MXPA96002767A - Dimalate of n, n-dietil-8,8-dipropil-2-azaspiro [4,5] decane-2-propanam - Google Patents

Abstract

The present invention relates to the dimaleate compound of N, N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-pr opanami

Description

DIMALATE OF N.N-DIETIL-a.a-DIPROPIL-2-AZASPIRQ ^. S3DECANO-2- PROPANAMINE This invention relates to an agen and immunomode or < improved, the dimaleate salt of N, N-die i i- &, ñ-dipro? i 1-2-aza ^ piroCU, 53tie ñno-2-propanamj na. The compound is represented by structure I: The compound of this invention is useful as an agent in a delivery, particularly in the treatment of rheumatoid arthritis.

DETAILED DESCRIPTION OF THE INVENTION La, Nd iet i 1- &, 6-d ipro i 1-2-azasp iroCW, 53decana-2-prcipanamine is a coniue that was described and claimed together with the pharmaceutically acceptable salts, hydrates and solvates thereof, for being useful as an agent: namodulator, particularly in the treatment of rheumatoid arthritis, in the US patent No. ^ t, 963, 557, whose full description is included in the present reference. Paricularly preferred among the pharmaceutically acceptable salts described in the patent of E.U.A. No. M-, 963, 557 and the only salt form prepared from it is the dihydrochloride salt. The N, N-diet i 1- & , fi-d iprop i-2-a? aspiroCl +, 53-decane-2-prc. "panama (hereafter Compound A) and the dihydrochloride salt of Compound A (di lorhideate of IM,? M- die'ci 1-ß, & -dipropi lZ-azaffiroCt, 5_decano-2-prapar.amina, hereinafter Compound B) can be prepared by methods such as those described in U.S. Pat. No. -, 963, 557. It has now been surprisingly found that the dimaleate salt of Compound A (N, N-diethyl-A, D-dipropyl-2-3-acetic acid-pyridoleate (+, 53decardo) 2-Propanamine, hereinafter Compound O has numerous advantages over dicralhydrate.Diaeate, although it is as highly soluble as dichloride, is more stable when it is stored in bulk before its manufacture, particularly before tabletting. Dihydrochloride is hygroscopic and therefore picks up moisture during storage.The diminished tendency towards the hygroscopicity of Compound C is very important because the accuracy of the or of the bulk compound for manufacturing and analytical purposes, particularly for tableting purposes, could be affected if the weight of the compound is partially attributed to the water of hydration. Thus, constant testing would be required to ensure that e is delivering the correct amount of active drug. - Dosage accuracy is particularly critical because the drug is effective in small doses. Although Compound B is highly useful as an inorganic agent, Compound C has the added advantages of the ease of its synthesis, the suitability of more accurate manufacturing procedures, particularly among the procedures of t It is hygroscopic and hygroscopic, which results in greater physical stability and easier testing of the drug content. The compound of this invention, Compound C, is useful as a 3n unmodulator agent, particularly in the treatment of rheumatoid arthritis. Compound C < active ingredient) can be administered in a conventional pre-poured dosage form by combining Compound C with a pharmaceutically acceptable carrier or diluent according to known techniques such as those described in U.S. Pat. No., 963, 557. The route of administration may be oral, parenteral or topical. The parenteral term used herein includes intravenous, intramuscular, subcutaneous, intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intrarenal routes of parenteral administration are generally preferred. The oral dosage regimen will preferably be from about 0.01 to about 10 mg / g of total body weight, more preferably from about 0.1 mg / kg to about 1 mg / kg. Preferably each oral unit dose will contain the active ingredient in an amount of approximately * >; l mg to approximately 100 mg. The daily parenteral dosage regimen will preferably be from about 0.01 to about 10 mg per kilogram (kg) of the total body weight, more preferably from about 0.1 to about 1 mg / kg. Preferably each parenteral unit dose will contain the active ingredient in an amount of about 0.1 mg to about 100 mg. The daily topical dosing regimen will preferably be from about 1 mg to about 100 mg per site of administration, the above doses refer to the preferred amount of N, N-diet i 1-y, A-dipro i 1- 2-azas iroC, 51decano-2-pro? Anamina, expressed as the free base. It will be recognized by one skilled in the art that the optimum amount and range of the individual doses of Compound C will be determined by the nature and extent of the condition as treated, the form, the route and site of administration, and the particular patient to be treated; and that such opt ionization can s > er determined by conventional techniques. It will also be appreciated by one skilled in the art that the optimum course of treatment, ie, the number of doses of Compound C given per day for a defined number of days, can be determined by those skilled in the art using conventional determination tests. of the course of treatment. Generally speaking, the compound of this invention is prepared by dissolving the base, N, N-diethyl-1-yl, fl-dipropy 1-2-aza-pyroC-, decene-2-propanamine, in an appropriate organic solvent such as acetate. of ethyl deoxygenated, with the subsequent addition of two or more equivalents of male or female. The compound of this invention is filtered and dried under vacuum or dried with air at an elevated temperature. 99% maleic acid was purchased from Aldrir. h Chemical Company, Milwaukke, Wisconsin. The following examples will further illustrate the present invention. The examples are not intended to limit the scope of the invention as defined above and as claimed later.

EXAMPLE 1 Preparation of N, N-diethyl-A, 6-diproyl-2-azas-pirof 4-, 5Ddec-2-propane dimaleate 45 g g of a crude oil of N, N-diethyl- &, d-propyl 1 -2- zp RoC +, decanter-2- ions were added containing residual solvent (purity of 69.1% by weight according to CLAR analysis, or Oß g, 1.21 mol of the pure compound) in a 3-neck glass vessel of J 2 1 under positive nitrogen pressure and equipped with an air-operated stirrer and dissolved in deoxygenated ethyl acetate (6.0 1) . Maleaic acid (261.9 g, 2.43 mol) was added to the solution with gentle stirring. The suspension was stirred at room temperature for 3 hours and then a white solid was filtered. The white solid was washed with ethyl acetate (500 ml) and dried under high vacuum for 120 hours to yield 667 g (1.17 mol, 96.7%) of the title compound. This material was ground by a cone mill (uadro) with a l & R sieve to yield 629.5 g (91.2%) of the title compound: m.p. im-14-2 ° C; JR (kBr) 3400, 3100-3000, 3000-2600, 2679, 161 + 6, 156, IS Lf, 1366, 1367, 1194, 676, and 664 cm-1; NMR (CDCla, 360 MHz) 6 0.66 (s, 6H), l.lft (s, 6H), l.?6 (m.4H), 1.33 (t, 6H, J = 7.9, 10.9 Hz), 1.52 < m,? + H), 1.93 (t, 2H, 3 = 10.0, 14.1 Hz), 2.32 (m, 2H), 3.19 (m, 6H), 3.30 (m, 2H) and 6.25 (s, 4H); i: 3 C-NMR (CDC1! 5I, 360 MHz) to 6.4, 14.9, 16.1, 20.7, 31.7, 32.5, 34.0, 35.2, 36.6, < +2.3, 46.6,? + D.7, 52.6, 52.9, 63.7, 135.7 and 169.3. Anal. Caled, for Ca8aHl + 1 »Na.-2 (Ct + Ht + 0l +) 63.35 C, 9.22 H, 4.93 N Found 63.17 C, 9.26 H, 4.92 N. The physical properties of compound B and compound C were compared EXAMPLE 2 Melting points The melting points of compound B and compound C are indicated below in table 1.

TABLE 1 Compound B 240 ~ 245 ° C dec, Compound C 141-142 ° C EXAMPLE 3 Hygroscopic character The moisture absorption rate of compound B and compound C were individually tested in an Integrated Microbalance System, MODEL MB 300 S (VTI Corpora ion, Hialeah, Florida), using the attached software manual. The two compounds were analyzed under identical parameters as indicated below in Table 2 (a). For comparison purposes, the results of both compounds are summarized below in Table 2 (b).

TABLE 2 (a) Parameters established for Compounds B and C in the Integrated Microbalance System Sample weight: Approx. 10 mg Drying temperature: 60 ° C Heating speed: 10 ° C / min Balance criterion, p .: 6 Ug Balance criterion,% g.p .: 200% g.p. Balance criterion, time: 240 min Sample interval: 2 min Exp. Temperature: 25 ° C% relative humidity, start: 10%% relative humidity, max. : 100%% relative humidity, range: 5% Balance criterion, g.p .: 6 Ug Sample interval: 2 min Interruption: 0% relative humidity Data collection interval: 3 min.

TABLE 2 (b) Moisture absorption Humidity Point Compound B Compound C data Relative No.% gain% gain% weight weight 1 0 0 0 2 10 0.20 -0.21 3 1 155 1 1..6611 -0.16 4 20 2.17 -0.06 5 25 2.64 -0.12 6 30 3.74 -0.06 7 35 3.15 -0.06 6 6 4 400 3 3..3300 -0.06 9 45 1 + .74 -0.05 50 5.1 + 9 -0.04 11 55 9.07 0.04 12 60 9.26 0.1 1 133 6 655 9 9..5500 0.16 14 70 15.47 0.41 75 31.30 0.56 16 60 36.53 0.69 17 65 44.16 1.70 1 166 9 900 - 5.37 19 95 _ 4-2.66 EXAMPLE »+ Relative solubilities The solubilities of compound B and compound C were determined in three different systems: water, 0.1 HCl and anol. The data is summarized in Table 3 below.

TABLE 3 Solvent Compound B mg / ml Compound C mg / ml HCl 0.1% > 100 -: 100 Metanal 100 > 100 The present invention includes within its scope the pharmaceutical compositions comprising Compound C as an active ingredient, in association with a pharmaceutically acceptable carrier or diluent. The compound of this invention can be administered by oral or parenteral routes of administration and can be formulated into appropriate dosage forms for each route of administration including capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert diluent such as sucrose, lactose or starch. The odosage forms may also comprise, as is normal practice, the addition of other substances than inert diluents, for example, lubricating agents such as magnesium stearate, glidants such as colloidal silicon dioxide, antioxidants such as butylated hydizoxytoluene. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can also be prepared for sustained release or can be prepared with enteric layers. Preparations according to this invention for parenteadministration include sterile aqueous solutions although non-aqueous suspensions or emulsions may be employed. Such dosage forms may also contain adjuvants such as preservatives, wetting agents, osmotic agents, buffering agents, emulsifiers and dispersants. They can be sterilized, for example, by filtration through a bacteria retainer filter, by incorporating sterilizing agents into the composition, by irradiating the compositions or by heating the compositions. The following examples will further illustrate the pharmaceutical compositions that are characteristic of this invention.

EXAMPLE 5 Composition of the tablet Lactose, cellulose micronella pill, sodium glycolate-starch, magnesium stearate and compound C are mixed in the proportions shown below in Table 4. The mixture is then compressed to form the tablets.

TABLE 4 Ingredient mg Dimaleate of N, N-die-6,6-dipropyl-2- 6.45 zas? IroC .53decano-2-prapane ina Cellulose my rocrystalline 1J2 Lactose 70 Sodium glycolate-starch 6 Magnesium stearate 2 EXAMPLE 6 Parental injectable composition An injectable form for the administration of Compound C ee is produced by stirring 5.0 mg of N, N-diethyl-l, 6,6-diproyl-2-azaspiroC4.5D-2-pro? Anami dimaleate in 1.0 ml of saline solution. normal.

Although the above illustrates preferred embodiments of the invention, it is understood that the invention is not limited to the precise structures described herein and reserves the right to all modifications that are within the scope of the following claimed ions.

Claims (4)

NEWS OF THE INJECTION CLAIMS

1. - The dimaleate compound of N, N-d ie i 1-6,6-di-il-2-azaspiraf .51 of non-2-propane ina.

2. A pharmaceutical composition comprising the di aleate of N, N-diet i 1-6, -di prop i l-2- a? > piroL "4-.53 decano-2-propanamine and a pharmaceutically acceptable carrier or diluent 3.- A method of induction of unmodulation comprising the administration of an effective immunomodulatory amount of N, Nd and 1-6,6- dimaleate dipropi 1-2-azaf-piroC4.51ldecano-2-propanami.na to Ltn patient who needs such treatment 4.- The method according to claim 3, further characterized in that the patient needs treatment for rheumatoid arthritis.