8 2',4',6'-Trichlorophenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 5 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 4.2 g of 2,4,6-trichlorophenol, 4.4 g of dicyclohexylcarbodiimide and 50 ml of dry pyridine was stirred at room temperature for 17 hours. After removal of any insoluble materials by filtration, pyridine was evaporated under reduced pressure. To the oily substance obtained was added ethyl acetate to give a pale yellow substance which was dissolved in warm chloroform.After removal of any insoluble materials by filtration, the solution was cooled to give a colorless powder which was washed with cold chloroform and then with ether to obtain 4 g (yield: 45.5%) of 2',4',6'-trichlorophenyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride as colorless powder having a melting point of 151-1 550C.
I R P KBx cm ': 1760 (C=O) NMR(CD30D)a: 1.00--2.90 (1 OH, m, cyclohexane protons) 3.10 (2H, d, J=7Hz, -CH2-) 7.52 (2H, s, aromatic protons) EXAMPLE 9 2',4'-Dichlorophenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: 1 g of bis(2,4-dichlorophenyl)sulfite and 5 ml of dry pyridine were added to a mixture of 3 g of trans-4-guanidinomethylcyclohexanecarboxylic acid and 1 5 ml of dry dimethylformamide with cooling in a water bath, and the mixture was stirred for 2 hours. The solvent was removed, and the residue was washed with ether to give a gummy substance which was dissolved in 30 ml of methanol. The solution was treated with charcoal, and the resulting solution was evaporated to dryness under reduced pressure.Ether and 20 ml of acetone were added to the residue, and the mixture was stirred to crystallize it. The crystals were separated by filtration and washed with a small amount of acetone and then with diethyl ether to obtain 2.7 g (yield: 56%) of 2',4'-dichlorophenyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride as colorless powder having a melting point of 133-138 C.
IR PKax cm 1: 1760 NMB(CD3OD)8: 0.84-2.80 (1 OH, m, cyclohexane protons) 2.96-3.16 (2H, m, -CH2-N) 7.00-7.52 (3H, m, aromatic protons) EXAMPLE 10 4'-Chlorophenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 2.0 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride and 8.5 g of bis(p-chlorophenyl)-sulfite obtained from p-chlorophenol and thionyl chloride was stirred at room temperature for 1 hour in a mixture of 18 ml of dry dimethylformamide and 9 ml of dry pyridine. The solvent was removed under reduced pressure, and the residue was washed with diethyl ether to give crystals. The crystals were washed with diethyl ether and then with ethyl acetate, and thereafter recrystallized from methanol-diethyl ether to obtain 1.77 g (yield: 60.2%) of 4'-chlorophenyl trans-4 aguanidinomethylcyclohexanecarboxylate hydrochloride as colorless crystals having a melting point of 163-1 650C.
IR#KBr max cm-: 1747 NMR(CD30D)ss: 0.81-2.88 (1 OH, m, cyclohexane protons) 3.26 (2H, d, N-CH2-) 7.28-7.99 (4H, m, aromatic protons) EXAMPLE 11 4'-Chlorophenyi trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 2.35 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 2.47 g of dicyclohexylcarbodiimide, 1.54 g of p-chlorophenol and 50 ml of dry pyridine was stirred at 300C for 3 days. After being filtered, the precipitate was washed with 10 ml of pyridine. The filtrate and the washings were combined and evaporated. 5 ml of cold water was added to the residue, and the precipitate was removed by filtration.The filtrate was evaporated under reduced pressure, and the residue was washed with ether and then with ethyl acetate. Warm acetone was added to the residue, and the solution was cooled to obtain crystals. The crystals were recrystallized from methanol-ether to obtain 4'-chlorophenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride.
EXAMPLE 12 2',4'-Dimethylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 5.9 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 6.18 g of dicyclohexylcarbodiimide, 3.66 g of 2,4-dimethylphenol and 100 ml of dry pyridine was stirred at 300C for 4 days. After removal of any insoluble materials by filtration, the filtrate was concentrated under reduced pressure. The residue was washed with ether and then with ethyl acetate. Benzene was added to the resulting residue, and the solution was stirred to crystallize it The crystals were recrystallized from isopropanol-ethyl acetate to obtain 6.22 g (yield: 73%) of 2',4'-dimethylphenyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride as colorless crystals having a melting point of 1 51-1530C.
IR vmKBxrcml: 1745 (C=O) EXAMPLE 13 2'-iso-Propyl-5'-methylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 10.0 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 6.4 g of thymol, 8.75 g of dicyclohexylcarbodiimide and 100 ml of dry pyridine was stirred at room temperatule for 36 hours. After removal of any insoluble materials, the filtrate was concentrated under reduced pressure 200 ml of 0.1 N hydrochloric acid was added to the residue with cooling, and the mixture was stirred at room temperature for 12 hours. After removal of the precipitate by filtration, a small amount of water was added to the filtrate, and the mixture was allowed to stand to give white crystals.The crystals were dissolved in methanol, and the precipitate was removed by filtration. The filtrate was evaporated, and water was added to the residue to give white crystals which were recrystallized from water-methanol to obtain 6.0 g of 2'-iso-propyl-5'-methylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride as colorless crystals having a melting point of 1 58-1 600 C.
IR v,K cm'-': 1730 (C=O) NMR(CD30D)S: 1.15 (6H,d, CH(CH3)2) 0.91-2.36 (1 OH, m, cyclohexane protons) 2.27 (3H, s, CH3) 2.95 (1 H, m, CH(CH3)2) EXAMPLE 14 2'-iso-Propyl-4'-chioro-5'-methy!phenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 10 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 7.83 g of 2-iso-propyl-4-chloro-5-methyl phenol and 8.75 g of dicyclohexylcarbodiimide was suspended in 100 ml of dry pyridine, and the suspension was stirred at room temperature for 14 hours. After removal of any insoluble materials, the precipitate was washed with pyridine.The filtrate and the washings were combined, and the solvent was removed. 200 ml of 0.1 N hydrochloric acid was added to the residue, and the mixture was stirred for 30 minutes to give crystals. The crystals were washed with water, ethyl acetate, benzene and then ether. The crystals were dissolved in isopropanol, and any insoluble materials were removed by filtration. The filtrate was evaporated, and to this residue was added isopropyl ether.
This solution was allowed to stand at 30C to give crystals which were recrystallized from isopropanolisopropyl ether to obtain 5 g of 2'-iso-propyl-4'-chloro-5'-methylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride as colorless crystals having a melting point of 185-1 870C.
IB vmKaBxrcml: 1735 (C=O) NMR(CD30D)S: 1.10 (3H, d, J=7.2Hz, CHCH3) 2.26 (3H, s, CH3) 3.03 (2H, d, J=6Hz, CH2N) 6.97 (1 H, s, aromatic proton) 7.36 (1 H, s, aromatic proton) EXAMPLE 1 5 4'-Nitrophenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 5.0 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 6.18 g of dicyclohexylcarbodiimide and 6.95 g of p-nitrophenol was suspended in 100 ml of dry pyridine, and the suspension was stirred at room temperature for 40 hours. After removal of any insoluble materials, the filtrate was evaporated. Acetone was added to the residue, and any insoluble materials were removed by filtration.Acetone was removed, and ethyl acetate was added to the residue to deposit crystals. The crystals were recrystallized from isopropanol to obtain 1.9 g (yield: 25%) of 4'-nitrophenyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride as colorless crystals having a melting point of about 1550C.
IR vmKaBxrcml: 1760 (C=O) EXAMPLE 16 4' -Acetaminophenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 1.1 7 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 1.1 3 g of dicyclohexylcarbodidimide and 0.83 g of p-acetaminophenol was suspended in 30 ml of dry pyridine, and the resulting suspension was stirred at 300C for 1 5 days. The crystals deposited were separated by filtration and suspended in about 10 ml of cold water. After removal of any insoluble materials, the filtrate was evaporated to give colorless crystals.The crystals were recrystallized from isopropanolethyl acetate to obtain 495 mg (yield: 27.2%) of 4'-acetaminophenyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride as colorless crystals having a melting point of 223-2240C.
IR v,K cm-': 1755 (C=O) EXAMPLE 17 4'-Benzoylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 1.1 8 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 1.24 g of dicyclonexylcarbodiimide and 1.18 g of 4-hydroxybenzophenone was suspended in 20 ml of dry pyridine, and the suspension was stirred at room temperature for 9 days. After removal of any insoluble materials, the filtrate was evaporated. The residue was washed with benzene and dried, and acetone was added to the residue to deposit crystals.The crystals obtained were recrystallized from isopropanol to obtain 442 mg (yield: 21%) of 4'-benzoylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride as colorless crystals having a melting point of 1 99-2000C.
IR PKBxcm ': 1755 (C=O) EXAMPLE 18 4'-Aminosulfonylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 5.90 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 6.1 8 g of dicyclohexylcarbodiimide and 5.19 g of p-phenol sulfonamide was suspended in 100 ml of dry pyridine, and the suspension was stirred at 300C for 12 days. After removal of any insoluble materials, the filtrate was evaporated. Ethyl acetate was added to the residue, and the mixture was stirred and allowed to stand. To the residue obtained by decantation was added ethyl acetate.The crystals were recrystallized from ethanol-ethyl acetate to obtain 6.4 g (yield: 65%) of 4'-aminosulfonylphenyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride as pale yellowish brown powder having a melting point of 194-1960C.
EXAMPLE 19 2'-Phenoxyphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: a) A mixture of 10 g of o-phenoxyanisol, 80 ml of hydroiodic acid (52%), 80 ml of acetic acid and 40 ml of acetic anhydride was refluxed for 1.5 hours. After being cooled, the reaction mixture was poured into ice-water to deposit a precipitate. The precipitate was dissolved in ether, and the solution was washed with a saturated aqueous sodium chloride solution, an aqueous sodium thiosulfuric acid solution and then a saturated aqueous sodium chloride solution. This ether solution was dried over anhydrous sodium sulfate, and the solvent was removed to give yellow solids. The solids were dissolved in acetic acid and stirred. The mixture was poured into cold water to deposit crystals. The crystals were washed with water and then with n-hexane, and dried at 800C under reduced pressure to obtain 7.8 g of o-phenoxyphenol as slightly yellow powder.
NMR (CDCl3) S: 5.50 (1 H, broad s, OH) 6.60-7.40 (9H, m, aromatic protons) b) A mixture of 7.5 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 6 g of o-phenoxyphenol, 6.5 g of dicyciohexylcarbodiimide and 80 ml of dry pyridine was stirred at room temperature for 24 hours. After removal of any insoluble materials, the solvent was removed under reduced pressure. Water was added to the residue, and any insoluble materials were removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was washed with benzene and then with dry benzene.After being dried, the residue was washed twice with dry ether to obtain 9 g (yield: 69.2%) of 2'-phenoxyphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride as hygroscopic, slightly yellow powder having a melting point of 73-750C.
IR#KBr max cm-: 1755 (C=O) NMR (CD3OD) S: 1.70-2.56 (1 OH, m, cyclohexane protons) 3.00 (2H, d, J=8Hz, -Cli2) 6.80-7.40 (9H, m, aromatic protons) EXAMPLE 20 3'-Trifiuoromethylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 10.0 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 6.9 g of m-trifluoromethylphenol and 8.75 g of dicyclohexylcarbodiimide was suspended in 1 00 ml of dry pyridine, and the suspension was stirred at room temperature for 18 hours.After removal of any insoluble materials, the filtrate was evaporated under reduced pressure to give pale yellow crystals. 200 ml of 0.1 N hydrochloric acid was added to the crystals, and the mixture was stirred for 1 hour to give crystals. The crystals were washed with water and recrystallized from ethyl acetate-ether to obtain 9.6 g (yield: 59.7%) of 3'-trifluoromethylphenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride as needles having a melting point of 88-91 OC.
IR #KBr max cm1:1 1742 (C=O) NMR (CD3OD) N: 0.98-2.1 6 (1 OH, m, cyclohexane protons) 3.11 (2H,d,CH2N) 7.34-7.83 (4H, m, aromatic protons) EXAMPLE 21 2'-Cyanophenyl trans-4-guanidinomethylcyciohexanecarboxylate hydrochloride: A mixture of 9.88 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 5 g of o-cyanophenol and 8.64 g of dicyclohexylcarbodiimide was suspended in 100 ml of dry pyridine, and the suspension was stirred at room temperature for 66 hours. Any insoluble materials were removed by filtration and then washed with pyridine. The filtrate and the washings were combined and evaporated.
The residue was washed with ethyl acetate and then dissolved in 30 ml of ethanol. After removal of any insoluble materials, 10 ml of water was added to the filtrate. The mixture was cooled to obtain 9.82 g of 2'-cyanophenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride as colorless needles having a melting point of 102-1050C.
IR #Nujol max cm-1: 2250 (CN),1760 (C=O) NMR (CD3OD) b: 0.92.8 (1 OH, m, cyclohexane protons) 3.01 (2H, d, J=6Hz, CH2N) 7.14-7.65 (4H, m, aromatic protons) ("Nujol" is a registered Trade Mark).
EXAMPLE 22 4'-Cyanophenyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 9.88 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 5 g of p-cyanophenol and 8.64 g of dicyclohexylcarbodiimide was suspended in 100 ml of dry pyridine, and the suspension was stirred at room temperature for 18 hours. After removal of any insoluble materials, the filtrate was washed with pyridine and then with ether. 100 ml of methanol was added to the crystals obtained, and the mixture was stirred for 1 5 minutes. Any insoluble materials were removed by filtration, and the filtrate was cooled to -500C to deposit insoluble materials which were removed by filtration.The filtrate was evaporated to obtain 7.7 g of 4'-cyanophenyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride as colorless crystals having a melting point of 182-1 860C.
IR PKaBxr cm 1: 2225 (CN), 1735 (C=O) NMR (CD3OD) or #: O 0.9--2.8 (1 OH, m, cyclohexane protons) 3.08 (2H, d, J=6.4Hz, CH2N) 7.30 and 7.79 (each 2H, each d, J=8Hz, aromatic protons) EXAMPLE 23 5'-lndanyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 5.6 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 3.1 8 g of 5-hydroxyindane and 5.9 g of dicyclohexylcarbodiimide was dissolved in a solution of 30 ml of dry pyridine and 35 ml of dry dimethylformamide, and the solution was allowed to stand overnight at room temperature.After removal of any insoluble materials, the filtrate was evaporated under reduced pressure. 50 ml of 0.1 N hydrochloric acid was added to the residue to give crystals which were recrystallized from isopropanol to obtain 4.39 g (yield: 53%) of 5'-indanyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride having a melting point of 157--159"C.
IR PKaX cam : 1760 (C=O) EXAMPLE 24 7'-(2'-Oxochrnmenyl)trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 5.6 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 3.84 g of 7-hydroxycoumarin and 5.9 g of dicyclohexylcarbodiimide was dissolved in a mixture of 35 ml of dry dimethylformamide and 30 ml of dry pyridine, and the solution was allowed to stand overnight at room temperature. After removal of any insoluble materials, the filtrate was evaporated under reduced pressure. 50 ml of water was added to the residue to give crystals which were recrystallized from isopropanolmethanol to obtain 6.04 g (yield: 72%) of 7'-(2'-oxochromenyl)-trans-4guanidinomethylcyclohexanecarboxylate hydrochloride having a melting point of 179-181 0C.
IRsKBrcm 1: 1740,1762 (C=O) EXAMPLE 25 4'-lndolyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 5.2 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 2.93 g of 4-hydroxyindole and 5.0 g of dicyclohexylcarbodiimide was dissolved in a mixture of 25 ml of dry pyridine and 25 ml cf dry dimethylformamide, and the solution was allowod to stand overnight at room temperature. After removal of any insoluble materials, the filtrate was evaporated under reduced pressure. 20 ml of isopropanol and 1 ml of water were added to the residue, and the mixture was allowed to stand for 1-2 hours. Insoluble materials were removed by filtration, and the filtrate was evaporated under reduced pressure.Water was added to the residue to give crystals which were recrystallized from ethanol to obtain 5.22 g (yield: 67.5%) of 4'-indolyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride having a melting point of 182-183 C.
IR p KBx cm 1: 1740 (C=0) EXAMPLE 26 8'-Quinolyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 5.2 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 3.19 g of 8-hydroxyquinoline and 5.0 g of dicyclohexylcarbodiimide was dissolved in a mixture of 30 ml of dry pyridine and 30 ml of dry dimethylformamide, and the solution was allowed to stand overnight at room temperature. After removal of any insoluble materials, the filtrate was evaporated under reduced pressure. 50 ml of ethyl acetate and 100 ml of 0.1 N hydrochloric acid were added to the residue. The aqueous layer was washed with ethyl acetate and evaporated to obtain 5.4 g of 8'-quinolyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride as slightly green syrup.
EXAMPLE 27 3'-Flavonyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 9.89 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 10.1 g of 3-hydroxyflavon and 8.66 g of dicyclohexylcarbodiimide was added to 100 ml of dry pyridine, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered to remove any insoluble materials which were washed with pyridine. The filtrate and the washings were combined and evaporated. 0.1 N hydrochloric acid was added to the residue, and the mixture was washed with ethyl acetate. The aqueous layer was concentrated to 30 ml and allowed to stand overnight in a refrigerator to obtain 1 g of 3'-flavonyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride as colorless needles having a melting point of 201-2030C.
IR p Kax cm : 1768 (C=O) NMR (CD3OD) 8: 1.98-2.66 (10H, m, cyclohexane protons) 3.06 (2H, d, J=6.OHz, CH2N) 7.22-8.14 (9H, m, aromatic protons) EXAMPLE 28 4'-Chloronaphthyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride: A mixture of 3.3 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 2.5 g of 4-chloronaphthol and 3.2 g of dicyclohexylcarbodiimide was suspended in 42 ml of dry pyridine, and the suspension was stirred at room temperature for 48 hours. After removal of any insoluble materials, the filtrate was concentrated. 42 ml of 0.1 N hydrochloric acid was added to the residue, and the mixture was stirred at room temperature for 30 minutes to give crystals.The crystals were washed with ether and recrystallized from ethanol-ether to obtain 4.2 g (yield: 75.7%) of 4'-chloronaphthyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride having a melting point of 200-201 .50C.
B c,Kcm-': 1755 (C=0) EXAMPLE 29 2'-(1'-Nitro)naphthyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochioride: A mixture of 10.0 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 8.0 g of 1 -nitro-2-naphthol and 8.75 g of dicyclohexylcarbodiimide was suspended in 100 ml of dry pyridine, and the suspension was stirred at room temperature for 15 hours. After removal of any insoluble materials. the filtrate was concentrated under reduced pressure. 200 ml of hydrochloric acid was added to the residue, and the mixture was stirred for 1 hour to give crystals. The crystals were washed with water and then with ethyl acetate, and thereafter dried. The crystals obtained were suspended in waterchloroform, and the suspension was stirred overnight to give crystals. These crystals were washed with water and then with ethyl acetate, and dried to obtain 14 g of 2'-(1 '-nitro)naphthyl trans-4guanidinomethylcyclohexanecarboxylate hydrochloride having a melting point of 159-1 60.50C.
IR DmKaBX cm 1 1762 (C=O) NMR (DMSO-d6) b: 0.96-2.08 (10H, m, cyclohexane protons) 3.08 (2H, d, CH2N) 7.10t.78 (6H, m, aromatic protons)

Claims (6)

1. A compound of the formula:
wherein R1 represents an indanyl, indolyl, quinolyl or chromonyl group, or a group of the formula
(in which R2 represents a halogen atom or a nitro group), or a group of the formula
(in which R3 represents a halogen atom, or an alkyl, nitro, cyano, acetamino, aminosulfonyl, benzoyl, phenoxy or trifluoromethyl group, R4 represents a hydrogen or halogen atom, or an alkyl group, and B5 represents a hydrogen or halogen atom, or an alkyl group), or a pharmaceutically acceptable salt thereof.
2. A compound of the formula:
wherein R3 represents a halogen atom, or an alkyl, nitro, cyano, acetamino, aminosulfonyl, benzoyl, phenoxy or trifluoromethyl group, R4 represents a hydrogen or halogen atom, or an alkyl group, and B5 represents a hydrogen or halogen atom, or an alkyl group, or a pharmaceutically acceptable salt thereof.
3. 4'-t-butylphenyl tra ns-4-guanidinomethylcyclohexanecarboxylate hydrochloride.
4. A process for producing a compound of the formula:
wherein R, represents an indanyl, indolyl, quinolyl or chromonyl group, a group of the formula
(in which R2 represents a halogen atom or a nitro group), or a group of the formula
(in which R3 represents a halogen atom, or an alkyl, nitro, cyano, acetamino, aminosulfonyl, benzoyl, phenoxy or trifluoromethyl group, R4 represents a hydrogen or halogen atom, or an alkyl group, and B5 represents a hydrogen or halogen atom, or an alkyl group), which process comprises reacting 4 guanidinomethyicyclohexanecarboxylic acid or a reactive derivative thereof with a compound of the formula: B1-OH wherein R1 is the same as defined above, or with a reactive derivative thereof.
5. A compound according to Claim 1 of the formula (I) or a pharmaceutically acceptable salt thereof substantially as described with reference to any of the foregoing Examples.
6. A process as claimed in Claim 4 for producing a compound of the formula (I), substantially as described with reference to any of the foregoing Examples.
GB8201092A 1981-01-22 1982-01-15 Novel guanidinocyclohexanecarboxylic acid derivatives and a process for producing the same Expired GB2093835B (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP728481A JPS57122061A (en) 1981-01-22 1981-01-22 Novel cyclohexanecarboxylic acid derivative and its preparation
JP728381A JPS57122059A (en) 1981-01-22 1981-01-22 Novel cyclohexanecarboxylic acid derivative and its preparation
JP1083281A JPS57126463A (en) 1981-01-29 1981-01-29 Novel carboxylic ester and its preparation
JP1083181A JPS57126462A (en) 1981-01-29 1981-01-29 Novel carboxylic ester and its preparation

Publications (2)

Publication Number Publication Date
GB2093835A true GB2093835A (en) 1982-09-08
GB2093835B GB2093835B (en) 1984-10-31

Family

ID=27454693

Family Applications (1)

Application Number Title Priority Date Filing Date
GB8201092A Expired GB2093835B (en) 1981-01-22 1982-01-15 Novel guanidinocyclohexanecarboxylic acid derivatives and a process for producing the same

Country Status (1)

Country Link
GB (1) GB2093835B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6204278B1 (en) 1996-05-17 2001-03-20 Kowa Company, Ltd. Anilide compounds, including use thereof in ACAT inhibitition
WO2003035107A1 (en) * 2001-10-25 2003-05-01 Molecular Skincare Limited Enzyme inhibitors for inactivating allergens

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6204278B1 (en) 1996-05-17 2001-03-20 Kowa Company, Ltd. Anilide compounds, including use thereof in ACAT inhibitition
WO2003035107A1 (en) * 2001-10-25 2003-05-01 Molecular Skincare Limited Enzyme inhibitors for inactivating allergens

Also Published As

Publication number Publication date
GB2093835B (en) 1984-10-31

Similar Documents

Publication Publication Date Title
SU1248533A3 (en) Method of producing sulfamoyl-substituted derivatives of phenethylamine or hydrochloride thereof
EP0261254B1 (en) 3,4-dihydro-4-oxo-2h-1-benzopyranyloxy alkanoic acid derivatives
SU820659A3 (en) Method of preparing 4-amino-5-alkylsulfonyl-o-anisamide derivatives,their salts,oxides,left-and right-rotational isomers (their variations)
US3897519A (en) Secondary phosphoric acid esters
US5281620A (en) Compounds having antitumor and antibacterial properties
EP0211363B1 (en) 3-phenylthiomethylstyrene derivative, process for preparing the same, and antiallergic agent and tyrosinekinase inhibiting agent containing the same
US6159988A (en) Arylcycloalkyl derivatives, their production and their use
EP0278176B1 (en) Compounds having antitumour and antibacterial properties
US4465851A (en) Guanidinocyclohexanecarboxylic acid derivatives
CS267551B1 (en) Pharmaceutical agents for asthma treatment and method of effective substance production
CA1146563A (en) Benzimidazole derivatives, their preparation and use, and compositions containing these derivatives
FI61688C (en) PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC ANALYSIS
GB2093835A (en) Novel guanidinocyclohexanecarboxylic acid derivatives and a process for producing the same
AU601464B2 (en) Pyrimidine derivatives
US4970214A (en) Quinoline substituted oxomethyl or thioxomethyl glycine derivatives and aldose reductase inhibition therewith
US4082751A (en) Therapeutic agents
US4031093A (en) 1,6-Dihydro-6-oxo-2-(ortho-substituted phenyl)pyrimidine-5-carboxylic acid derivatives
EP0638564A1 (en) Benzothiazolesulfonamide derivative, process for producing the same, and use thereof
US4192944A (en) Optionally substituted 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-N-(1H-tetrazol-4-yl)carboxamides and their use as antiallergy agents
USRE38460E1 (en) Huperzine A derivatives, their preparation and their use
US4318925A (en) 4-Homoisotwistane derivatives
HU199813B (en) Process for producing new benzothiazinone derivatives and pharmaceutical compositions comprising such active ingredient
US3989825A (en) Secondary phosphoric acid esters
US4729995A (en) Pyrimidine 2,4-dioxamate compounds and pharmaceutical compositions
US4798832A (en) Pyrido[1,2-a]pyrimidine compounds, corresponding intermediates and use as SRS-A antagonists

Legal Events

Date Code Title Description
PCNP Patent ceased through non-payment of renewal fee

Effective date: 19970115