KR810000632B1 - Process for preparation of histamine h2 receptor antagomist and montoxic pharmaceutically acceptable acid addition salts thereof - Google Patents

Abstract

Guanidines I (R = C3-9 alkymyl), useful as inhibitors of gastric acid distribution and digestive ulcer, were prepd. Thus, I (R = propagyl) was obtained in 7.7 % yield by treating the corresponding S-methyl-isothiourea with HC:CCH2NH2. I(R = propagyl) was 5.7 times more active than cimetidine H2 receptor antagonist in the isolated guinea pig auricle test.

Description

A process for preparing a histamine H 2 receptor antagonist or a non-toxic pharmaceutically acceptable acid addition salt thereof.

The present invention relates to a histamine H ₂ receptor antagonist of the following structural formula 1, a pharmaceutically acceptable acid addition salt thereof, and a method for preparing the same, which are effective in suppressing gastric acid aberration and treating gastrointestinal ulcers in animals.

Wherein R 'is a straight or branched alkynyl group having 3-9 carbon atoms.

Preferred examples of the compound of the present invention include a compound of the following structural formula wherein R ⁴ is hydrogen or methyl or a non-toxic pharmaceutically acceptable acid addition salt thereof.

Another preferred embodiment of the invention is a compound of the formula wherein R ⁴ is hydrogen or methyl, n is an integer up to 1-6, or a non-pharmacologically usable acid addition salt thereof.

Another preferred example of the invention is a compound of the formula wherein R ⁴ is hydrogen or methyl or a pharmaceutically acceptable acid addition salt thereof which is nontoxic.

A more preferred example of the invention is N-cyano-N '-{2-[(4-methyl-5-amitazolyl) methylthio] ethyl} -N' '-(2-butyn-1-yl) -guanidine Or non-toxic pharmaceutically acceptable acid addition salts thereof.

Another more preferred example of the invention is N-cyano-N '-{2-[(4-methyl-5-imidazolyl) methylthio] -ethyl} -N' '-(3-butyn-1-yl Guanidine or a non-toxic pharmaceutically acceptable acid addition salt thereof.

Another more preferred example of the invention is N-cyano-N '-{2-[(4-methyl-5-imidazolyl) methylthio] -ethyl} -N' '-(4-peptin-1- (I) guanidine or a non-toxic pharmaceutically acceptable acid addition salt thereof.

Another more preferred example of the invention is N-cyano-N '-{2-[(4-methyl-5-imidazolyl) methylthio] -ethyl} -N' '-(2-methyl-3- Butyn-1-yl) guanidine or a non-toxic pharmaceutically acceptable acid addition salt thereof.

Another more preferred example of the invention is N-cyano-N '-{2-[(4-methyl-5-imidazolyl) methylthio] ethyl} -N' '-(3-butyn-2-yl Guanidine or a non-toxic pharmaceutically acceptable acid addition salt thereof.

Most preferred examples of the invention are N-cyano-N '-{2-[(4-methyl-5-imidazolyl) methylthio] ethyl} -N' '-propargyl guanidine or a nontoxic agent thereof. Possible acid addition salts.

The present invention also provides a compound of formula (II)

기이다)과 반응시켜 하기 구조식 I의 화합물 혹은 비독성인 그의 산 첨가염을 생성하고, 필요에 따라, 염기 형태의 구조식 I 화합물R ₆ NHR ¹ of Formula II wherein R ¹ is as defined above and R ₅ and R ₆ are not equal to each other H or R are any substituents, where -SR is a suitable leaving group

To form a compound of formula (I) or a non-toxic acid addition salt thereof, if necessary, in the form of a base formula (I)

(Wherein R ¹ is a red or branched alkynyl group having 3-9 carbon atoms) or an acid addition salt thereof is provided in the form of a corresponding non-toxic pharmaceutically acceptable acid addition salt or free base form.

The reaction proceeds in a non-reaction solvent that is at a temperature above room temperature. In a preferred embodiment, equimolar amounts of the compounds of formulas II and III are used.

The process for preparing the preferred compounds of the present invention is shown in the following semiconductors I and II.

The reaction proceeds in an unreacted solvent above room temperature. As is known to those skilled in the process, R is any substituent and -SR is a suitable leaving group. Therefore, R includes (lower) alkyl, atyl, substituted aryl (eg p-nitrophenyl), aralkyl, -CH ₂ CN, -CH ₂ COOH-CH ₂ COOR 'and the like. N-cyano-N '-{2-[(4-methyl-5-imidazolyl) methylthio] ethyl} -SR isothiourea starting materials can be prepared by the method described in Belgian patent No. 804,144. . Alkynylamine starting materials are already commercially available or are available from Bull. Soc. Chim. Fr., 490 (1958), Bull. Soc. Chim. Fr., 592 (1967) and Annales de Chemie (Paris), 3 , 656 (1958).

The reaction is reacted in a non-reaction solvent at room temperature or above. Substituent R is as mentioned in Table I above. 2-[(4-methyl-5-imidazolyl) methylthio] ethylamine starting material can be prepared by the method of US Pat. No. 3,950,353.

The disubstituted cyano dithioiminocarbonates used as starting materials in the preparation of N-cyano-N'-propargyl-SR isothioureas (see b of Example 2) can be prepared from J, organic chemistry, 32 , 1566 (1967).

In the process of reaction table I, in the final step when preparing N-cyano-N '-{2 [(4-methyl-5-imidazolyl) methylthio] ethyl} -N''propargylguanidine, Selected reaction conditions can be used to obtain products with higher yields and less impurities.

The above reaction conditions can be highly purified by simply recrystallizing the early (crude) product which is separated into crystalline solids, and the chromatographic purification step of the initial crude product which has been regarded as a necessary step so far when using other reaction conditions. There is an advantage that does not have to go through.

The above-mentioned selective reaction conditions include using methanol as a solvent, a nitrogen quenching reaction apparatus during the reaction by utilizing a more concentrated solution (about 1 g of isothiourea substituted per 5 ml of methanol) in the reaction. It means using freshly distilled propargylamine.

During the reaction, when a nitrogen scavenging apparatus is used, it is possible to prevent the formation of small amounts of two substances as an unidentified by-product produced when the nitrogen scavenging apparatus is not used. The byproduct, once produced, is not removed by column chromatography and recrystallization methods. The nitrogen inlet was found to be removed as methyl mercaptan gas was generated to prevent the formation of the byproduct.

The present invention is also obtained by reacting a compound of formula V with a compound of formula S = C = NR ¹ , wherein R ¹ is as defined above

A compound of formula VI with methyliodide and cinnamid

Reacting to prepare the following structural formula I compounds in base form, or non-toxic pharmaceutically acceptable acid addition salts, and, if necessary, to convert to corresponding non-toxic pharmaceutically acceptable acid addition salts according to known methods. .

R ¹ is a straight or branched alkynyl group having ³ to 9 carbon atoms.

The process for preparing the preferred compounds of the present invention is shown in Scheme III below.

The invention of the present application is further prepared by reacting a compound of formula VII (X is a hydroxyl group or a known leaving group) or an acid addition salt thereof with a compound of formula VII (R ¹ is as defined above)

To prepare a compound of formula I (R ¹ is a straight or branched chain alkynyl group having 3-9 carbon atoms) or a non-toxic pharmaceutically acceptable acid addition salt thereof

If necessary, a method of converting a base formula Structural Formula I compound or an acid addition salt thereof into a corresponding nontoxic pharmaceutically acceptable acid addition salt or free base form is provided.

The reaction proceeds in an inert organic solvent.

In a preferred embodiment, equimolar amounts of the structural formulas (VII) and (VII) compounds are used, and the reaction proceeds in the presence of a base.

Suitable leaving groups XX for use in the present invention are known to those skilled in the art. Examples include fluoro, chloro, bromo, iodo, -O ₃ SR ² (R ² is (lower) alkyl: e.g. methanesulfonate), -O ₃ SR ³ (R ³ is aryl or substituted aryl: Benzenesulfonate, p-bromobenzenesulfonate or p-toluenesulfonate), -O ₃ SF, acetooxy and 2,4-dinitrophenoxy. For convenience and economics, it is preferable to use a compound of formula II wherein X is chloro.

In the process of this invention, it is preferable to use the compound of structural formula (VII) in the form of an acid addition salt. Structural Formula (VIII) compounds in free base form are quite inadequate and are therefore preferably prepared and stored in the form of acid addition salts. Formula II compounds in free base form can be regenerated prior to the reaction, in which case no benefit is obtained. All inorganic or organic acids are acidic additions of compounds of formula VII such as, for example, hydrochloride, sulfamate, sulfinate, oxalate, benzoic acid salt, succinic acid salt, acetate salt, nitrate salt, citrate salt, and the like. It can be used to produce salts. In general, the compounds of formula II are convenient and economic to use in their hydrochloride form.

The reaction of compounds VII and VII to produce compound I proceeds in an inert organic solvent such as alkanol, acetonitrile, dimethylformamide, dimethylsulfoxide, acetone and the like. Preferably, the reaction is carried out in alkanols such as ethanol or 2-propanol.

The reaction temperature is not critical and is usually carried out at temperatures between 0 ° C and 200 ° C. At low temperatures, the reaction occurs slowly, and at high temperatures, decomposition and formation of by-products result in poorly purified products. In general, the reaction is advantageously carried out at room temperature.

The reaction of compounds (V) and (V) to produce compound (I) is preferably carried out in the presence of a base which acts as an acid acceptor to facilitate the reaction. Suitable bases used in the reaction include organic bases and inorganic bases such as NaOH, KOH, LiOH, triethylamine, dimethylaniline, sodium ethoxide and the like.

Scheme IV of the above process for preparing preferred compounds of the present invention is shown below.

The present invention also relates to novel intermediates of formula (VIII) and acid addition salts thereof, which are used when preparing histamine H ₂ receptor antagonists of formula (I).

R ¹ is a straight or branched alkynyl group having ³ to 9 carbon atoms.

이며 다른 바람직한 실시예에서, R¹은 n이 1-6까지의 정수, R₄가 수소 혹은 메틸인

이고, 또 다른 바람직한 실시예에서 R¹은 R⁴가 수소 혹은 메틸인

이다.In a preferred embodiment, R ¹ of formula VII compound is that R ⁴ is hydrogen or methyl

And in another preferred embodiment, R ¹ is an integer up to 1-6, R ₄ is hydrogen or methyl

In another preferred embodiment, R ¹ is R ⁴ is hydrogen or methyl

to be.

In a more preferred embodiment, R ¹ is a 2-butyn- ¹ -yl group, in another more preferred embodiment R ¹ is a 3-butyn- ¹ -yl group, in another more preferred embodiment, R ¹ is 4- Fentin- ¹ -yl group, in another more preferred embodiment R ¹ 2-methyl-3-butyn 2-2-yl group, and in another more preferred embodiment, Z ¹ is a 3-butyn-2-yl group. In the most preferred embodiment, R ¹ of the formula VII compound is a propargyl group.

The present invention also relates to compounds of formula VII wherein p is in a suitable sulfhydryl protecting group

Provided is a method of preparing a novel intermediate compound of formula (VIII), wherein the compound is reacted with the compound and then the sulfhydryl preservation group of the final compound is removed to prepare the intermediate compound (VII).

The process is shown in Table V below.

Dimethyl cyanodithioiminocarbodate, used as starting material for preparing N-cyano-N'-alkynyl-S-methylisothiourea, is prepared by the method described in J., Organic Chemistry, 32, 1566 (1967). can do. Alkynylamine starting materials are already commercially available or are available from Bull. Soc. Chim. Fr., 490 (1958); Bull. Soc. Chim. Fr., 592 (1967) and Annsles de Chimie (Paris), 3 , 656, (1958).

Reacting cysteamine hypochlorotide with N-cyano-N'-alkynyl-S-methylisothiourea to yield N-cyano-N'-alkynyl-N ''-(2-mer) When preparing camptoethyl) guanidine, it has been found that it is more advantageous to proceed the reaction in the presence of a small amount of hydroquinone and to bubble through the reaction mixture through nitrogen. (See step B of Example 14). Under the above reaction conditions, a high yield and high purity structural compound can be prepared. The nitrogen quenching step eliminates the methyl mercaptan produced during the reaction, thereby avoiding secondary reactions caused by the addition of methyl mercaptan to the carbon-carbon triple bond.

Hytroquinone as used above prevents the formation of free groups and prevents secondary reactions occurring in the presence of such groups.

As used herein, the term “non-toxic pharmaceutically acceptable acid addition salt” refers to a mono- or di-salt compound of the present invention obtained by participating in a non-toxic pharmaceutically acceptable organic or inorganic acid. The kinds of the acid are already known, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, sulfinic acid, oxalic acid, benzoic acid, metalsulfonic acid, metaldisulfonic acid, benzene sulfide Phonic acid, acetic acid, propionic acid, tartaric acid, citric acid, camphorsulfonic acid, and the like. The salts are prepared by known methods.

As used herein, the term lower alkyl refers to a straight or branched chain alkyl group having 1-6 carbon atoms.

For the purpose of treatment, the pharmacologically active compound of the present invention is administered with a pharmaceutically acceptable carrier in a pharmaceutical composition containing the compound in its basic form or a nontoxic pharmaceutically acceptable acid addition salt as the main active ingredient.

Pharmaceutical compositions may be administered by oral, parenteral or rectal insertion. Various pharmaceutical forms are available. Thus, when a solid carrier is used, the contents can be refined, enclosed in hard gelatin capsules in the form of powders or small pills, or in the form of tablets or tablets. If liquid carriers are used, they are prepared in the form of syrups, emulsions, soft gelatin capsules, sterile injectable solutions or aqueous or non-aqueous liquid suspensions. The pharmaceutical composition is prepared by known techniques depending on the form required.

In general, each dosage unit contains about 50 mg to 250 mg of active ingredient and most preferably contains about 100 to 200 mg of active ingredient. The active ingredient is preferably administered in two to four doses per day. The daily diet is preferably 250 to 1000 mg, most preferably 500 to 750 mg.

It has been found that histamine H ₂ receptor antagonists effectively inhibit gastric acid secretion in animals and humans. (Brimblecombe et al., J Int. Mcd Res., 3, 86 (1975)) The clinical value of histamine H ₂ -receptor antagonists indicates that the substance is an effective treatment for the urinary tract of the digestive tract. (Gray et al., Lan-cet, 1 (8001), 4 (1977)). In various tests, the compounds prepared in Examples 1 and 2 (hereafter referred to as BL-5641-5641) were compared with cimetidine, which showed that the compound was a histamine H ₂ -receptor antagonist of an isolated guinea pig atrium. In addition, rats and dogs have been shown to act much more effectively than cimetidine as an inhibitor of gastric acid secretion. In addition, studies on the distribution of gastric acid in dogs have shown that BL-5641 lasts longer than cimetidine even at the same dose.

Analysis of histamine H ₂ -receptor antagonist-isolated guinea pig atria

The contraction rate of pulsed isolated guinea pig right atrial increases with the concentration of histamine. 236 , 385 (1972) of Black's co-investigator, who reports on the properties of bridamide, an antagonist of receptors, describes the fact that the histamine effect includes receptors in the form of histamine H ₂ -receptors.

Hughes and Cote (Proc. Soc. Exp. Biol. Med. 148, 127 (1975)) and Bezma and McNeil (J, Pharmacol. Exp. Ther 200 , 352, 1977)) found separate guinea picks. Supporting the conclusions of Black and co-investigators that the defining cyclic variable effect of histamine on the right atrium is regulated by histamine H ₂ -receptors. Black and collaborators (see Agents and Actions, 3 , 133 (1973)) and Brimblecome and senior researchers (Fed. Proc., 35 , 1931 (1976)) compared the activity of histamine H ₂ -receptor antagonists. A separate guinea pig right atrium was used.

The comparative study was carried out by modifying the method of Reinhardt et al (Agents and Actions, 4, 217 (1974)).

Male Hartley strain Slap the head of a guinea pig (350-450 gm) as a test material. After cardiac arrest, oxygen-saturated (95% 02, 5% CO ₂ ) quartz crystal solution (g / liter: NaCl: 6.6, KCI 0.35, MgSO ₄ 7H ₂ O 0.295, KH ₂ PO ₄ 0.162, CaCl ₂ 0.238, Soak in a Petri dish containing NaHCO ₃ 2.1 and Texrose 2.09). Separate the pulsed right atrium from the other tissues in the detached state and connect both ends with silk thread (4-0). The atrium is immersed in 20 ml of cardiac muscle containing a modified Kreb solution of oxygen saturation maintained at a temperature of 32 ° C. The operation of the atrial was recorded as a Grass FT 0.03 reverse displacement transducer with operability, and the retraction force and contraction rate were recorded as Beckman RP Dynograph.

1 g of resting tension is applied to the atrium and left for 1 hour. The dish is added with the lowest concentration of histamine dihydrochloride (3 × 10 ⁻⁶ M) and the tissue first washed. Histamine is added in a duplicate addition method with 1/2 log 10 spacing to a concentration of 1 × 10 ⁻⁷ to 3 × 10 ⁻⁵ moles.

The rate of increase in histamine influx in the atria is left in a plateau until the next continuous concentration is added. Maximum response always occurs at 3 × 10 ⁻⁵ M concentration. Add 1 × 10 ⁻⁵ M) of test compound, warm for 30 minutes, and then add higher concentrations as needed to repeat the histamine concentration-response.

Histamine ED ₅₀ values (histamine concentrations that increase shrinkage by 50% of maximum) and 95% confidence limits before and after test compounds are found in Finney, Probit Analysis, 3rd ed., Cambridge (1971). The concentration-response curve displacements are calculated as follows;

Arguments obtained with BL-5641 are expressed as a ratio with those obtained with cimetidine.

The results obtained in this study are summarized in Table 1 below.

Cimetidine and BL-5641 shift the histamine concentration-response curve to the right by a number of 6.6 and 32.7, respectively. Depending on the concentration-response curve displacement factor, BL-5641 is 5.7 times more active than cimetidine as a histamine H ₂ -receptor antagonist in the isolated guinea pick right atrium.

TABLE 1

N: number of experiments

Determination of Gastric Acid Secretion Activity in Ligated Rats for 2 Hours To study perforated gastric ulcers, Shay et al. (Gastroenterology, 5, 53 (1945)) Devised. However, once this method is known, it has also been used as a method for studying gastric acid distribution in rats.

(Shay et al., Gastroenterology, 26 , 906 (1954), Brodie, DA, Am. J. Dis., 11 , 231 (1666))

Currently, this method is used to determine the gastric acid secretory activity of a compound.

Male Long Evans rats of 280-300 gm are used. The animals are kept in each cage and starved for 24 hours with only water. Under anesthesia with ether, the stomach is exposed by abdominal incision and ligation is performed with cotton line. After the wound is closed, ether administration is stopped and 1 mg / kg of BL-5641, cimetidine or excipients are administered intraperitoneally. BL-5641 and cimetidine are dissolved in equivalent HCl and mixed with an appropriate amount of water. The animals are re-contained in cages that have ceased watering and anesthesia with ether after 2 hours. The stomach is removed and drained into graduated test tubes to determine the amount of gastric acid collected over 2 hours. The titratable acidity is measured by calibrating pH 7.0 by adding 0.02 N NaOH to 1 ml of the sample using an autoburette and a potential pH (Radiometer).

The titration of acid extraction is calculated in microequivalent units by increasing the volume in milliliters by adding mille equivalents of acid concentration per liter. The% inhibition of acid ejection amount is calculated as follows.

The results obtained with BL-5641 and cimetidine are shown in Table 2 below.

Experiments with mice pyrolyzed for two hours revealed that BL-5641 acts at least as effectively as cimetidine in inhibiting phase ejection.

TABLE 2

a: Each dose was used for at least 5 animals.

Determination of Gastric Acid Secretion Activity in Gastric Dogs

Thomas, JE, Proc. Soc.exp. Biol. Med, 46 260 (1941) stainless steel tubing was inserted from the mouth of the beagle dog (10-12 kg body weight) to the tandem near the top of the valley. It causes phenomenon over elasticity. Leave for at least 2 months for animals to recover before testing. Prior to the experiment, the dog is starved overnight (approximately 18 hours) and given only a random amount of water. The dog is placed on a tripod and an 8-inch inner saliva catheter with a 17-gauge needle of 2 inches is inserted into the leg vein to administer the drug. Every 15 minutes a gastric drainage is used to collect gastric secretions from the open duct. Main secretions are collected twice in series at 15 minute intervals and if the amount and pH are excessive (> 4 ml / 15 min; pH <5.0)) the animal is not used. The method described by Grossman and Comturek (Gastroenterplogy, 66, 517 (1974)) is modified. After the second week of secretion, 6 ml / hr. Inject histamine (100 g / kg / ha) for 90 minutes using a volume Harvard infusion pump. At this time, BL-5641 cimetidine (dissolved in 1 equivalent of HCl and used as a regular dietary form) or 0.1 ml / kg of volume is quickly injected (within 30 seconds), followed by another 150 minutes of histamine. Infusion for 4 hours) 0.5 ml of gastric fluid samples are immediately corrected for each 15 minutes, and the titratable acidity for 0.02 N NaOH (disadvantage: pH 7.0) is measured using an autoburette and a pH meter. The percent inhibition of acid output is calculated by the paid method for pyloric mice.

Five dogs are each dosed with animal quantities BL-5641 and cimetidine to obtain the results of Figure 3 below. BL-5641 and cimetidine show an immediate inhibitory effect on gastric acid ejection. However, in animal use, BL-5641 always shows a superior degree of inhibition over cimetidine and activity is also long lasting. The above results on inhibitors of histamine-induced gastric acid ejection in dogs indicate that BL-5641 is more effective and more active than cimetidine.

The invention is described in more detail in the following examples and is not limited to the following examples.

TABLE 3

EXAMPLE

N-cyano-N '-{2-[(4-methyl-5-imidazoryl) methylthio] ethyl} -N' '-propargylguanidine

N-cyano-N '-{2 [(4-methyl-5-imidazolyl) -methylthio] ethyl} dissolved in S-methyl isothiourea (3.00 g0.0111 mol) and acetonitrile (60 ml) A mixture of propargylamine (2.50 g, 0.045 mol) was stirred at reflux for 65 hours and then heated for 38 hours at 120-130 ° C. in a stainless steel pressure vessel. The reaction mixture was cooled, separated from tar, decanted and evaporated to produce a resin. This material was placed on silica gel (100-200 mesh) and washed with a mixture of methylene chloride (97 parts) and methanol (3 parts). The product obtained as an intermediate fraction was triturated under acetonitrile and crystallized and then recrystallized from acetonitrile to give the title compound (0.0236 g 7.7%). Melting Point: 146-149.5 ° C. Analysis of C ₁₂ H ₁₆ N ₆ S

Calculated Value: C, 52.15, H 5.83, N, 30.41,

Experimental Value: C, 5.86, H, 5.81, N, 30.70

Example 2

N-cyano-N '-{2-[(4-methyl-5-imidazoryl) methylthio] ethyl} -N' '-propargylguanidine

a) N-cyano-N'-propargyl-S-methylisothiourea

(A)

A solution of propargyldine (6.03 g, 0.109 mol) dissolved in dimethyl cyanodithio iminocarboate (16.00 g, 0.109 mol) and acetonitrile (320 ml) was stirred under reflux for 4 hours, then stirred at 25 ° C. for 12 hours. It was left for a while. This resulted in a melting point of 160-164 ° C. for the title compound A (13.58 g, 81%).

b) N-cyano-N '-{2-[(4-methyl-5-imidazolyl) methylthio] ethyl} -N' '-propargylguanidine

A solution of 2-[(4-methyl-5-imidazolyl) methylthio [ethylamine (13.10g 0.0765mol) dissolved in A (11.71g, 0.0765mol) and methanol (250ml) was heated under reflux for 64 hours. It was. After removal of the solvent, the residue was placed on silica gel (100-200 mesh) and chromatographed by component effluent with methylene chloride / methanol to afford 4.0 g of the title compound. Recrystallization from acetonitrile gave a clarified product with a melting point of 150-152.5 ° C. identical to the product prepared in Example 1 (IR.NMR, TLC).

Example 3

N-cyano-N '-{2-[(4-methyl-5-imidazolyl) ditylthio] ethyl} -N' '-(2-butyn-1-yl) guanidine

a) N- (2-butyn-1-yl) -N'-cyano-S-methylisothiourea (B)

A solution of dimethyl cyanodithioiminocarbonate (10.00 g, 0.0684 mole) and 2-butyn-1-amine (4.73 g, 0.0684 mole) in acetonitrile (200 ml) was stirred at 25 ° C. for 0.5 hour, and then 2.5 Reflux over time. After cooling the mixture was filtered to give the title compound B, Melting point 180-183 ℃.

b) N-cyano-N '-{2-[(4-methyl-5-imidazoyl) methylthio] ethyl} -N' '-(2-butyn-1-yl) guanidine

A solution of B (6.82 g, 0.0407 mol) and 2-[(4-methyl-5-imidazoryl) methylthio] ethylamine (6.98 g, 0.0407 mol) in methanol (140 ml) was refluxed for 40 hours. Heated. When the title compound is prepared by the method of Example 1 by chromatography as in Example 2, the melting point is 128-130 ° C.

Example 4

N-cyano-N '-{2-[(3-methyl-5-imidazoryl) methylthio] ethyl} -N' '-(3-butyn-1-yl) guanidine

The procedure of Example 1 was repeated except that propargylamine in Example 1 was replaced with an equimolar amount of 3-butyn-1-amine, to yield the title compound.

Example 5

N-cyano-N '-{2-[(4-methyl-5-imidazoyl) methylthio] ethyl} -N' '-(4-pentin-1-yl) guanidine

The procedure of Example 1 was repeated except that propargylamine in Example 1 was replaced with an equimolar amount of 4-pentyn-1-amine to produce the title compound. Melting point 99-103 ℃

Example 6

N-cyano-N '-{2 [(2-methyl-5-imidazoryl) methylthio] ethyl} -N' '-(2-methyl-3-butyn-2-yl) guanidine

The title product was obtained by repeating the method of Example 3 except for replacing the 2-butyn-1-amine in Example 3 with an equimolar amount of 1.1-dimethylpropargylamine.

Example 7

N-cyano-N ''-{2-[(4-methyl-5-imidazoyl) methylthio] ethyl} -N ''-(3-butyn-2-yl guanidine

The title compound was obtained by repeating the method of Example 3 except for replacing the 2-butyn-1-amine in Example 3 with an equimolar amount of 1-methyl propargylamine.

Example 8

N-cyano-N '-{2-[(4-5-imidazolyl) methylthio] ethyl} -N' '-(2-butyl-butyl- (yl) guanidine

N-cyano-N '-{2-[(4-methyl-5-imidazolyl) -methylthio] ethyl} -S--methylisothiourea (3.00 g, 0.0111 mol) and 2-butene-1 A mixture of amines (3.07 g, 0.445 mol) was stirred in reflux for 60 hours in 60 ml propionitrile. TLC analysis of the reaction mixture indicated that isothiourea was the starting material, so the mixture was further refluxed for 6 hours and then stirred at room temperature for 64 hours. The solvent was removed under reduced pressure (with excess amine) and the residual resin was placed on silica gel (100-200 mesh) and washed with a mixture of methylene chloride (97 parts) and methanol (3 parts). The intermediate fractions were combined and evaporated to yield 1.81 g of yellow resin. The resin was dissolved in 20 ml of ethyl acetate and crystallized at -15 ° C. The resulting pale yellow solid (1.2 g) was dissolved in 11 ml of hot acetonitrile and recrystallized at -15 ° C. Yield 1.072 g, melting point 128-130 ° C. Assay C ₁₃ H ₁₈ N ₆ S

Calculated Value: C, 55.77 H, 6.25 N, 28.94 S, 11.08

Experimental Value: C, 53.72 H, 6.29 N 29.62 S, 11.34

Example 9

N-cyano-N '-{2-[(4-methyl-5-imidazoyl) methylthio] ethyl} -N' '-(3-butyn-1-yl) guanidine

N-cyano-N '-{2-[(4-methyl-5-imidazolyl) methylthio] ethyl} 3-S-methylisothiourea- (3.00 g, 0.011 mol) and 3-butyne-1 A mixture of amines (3.13 g, 0.0453 mol) was stirred at 60 ml propionitrile at reflux for 40 h. The solvent was evaporated to yield 5.40 g of syrup placed on 70 g of 100-200 mesh silica gel, and the components were chromatographed by eluting with methylene chloride / methanol.

TLC (silica gel, 90CH ₂ Cl ₂ / 10MeOH) results show that 9-12 is pure and must be bound. 1-8 shows the rapidly changing impurities. 13 and 14 show some miscellaneous impurities. 9-12 were combined and evaporated to give 1.72 g of a yellow resin. The resin was dissolved in 11 ml of nitromethane and crystallized at −15 ° C. (1.18 g of pale yellow solid) and recrystallized from 9 ml of nitromethane to 0.987 g; Melting point 86-89 ° C. (softened at 85 ° C.) was obtained. Infrared and NMR (100MH ₂ ) showed a clean and desirable structure.

NMR shows that the product is solvated with about 0.08 moles of nitromethane.

Analysis: CH ₁₃ H ₁₈ N ₆ S 0.08 (CH ₃ NO ₂ )

Calculated Value: C, 53.21 H, 6.22 N, 28.84 S, 10.86

Experimental value: C, 52.68, 52.87, H, 6.28 6.02 N, 29.39, 29.50, S, 11.22

Example 10

N-cyano-N '-{2-[(4-methyl-5-imidazoyl) methylthio] ethyl} -N' '-(4-pentin-1-yl) guanidine

N-cyano-N '-{2-[(4-methyl-5-imidazoryl) methylthio] ethyl} -S-methylisothiourea (3.00 g, 0.0111 mol) and 4-pentin-1-amine (3.69 g, 0.445 mol) was stirred at reflux for 24 hours in 60 ml of acetonitrile and then kept at room temperature for 96 hours.

The solvent and excess amine were removed under reduced pressure and the remaining yellow resin was eluted with methylene chloride / methanol (99: 1-96: 4) and purified by chromatography on 50 g of 100-200 mesh silica gel. The intermediate fractions indicated by TLC were combined and evaporated to yield 1.91 g yellow resin that crystallized at -15 ° C. in 18 ml of ethyl acetate. The resulting white solid (1.25 g) was recrystallized from 10 ml of acetonitrile at −15 ° C. to obtain 1.063 g of product melting point 99-103 ° C.

Analysis: C ₁₄ H ₂₀ N ₆ S

Calculated Value: C, 55.24 H, 6.52 N, 27.61 S, 10.53

Experimental Value: C, 55.43 H, 6.58 N, 28.26 S, 10.97

Example 11

N-cyano-N '-{2 [(4-methyl-5-imidazolyl) methylthio] ethyl} -N' '-propargyl guanidine

N-cyano-N '-{2-[(4-methyl-5-imidazolyl) methylthio] ethyl} -S-methylisothiourea (10.0 g; 0.0371 mol) and distilled propargylamine (20 g 0.325 mol) was stirred under reflux in methanol (50 ml) for 20.5 hours under nitrogen atmosphere. The solvent and excess amine were evaporated off to yield a tan fraction that readily crystallized.

The crude product was triturated under isopropanol (30 ml) to yield the title compound as a brittle white solid (8.11 g 79%).

Example 12

N-cyano-N '-{2-[(4-methyl-5-imidazoryl) methylthio] ethyl} -N' '-propargylguanidine

N-cyano-N '-{2-4-methyl-5-imidazoryl) -methylthio] ethyl} -S-methylisothiourea (100 g; 0.371 mol) and distilled propargylamine (150 ml; 2.44 Mole) was stirred at reflux in methanol (500 ml) for 22 h under nitrogen atmosphere.

The reaction product was cooled and the solvent and excess amine were evaporated off to yield amber and oil which easily crystallized. The crude product was triturated under isopropanol (250 ml), cooled at 0 ° C. for 2 h, filtered and integrated.

The filtered residue was washed with cold isopropanol and dried under vacuum on P ₂ O ₅ for 16 hours. The dried title product is a near white solid. Yield 73.5 g (71.7%) Melting point 147-149 ° C

Example 13

Recrystallization of N-cyano-N '-{2-[(4-methyl-5-imidazolyl) -methylthio] ethyl} -N''propargylguanidine Combine the final product obtained in Examples 11 and 12 (81.3 g total), dissolved in hot isopropanol (1000 ml), filtered through “super-cell” and cooled at room temperature for 68 hours. The resulting crystal product was collected by filtration, washed with cold isopropanol, pulverized and dried in a heat dryer for 45 hours under reduced pressure. Yield 72.4 g (89% yield) Melting point 149-151 ° C HPLC showed purity 99.5% and NMR (100MH ₂ ) spectrum was clean and consistent.

Anal: calcd for C ₁₂ H ₁₆ N ₆ : C, 52.15, H, 5.83, N, 30.41; S, 11,60

Found: C, 52.42; H, 5.94; N, 30, 51; S, 11.35

Example 14

N-cyano-N '-{2 [(4-methyl-5-imidazolyl) methylthio] ethyl} -N' '-propargylguanidine

A.N-cyano-N'-propargyl-S-methylisothiourea

A solution of dimethylcyanothioimino carbonate (16.00 g, 0.109 mol) and propargylamine (6.03 g, 0.109 mol) dissolved in acetone (320 ml) was refluxed for 4 hours, stirred, and left at 25 ° C. for 12 hours. . The mixture was cooled and filtered to give 160-164 ° C. of the title mixture (13.58 g, 81%).

B. N-cyano-N'-propargyl-N ''-(2-mercaptoethyl) guanidine

1.136 g (10 mmol) of cysteamine hydrochloride, 1.53 g (10 ml) The resulting mole of step A 0.055 g of hydroquinone was dissolved by heating slightly in 10 ml of DMF. To the solution was added 10 ml of 1N aqueous sodium hydroxide solution and nitrogen was removed from the solution. After standing at room temperature for 17 hours, the reaction mixture was evaporated to dryness to obtain a mixture of foam formulation and sodium chloride. The title compound was extracted from the mixture with 10 ml of ethanol and used for the following reaction.

C. N-cyano-N '-{2-[(4-methyl-5-imidazoryl) methylthio] ethyl} -N'-propargylguanidine

The ethanol solution of the product of reaction B was added to 0.46 g sodium (0.02 g-atomic melt dissolved in tanol in 10 ml under nitrogen at 4 ° C.) 1.67 g (10 ml mole) of 4- dissolved in 14 ml ethanol after 5 minutes. Methyl-chloromethyl-imidazole HCl solution was added and the mixture was stirred at rt for 70 min under nitrogen The reaction mixture was filtered through a cetrit filter bed to remove inorganic salts and washed with cetryl ethanol. The product was dried and purified by chromatography on a silica gel column (20 g silica 3.2 × 4.5 cm bad) as a solvent, as an ethanol-chromoform mixture, the ethanol content gradually increased from 2 to 15%. g of crystals were obtained, recrystallized from 2-propanol to give 1.49 g (54) of the title product.

Example 15

N-cyano-N '-{2-[(4-methyl-5-imidazoryl) methylthio] ethyl} -N' '-(2-butyn-1-yl) guanidine

A. N-N'-cyano- (2-butyn-1-yl) -S-methyl isothiourea

A solution of dimethyl cinnadio dithio iminocarbonate (10.00 g, 0.0684 mole) and 2-butyn-1-amine (4.73 g, 0.0684 mole) dissolved in acetonitrile (200 ml) was stirred at 25 ° C. for 0.5 hour. It was refluxed for 2.5 hours. The mixture was cooled and then filtered to afford the title compound. Melting Point 180-183 ° C. N-Cyano-N '-(2-butyl-1-yl) N' '-2 (2-Metcaptoethyl) -Guanidine

Equivalent molar amount of N-cyano-N '-(2-butyn-1-yl) -S-methylisothiourea instead of N-cyano-N'-propargyl-S-methylisothiourea in Example 14B The method of Example 14B was repeated except that was used to afford the title product.

C ₁ N-cyano-N '-{2-[(4-methyl-5-imidazoyl) methylthio] -ethyl} -N''-(2-butyn-1-yl) guanidine

N-cyano-N'-propargyl-N ''-(2-megcaptoethyl) guanidine in equivalent molar amount of N-cyano-N '-(2-butyn-1-yl) -N' '- The method of Example 14C was repeated except that (2-mercaptoethyl) guanidine was used to produce the title product.

Example 16

N-cyano-N '-{2-[(4-methyl-5-imidazoyl) methylthio] ethyl} -N' '-(3-butyn-1-yl) guanidine

A.N-Cyano-N '-(3-butyn-1-yl) -N' '-(2-mecaptoethyl) -guanidine

The procedure of steps A and B in Example 14 was repeated except that equimolar amounts of 3-butyn-1-amine were used in place of propargylamine in step A to produce the title molar.

B, N-cyano-N '-{2-[(4-methyl-5-imidazoyl) methylthio] -ethyl} -N' '-(3-butyl-1-yl) guanidine

Equivalent molar amount of N-cyano-N '-(3-butyn-1-yl-N' '-instead of N-cyano-N'-procargyl-N' '-(2-mercaptoethyl) guanidine The method of Example 14C was repeated except that (2-mercaptoethyl) guanidine was used to produce the surface compound.

Example 17

N-cyano-N '-{2-[(4-methyl-5-imidazolyl) methylthio] ethyl} -N' '-(4-pentyl-1-yl) guanidine AN-cyano-N' -(4-pentin-1-yl) -N ''-(2-mercaptoethyl) -guanidine

The title product was prepared by repeating the process of steps A and B in 14 except that an equimolar amount of 3-pentyn-1-amine was used instead of propargylamine in step A.

B, N-cyano-N ''-{2-[(4-methyl-5-imidazoyl) methylthio] -ethyl} -N ''-(3-butyl-1-yl) guanidine

Equivalent molar amount of N-cyano-N '-(3-butyl-1-yl) guanidine-N' 'instead of N-cyano-N'-procargyl-N' '-(2-mercaptoethyl) guanidine The title product mole was prepared by repeating the method of Example 14C except using-(2-mercaptoethyl) guanidine.

Example 18

N-cyano-N '-{2-[(4-methyl-5-imidazolyl) methylthio] ethyl} -N' '-(2-methyl--3-butyn-2-yl) guanidine AN- Cyano-N '-(2-methyl-3-butyn-2-yl) -N' '-(2-mercaptoethylguanidine)

The title product was prepared by repeating the method of Example A, B in Example 14, except that an equal molar amount of 1,1-dimethylchloropagyl amine was used in place of propargylamine in Step A.

B, N-cyano-N ''-{2-[(4-methyl-5-imidazoyl) methylthio] -ethyl} -N ''-(2-methyl-3-butyn-2-yl) Guanidine

Equimolar amount of N-cyano-N '-(2-methyl--3-butyn-2-yl) instead of N-cyano-N'-propargyl-N' '-(2-mercaptoethyl) guanidine The title product was prepared by repeating the method of Example 14C except using -N '' (2-metcaptoethyl) guanidine.

Example 19

N-cyano-N '-{2-[(4-methyl-5-imidazoryl) methylthio] ethyl} -N' '-(3-butyn-2-yl) guanidine

A.N-cyano-N '-(3-butyn-2-yl) -N' '-(2-metcaptoethyl) guanidine

The method of Example A and B of Example 14 was repeated except that an equivalent molar amount of 1-methyl-propargylamine was used in place of propargylamine in Step A to prepare the title product.

B.N-cyano-N '-{2-[(4-methyl-5-imidazoyl) methylthio] -ethyl} -N' '-(3-butyn-2-yl) guanidine.

Equimolar amount of -N-cyano-N '-(3-butyn-2-yl) -N'- instead of N-cyano-N'-propargyl-N' '-(2-mercaptoethyl) guanidine The title compound was prepared by repeating the method of Example 14 except using (2-mercaptoethyl) guanidine.

Claims (1)

A process for preparing a compound of formula (I) or a pharmaceutically acceptable acid addition salt by reacting a compound of formula (II) or an acid addition salt thereof with a compound of formula (III) in a nonreactive solvent at or above room temperature.

In the above structure, R ¹ is a straight or alkynyl group containing 3 to 9 carbon atoms R ₅ and R ₆ are different and each H or group

R is any substituent such as -SR which is a suitable leaving group.