JPS6191122A - Treatment of chronic articular rheumatism by 2-guanidino-4-(2-methyl-4-imidazolyl)thiazoles - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION This application is a continuation-in-part of co-pending US patent application Ser. No. 659,750, filed October 11, 1984.

Industrial Application Field The present invention relates to 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole, 2-(N-pentel-N'-guanidino)-4-(2) in the treatment of rheumatoid arthritis.
-Methyl-4-imidazolyl)thiazole and its analogous compound (or its pharmaceutically suitable salt).

Problem to be Solved by the Invention Despite the widespread use of steroidal and non-steroidal anti-inflammatory agents, rheumatoid arthritis remains an unsuitable substratum for treatment. For example, the gastrointestinal side effects associated with the anti-inflammatory agents mentioned above preclude practical use in many individuals. Therefore, 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole and its N-? The present use of methyl analogs could be a great addition to the drugs available to physicians for the treatment of rheumatoid arthritis.

2-guanidino-4-(2-methyl-4-imidazolyl)thiazole analogues and their pharmaceutically suitable salts have been previously reported as histami-H2 antagonists;
Useful as gastric acid antisecretory and antiulcer agents; LaMattina and Lipinski
ipinski), U.S. Pat. No. 4,374,843 (1983). 2-guanidino-4-(2-methyl-4
-imidazolyl)-thiazole and its salts, particularly the dihydrochloride salts suitable for use in the present invention, are also described below in the specific examples below.

2-(N-inchruN'-daanidino)-4-(2-
Methyl-4-imidazolyl)thiazole was released in 1984.
No. 12, pending U.S. Patent Application No. 605.510, filed by Reiter, dated May 30,
- (N-substituted guanidino)-4-heteroarylthiazole anti-ulcer agents. Methods for the synthesis of said N + "interguanidino compounds and their use as anti-ulcer and/or gastric acid anti-secretory agents. is also described in detail below.

The present invention provides 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole, 2-(N-inter-N'-
guanidino)-4-(2-methyl-4-imidazolyl)
The present invention relates to a method for treating mammals (including leeches) suffering from rheumatoid arthritis, which comprises administering an anti-chronic arthritis anti-arthritis dose of thiazole or a pharmaceutically suitable salt thereof.

A good route of administration is oral. 2-guanidino-4-(
The preferred form of 2-methyl-4-imidazolyl)thiazole and its N-pentyl analogues is its dihydrochloride salt, the method of synthesis of which is generally described by LaMatt1.
na+) and writer (RsiterX above document)
and in particular below.

The present invention also provides 2-guanidino-4-in the form of tablets or capsules suitable for oral administration in mammals, including humans.
(2-methyl-4-imidazolyl)thiazole, its N
- Concerning a unit dosage form consisting of an anti-rheumatoid arthritis amount of the anti-rheumatoid analogue or a pharmaceutically suitable salt thereof.

The clinical utility of 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole and its N-intyl analogues in the treatment of human rheumatoid arthritis has been linked to secondary responses in adjuvant 9-induced arthritis in rats. It is believed that laboratory studies have shown its beneficial effects. Typical protocols for these studies are described in the specific examples below, in which the process of 7-diupandoarthritis [2-guanidino-4-(2-methyl-4
-imidazolyl)thiazole only beneficial effects have been observed. These examples include symmetric experiments with the anti-inflammatory pyroquincum.

For purposes of this specification and claims, treating arthritis with an anti-rheumatoid amount of the active agent i, V, i
The method is intended to include sufficient J5 to alleviate the immediate symptoms of rheumatoid arthritis and to slow the progression of the disease. For this purpose, 2-daedino-4-(2-methyl-4-imidazolyl)thiazole, its N-pentyl analogs and its pharmaceutically suitable salts are administered orally and parenterally to subjects suffering from rheumatoid arthritis. including 11
Administer by many conventional routes of administration. Conveniently these compounds are administered orally. Generally, from about 0.1 to 20,169 per day of the subject's body weight undergoing treatment.
It will be administered orally in an amount between about 0.2 and 2.5 η/'Q per day which is good.

If parenteral administration is desired, these compounds are administered in an amount between 0.1 and 1.0 η per body weight of the subject being treated per day. However, the attending physician's
Some variation in dosage will necessarily occur depending on the condition of the subject being treated with k.

The compounds may be administered alone or with pharmaceutically suitable carriers or diluents in single or multiple doses. Suitable pharmaceutical carriers include inert diluents or excipient systems, sterile aqueous solutions and various organic solvents. 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole,
Pharmaceutical compositions formed from the intyl analog or its salt and a pharmaceutically suitable carrier can be prepared in the form of tablets, powders,
It is readily administered in a variety of dosage forms such as capsules, lozenges, syrups, and the like. These pharmaceutical compositions can contain flavoring agents, binders, excipients and the like, if desired. Therefore, for oral administration (polyvinylpyrrolidone, sucrose,
Along with binders such as gelatin and gum arabic,
Tablets contain various excipients such as sodium phosphate, and lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type can also be used as excipients in soft and hard-filled gelatin capsules. Good substances for this include lactose or milk sugar and high molecular weight polyethylene glycols.

If an aqueous suspension or elixir is desired for oral administration, the essential active ingredient may be water, a diluent such as ethanol, propylene glycol, glycerin, or mixtures thereof, and various sweetening or flavoring agents and colorants. agents or dyes and, if desired, emulsifying or suspending agents. Good results include 2-guanidino-4-(2-methyl-4
-imidazolyl)thiazole or its salts are administered orally in solid unit dosage form, i.e., as a single physically discrete floating unit containing a suitable amount of the active compound together with a pharmaceutically suitable carrier or diluent. . A particular example of such a unit dosage form is a tablet or capsule containing about 5 to 1000 q of active ingredient, comprising about 10 to 90% of the total weight of the unit.

For parenteral administration, 2-guanidino-4-(2-methyl-
Suspensions or solutions of 4-imidazolyl)thiazole, its intyl analogues or their salts in sterile aqueous media, such as aqueous propylene glycol, sodium chloride, dextrose or sodium bicarbonate solutions, are used. Such bath solutions are suitably buffered, if necessary, and are usually made isotonic with sufficient salt or glucose to make the liquid diluent.

The preparation of suitable sterile liquid vehicles for parenteral administration will be familiar to those skilled in the art.

The invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these embodiments.

Examples Example 1 2-guanidino-4-(2-methyl-4-imidazolyl) 2-guanidino-1-(2-methyl-4-imidazolyl)thiazole monohydrobromide (360.7 g; 1.1
9 mol; U.S. Pat. No. 4,374,843) to 7500
m1f) Slurry in H20 at 19°C for 15 minutes. While stirring, gradually adjust the pH to 5 with 10% NaOH.
From 6B to a stable value of 9.5: J'41n (500
±51+! 6 is required). Another 0.5 hours (-
Upon stirring, the Table I product is recovered by filtration over smelt glass. Add 200 (l) of H2O to the sticky cake.
10001I in open bales.
Wash with hexane in e. After air drying on the funnel for 18 hours, any cake that is still partially wet is taken to the next step.

If required in the formulation, the free base can be added at a constant point fI'
Dry until it reaches C, and correct the formula so that it does not contain water.

Example 2 2-guanidino-4-(2-methyl-4-imidazolyl) anhydride has a physical value of 265.3. lit play l, l
The entire partially wet batch of the free base before the base containing base is estimated is mixed into 1030 d of CH30H and 4125 t/m of impropat tool and heated to flush. The hot bath t■ is treated with 62.9 activated carbon.

After 30 minutes of high-wave flow, the A mixture is filtered through Quaint earth and washed with 275g of isopropanol. The temperature is 60°C.

While stirring, add U,'% HCl (345 shoulder t)
is made into a thin stream and ``1: is added.The resulting suspension is L
Concentrate to 2,750 scraps under L vacuum, add 5,500 scraps of isopropanol, maintain the volume, cool to 0-5°C, stir at that temperature for 1.5 hours and the title product is recovered by filtration. washed with a 700 d cold inproper tool and dried under vacuum at room temperature; 307.2 g (87 g in two steps);
%) p m/e 222; U, V, lambda maximum value (0, OIN HC1/CH30H) 229 and 260 (0,01N NaOH/CH30H)
248 and 274 nm < E 1chi 681 and 475); Neutralized by our company (1:1 methanol: H2O, O8N NaOH) calculated value 29
5.2; Actual value 299.9° Elemental analysis csI (ioN6S, calculated value as 2HC/: C, 32,55; H, 410; N, 28
．． 47; S, 10J36; CJ-, 24,02% Actual value: C, 32,30; H, 4,06; N,
28.29; S, 11.05; C6-, 24,05
or free base (10, (1,0,045 mol 20
Weight correction assuming that it contains up to % water) is 1001!
Dissolve Il in hot acetic acid (just enough to completely dissolve near reflux temperature). One more heat ill
7.5M (0,090
mol) of aH (J) is added. The title product, which starts to crystallize almost immediately after cooling to room temperature, is collected in several portions and dried under vacuum at 40°C; yield 12.63. !i
+ (95%), identical to the product crystallized from isoprolol.

or free base (1.0 g, 0.0045 mol)'
? : Dissolve in 2 d of concentrated HCIt. The dihydrochloride crystallizes almost immediately. The mixture is diluted with 51 Le of acetone, stirred for 5 minutes, and the title product is collected in portions and precipitated with acetone. 1.15F (86.6%
) is the same as the product of the above method.

Carbon analysis C3H1oN6S, as 2HC1: Calculated value: C, 32,55; H, 4,10; N,
28.47 Actual measurement value: C, 32, 16; H, 4
, 40;
, 0,0322 mole; US Pat. No. 4,374,843) in 48% HBr (40yti, 0.351 mok), the temperature increases to 33°C. Heat the bath liquid to 50°C. , 5 ml of 48% HBr KM dissolved Br2 (1,65 ml = 5.15 Its o, o
322 mol) was added dropwise over 17 minutes, during which time the temperature was maintained by external heating if necessary. The stirred reaction was heated to 65°C for 1.5 hours, cooled, and stripped to a creamy slurry. The mixture is 2 x 2
Purge with 0 txl H2O (this will dissolve the solids and return to a thick slurry). intermediate 2-methyl-4-
Without further isolation of the (bromoacetyl)imidazole, absolute ethanol (29.2 mC) is added, N-amidinothiourea (3,81 F, 0.0322 mol) is added and the slurry is heated to reflux. The resulting solution is refluxed for 2 hours, during which time a heavy precipitate of crystalline title product separates out. The slurry is distilled to half a grain, cooled to room temperature and the title product is recovered by filtration, washed with a small amount of ethanol and dried under vacuum at 35°C; ) ; Uniform in txe, Rf O,7
5 (19:1 nitanol: 1NH40H); m
, p, 300 °C (minute angle i).

Elemental analysis CBHl gN6S-2HBr ・0.5
Weighed as H2O: fi: C,24,44; H,
3,33; N, 21.38% Actual value: C, 24,2
0; H,3,18; HBr 3.67*t(0,
0322 mol) of 48% HBr and 4d of acetic acid, and instead of the 48th HBr, Br2 (1.65 m/) dissolved in 4d of acetic acid is added. 1.5
At the end of the heating period (cooling, suction) for an hour (cooling, suction) and expulsion (without expulsion) N-amidinothiouric acid
(3,811 is added. The reaction exotherms from 67 to 77°C and the resulting solution is heated at 80°C for 1 hour during which time the title product begins to precipitate heavily. 9.34 ji+ (73 ji in two chemical steps), which was recovered as a product and was identical to the product of Method A.

Method C 48% HBr (16,9111 2-methyl-4
- Add acetylimidazole (7,36,9,0,059 mol) to form a clear yellow solution. 48chi HBr (3
, 31) dissolved in Br2 (3.0 ml, 0.0
59 mol) was added dropwise, and the reaction solution was heated to 45°C. Temporary precipitation is observed during addition, fd and heating. 4
After stirring at 5 °C for 18 h, the reaction mixture is cooled to 30 °C, diluted with 22 mg of absolute ethanol, and N-amidinothiourea (7,O,F) is added. The resulting slurry becomes almost transparent and then solids form which are broken up with a spatula. The resulting fluid slurry is 55
Stir for 2 hours at 10°C, cool to 10°C, collect the title product by filtration and wash with 2 x 5 mA' of absolute ethanol.
1 (86 chi).

Example 4 2-Guanidino-4-(2-methyl-4-imidazolyl)thiazole [Free base] 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole 2-! Hydrotetrahydride salt (13,4g) k66
．． Stir with 9 d of H2O to obtain 22.6 me ('>3NNa
The pH is gradually adjusted to a stable value of 10.0 over 2 hours with OH while maintaining the temperature at 22-24°C. The title product was collected by suction filtration, washed with water, pulled under a rubber stub to form a hard cake, re-thickened in 28 at acetone for 2 hours, filtered again and reduced to 12 m
Washing with 1 of acetone and drying under vacuum at 40° C. gives the crystalline title product, 8.66.9 (contains about 15 of water).

The anhydrous free base is a water-moist cake (synthesized as above,
(do not make it mushy again with acetone) is synthesized as follows. 4.04 g water-moist cake (estimated to contain 1.60 g free base if dry)
was added to 80% of refluxing acetone, the solution was treated with 0.169% activated carbon, filtered while hot, the F solution was concentrated to 15%, stirred for 1 hour at room temperature, and the cake was dissolved in acetone. Wash and dry under vacuum at 40°C: Yield: 1.57L Example 5 4-(2-Methyl-4-imidazolyl)-2-(N-ba(N-intylguanyl)thiourea (21,12# .

0.112 mol) and 4-pulmoacetyl-2-methylimidazole hydrobromide (27.65 g, 0.09
7 mol) mixed in ζ acetone (400 ml), 24
Time QK. The resulting solid was collected, washed with acetone and dried to yield 40.63 g (92.2%) of the desired product's pale yellow dihydrobromide (81
, 14g, 0.179mol) warm water (1500m/
) and sodium carbonate hydrate (88.6 g, 0.2 g).
714 mol) in water (800 ml). After the addition is complete, the mixture is stirred for 30 minutes and filtered. Rinse the filter cake thoroughly with water and store under vacuum for 48 hours.
Dry for an hour. This solid was dissolved in acetone (21), a small amount of N porcelain was filtered off, and concentrated HC/r (3
4d, 0.408 mol) and further diluted with acetone (11). The resulting precipitate is collected, cleaned and dried to give an off-white solid of 62.44.193.2", mp299-301".

Elemental analysis CxaHzoN6S4HCA! , 0.5H
Calculated value as 20: C, 41, 71; H, 6,
19; N, 22.45; Cl-, 19,41 Actual value: C, 41,75; H, 621; N
, 22.42; CJ-, xc+, o3° Example 6 2-guanidino-4-(2-methyl-4-imidazolyl) in the adjuvant-induced F5 inflammatory process in rats, each weighing 250-270 grams of adult male custard. Wieter-Lewil rats (Charles River Breeding Laboratories (Cha)
rge Japan R1ver Blessing Labora
torIPel Kingston, N, Y,) Waltz (V/axz)' et al.
[Proc, 5ocJxptl, BiollMed, Adjuvant arthritis is induced by a single injection into the sole of the foot with a suspension of 0.1 mg of mineral oil. Seven rats were used in each group. Drugs administered orally are dissolved in water,
If necessary, add dilute sodium hydroxide to confirm i8M; control group receives water only. p the fI solution
After neutralization at H7.0, a volume of 10*j/klP body weight is administered by intubation with the blunt end of an 18-gauge needle. Administration of each drug begins 1 day before the injection of Adjuvant 2 and continues daily until 16 days after the induction of arthritic lesions.

The first posterior isometric volume fic (Vi) is measured on the day of adjuvant injection, and the swelling n (Yf-Vi) in the injected paw is determined 4 days after adjuvant injection. This is considered a secondary response or lesion. Swelling fq (V
r-v4) is a secondary response or lesion. Rats were weighed at the start of the round-like experiment 4 and 16 days after induction of disease. The R-cent inhibition of edema was calculated according to the following: The results are shown in Table 1. As calculated by linear regression analysis, the data in Table 3 shows that piroxicam alone has a correlation coefficient (r) of 0.95 for primary lesions and an ED of 2.
51 in 60 g/; r-1 for secondary lesions;
00 and ED50-0.45 W/. 2
-guanidino-4-(2-methyl-4-imidazolyl)
For thiazole, no significant activity was observed in primary lesions, whereas significant activity was observed in secondary lesions; a reliable ED, o, could not be extrapolated from this data.

Table 1 7) Piroxicam and 2-guanidino-4-(2-methyl-4-imidazolyl)033...33181** in Epanbee-induced arthritis
43 (4J**1.00...
・ 4 s (71** 64 (31 wood tree... 1.0 0161
3 (3)・・・・・・ 3.3
0131 28 +41**・・・・・・
10.0 2 +2+ 27 +31
**1 - Mean value of inhibition of edema +/- standard error: each M
: 21 rats were used for piroxicam (14 as free thiazole, 7 as ethanolamine salt); 7 rats each for two lower doses of the compound, and +7 doses at 10"r/ Fourteen rats were used in the group.

**-Stenipunt for unpaired data determined by one test non-treatment vt, value significantly different from lW node inflammation 2t***-2 production example as hydrochloride! N-inch-N'-cyanoguahisinebentylamine (17,43p% 0.20 mol) was mixed with 2-propanol (
175 mg) and concentrated HCI (17 m, 0.204
After acidification with sodium dicyanamide (23 mol)
, 1S L 0.26% L). After refluxing the mixture for 20 hours, it is allowed to cool and then passed through diatomaceous earth. Concentrate solution F under vacuum and dissolve the residue in chloroform. The solution is washed with water and dried over ma magnesium. After filtering and evaporating under vacuum, 20.93 g (67
, 9%) as an off-white solid; mass 4
Preparation example 2 (N-methylguanyl)thiourea N--/thi-N'-cyanoguanidine (30,0,9
．． 0.195 mol) and diethylamine (3d) in methanol (550d). Add this solution to 40
Cool to 85°C, saturate with hydrogen sulfide gas, transfer to a stainless steel bomb, and heat at 856°C for 40 hours. 5Q sea bream (!
After expelling hydrogen hydride of 1 from the reaction θ9 compound with nitrogen gas, the solution is condensed under vacuum.

The residue was subjected to 7 column chromatography (140
silk column, chloroform containing 5% methanol). Fractions containing pure product were combined and evaporated to yield 22,0
A white solid of 11/C59, 9%) is obtained. A part is recrystallized from chloroform to obtain the substance mp9B-100@;
Mass is a cuttle: M+188° Patent applicant: Pfizer Inc. (5 others)

Claims (1)

[Claims] 1,2-guanidino-4-(2-methyl-4-imidazolyl)thiazole, 2-(N-pentyl-N'-guanidino)-4-(2-methyl-4-imidazolyl)thiazole A method for treating rheumatoid arthritis in a mammal suffering from rheumatoid arthritis, the method comprising administering to the mammal an anti-rheumatoid dose of a compound which is a compound or a pharmaceutically suitable salt thereof. 2. The method according to claim 1, wherein the route of administration is oral. 3. The compound is 2-guanidino-4-(2-methyl-4-
2. The method according to claim 1, wherein the method is imidazolyl)thiazole dihydrochloride. 4. The method according to claim 3, wherein the administration route is oral.