|Title of Invention||
"N,N-DIETHY-8, 8-DIPROPYL-2-AZASPIRO[4,5] DECANE-2-PROPANAMINE DIMALEATE"
|Abstract||The compound N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine dimaleate.|
|Full Text||This invention relates to an improved immunomodulatofy agent, the dimaleate salt of N,N-diethyl-8,8-dipropyl-2-azaspko[4.5]decarje-2-propanainine. The compound is represented by Structure I:
The compound of this invention is useful as an immunorjnodulatory agent, particularly in the treatment of rheumatoid arthritis.
Detailed Description of the Invention
N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine is a compound which is disclosed and claimed, along with pharmaceutically acceptable salts, hydrates and solvates thereof, as being useful as an immunomodulatory agent, particularly in the treatment of rheumatoid arthritis, in U.S. Patent No. 4,963,557, the entire disclosure of which is hereby incorporated by reference. Particularly preferred among the pharmaceutically acceptable salts described in U.S. Patent No. 4,963,557 and the only salt form prepared therein is the dihjdrqchloride sajj. N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine (hereinafter Compound A) and the dihydrochloride salt of Compound A (N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine dihydrochloride - hereinafter Compound B) can be prepared by methods such as described in U.S. Patent No. 4,963,557.
It has now surprisingly been found that the dimaleate salt form of Compound A (N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-z-propanamine dimaleate -hereinafter Compound C) has numerous advantages over the dihydrochloride. The dimaleate, while being as highly soluble as the dihydrochloride, is more stable when stored in bulk prior to manufacture, particularly prior to tableting. The dihydrochloride is hygroscopic and thus picks up moisture upon storage. The lessened tendency toward hygroscopicity of Compound C is very important because the accuracy of weighing out bulk compound for manufacturing and analytical purposes, particularly for tableting purposes, would be affected if the compound's
weight is partially attributable to water of hydration. Thus, constant assaying would
be required to ensure that the proper amount of active drug is provided. Dose
accuracy is particularly critical since the drug is effective in small dosages.
While Compound B is highly useful as an immunomodulatory agent,
Compound C has the added advantages of ease of synthesis, lends itself to more
accurate manufacturing procedures, particularly tableting procedures, and is far less
hygroscopic which results in greater physical stability and greater ease of assaying
The compound of this invention, Compound C, is useful as an
immunomodulatory agent, particularly in the treatment of rheumatoid arthritis.
Compound C (active ingredient) can be administered in a conventional dosage form
prepared by combining Compound C with a conventional pharmaceutically
acceptable carrier or diluent according to known techniques, such as those described
in U.S. Patent No. 4,963,557. The route of administration may be oral, parenteral or
topical. The term parenteral as used herein includes intravenous, intramuscular,
subcutaneous, intranasal, intrarectal, intravaginal or intraperitoneal administration.
The subcutaneous and intramuscular forms of parenteral administration are generally
preferred. The daily oral dosage regimen will preferably be from about 0.01 to
about 10 mg/kilogram of total body weight, most preferably from about 0.1 mg/kg to
about 1 mg/kg. Preferably each oral dosage unit will contain the active ingredient in
an amount of from about 0.1 mg to about 100 mg. The daily parenteral dosage
regimen will preferably be from about 0.01 to about 10 mg per kilogram (kg) of total
body weight, most preferably from about 0.1 to about 1 mg/kg. Preferably each
parenteral dosage unit will contain the active ingredient in amount of from about 0.1
mg to about 100 mg. The daily topical dosage regimen will preferably be from
about 1 mg to about 100 mg per site of administration. The above dosages relate to
the preferred amount of N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-
propanamine expressed as the free base. It will be recognized by one of skill in the
art that the optimal quantity and spacing of individual dosages of Compound C will
be determined by the nature and extent of the condition being treated, the form, route
and site of administration, and the particular patient being treated, and that such
optimums can be determined by conventional techniques. It will also be appreciated
by one of skill in the art that the optimal course of treatment, i.e., the number of
doses of Compound C given per day for a defined number of days, can be
ascertained by those skilled in the art using conventional course of treatment
Generally speaking, the compound of this invention is prepared by dissolving
the base, N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine, in an
appropriate organic solvent, such as deoxygenated ethyl acetate, with subsequent
addition of two or more equivalents of maleic acid. The compound of this invention
is filtered off and dried in vacuo or air dried at an elevated temperature.
Maleic acid, 99%, is purchased from the Aldrich Chemical Company,
The following examples further illustrate the present invention. The
examples are not intended to limit the scope of the invention as defined hereinabove
and as claimed below.
Preparation of N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine
N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine, 458 g of a
crude oil containing residual solvent (89.1% by weight pure by HPLC analysis or
408 g, 1.21 mol of pure compound) was placed in a 12 L, 3-necked glass vessel
under positive nitrogen pressure and equipped with an air driven stirrer and
dissolved in deoxygenated ethyl acetate (6.9 L). Maleic acid (281.9 g, 2.43 mol) was
added to the vigorously stirring solution. The slurry was stirred at ambient
temperature for 3 hours then a white solid was filtered off. 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 milled
through a cone mill (Quadro) with an 18R sieve to yield 629.5 g (91.2 %) of the title
compound: mp 141-142 °C; IR(KBr)3400, 3100-3000, 3000-2800,2679,1646,
1584,1504, 1386,1367,1194, 876, and 864 cm'1; NMR (CDCls, 360 MHz) 6 0.88
(s, 6H), 1.18 (s, 8H), 1.26 (m, 4H), 1.33 (t, 6H, J = 7.9,10.9 Hz), 1.52 (m, 4H), 1.93
(t, 2H, J = 10.0, 14.1 Hz), 2.32 (m, 2H), 3.19 (m, 6H), 3.30 (m, 2H), and 6.25 (st
4H); 13C-NMR (CDC13, 360 MHz) 8 8.4,14.9,16.1,20.7, 31.7, 32.5, 34.0, 35.2,
38.8,42.3,46.6,48.7,52.6,52.9, 63.7, 135.7, and 169.3. Anal. Calcd for
C22H44N2 - 2(C4H404) 63.35 C, 9.22 H, 4.93 N found 63.17 C, 9.28 H, 4.92 N.
The physical properties of Compound B and Compound C were compared.
The melting points of Compound B and Compound C are indicated in Table
The rate of moisture absorption of Compound B and Compound C were
tested individually in an Integrated Microbalance System, MODEL MB 300 G (VTI
Corporation, Hialeah, Florida) using the accompanying Software Manual. The two
compounds were analyzed under identical parameters, as indicated in Table 2(a)
below. For comparison purposes the results of both compounds are summarized in
Table 2(b) below.
The solubilities of Compound B and Compound C were determined in three
different systems: water, 0.1 HCI and methanol. The data are summarized in Table 3
(Table 2b Removed)
The solubilities of Compound B and Compound C were determined in three different systems: water, 0.1 HCI and methanol. Teh data are summarized in Table 3 below.
The present invention includes within its scope pharmaceutical compositions
comprising Compound C, as the active ingredient, in association with a
pharmaceutically acceptable carrier of diluent. The compound of this invention can
be administered by oral or parenteral routes of administration and can be formulated
in dosage forms appropriate for each route of administration including capsules,
tablets, pills, powders and granules. In such solid dosage forms, the active
compound is admixed with at least one inert diluent such as sucrose, lactose or
starch. The oral dosage forms can also comprise, as is normal practice, addition
substances other than inert diluents, e.g., lubricating agents such as magnesium
stearate, glidants such as colloidal silicone dioxide, antioxidants such as butylated
hydizoxy toluene. In the case of capsules, tablets and pills, the dosage forms may
also comprise buffering agents. Tablets and pills can additionally be prepared for a
sustained release or may be prepared with enteric coatings.
Preparations according to this invention for parenteral administration include
sterile aqueous solutions although nonaqueous suspensions of emulsions can be
employed. Such dosage forms may also contain adjuvants such as preserving,
wetting, osmotic, buffering, emulsifying and dispersing agents. They may be
sterilized by, for example, filtration through a bacteria retaining filter, by
incorporating sterilizing agents into the compositions, irradiating the compositions
or by heating the compositions.
The following examples further illustrate the pharmaceutical compositions
which are a feature of this invention.
Lactose, microcrystalline cellulose, sodium starch glycolate, magnesium
stearate and Compound C are blended in the proportions shown in Table 4 below.
The blend is then compressed into tablets.
Injectable Parenteral Composition
An injectable form for administering Compound C is produced by stirring
5.0 mg. of N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine
dimaleate in 1.0 ml. of normal saline.
While the preferred embodiments of the invention are illustrated by the
above, it is to be understood that the invention is not limited to the precise
instructions herein disclosed and that the right to all modifications coming within the
scope of the following claims is reserved.
1. The compound N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-
dimaleate for use in therapy.
dimaleate for use in inducing an immunomodulatory effect in
4. N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine dimaleate for use in the treatment of rheumatoid arthritis
|Indian Patent Application Number||1557/DEL/1996|
|PG Journal Number||30/2008|
|Date of Filing||12-Jul-1996|
|Name of Patentee||ANORMED INC.|
|PCT International Classification Number||A61P 37/02|
|PCT International Application Number||N/A|
|PCT International Filing date|