MXPA98002000A - Salts of addition of acid of compounds of 2,3,4,5-tetrahidro-1h-3-benzacep - Google Patents
Salts of addition of acid of compounds of 2,3,4,5-tetrahidro-1h-3-benzacepInfo
- Publication number
- MXPA98002000A MXPA98002000A MXPA/A/1998/002000A MX9802000A MXPA98002000A MX PA98002000 A MXPA98002000 A MX PA98002000A MX 9802000 A MX9802000 A MX 9802000A MX PA98002000 A MXPA98002000 A MX PA98002000A
- Authority
- MX
- Mexico
- Prior art keywords
- dichloro
- chloro
- methyl
- tetrahydro
- dihydrobenzofuran
- Prior art date
Links
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- 150000003839 salts Chemical class 0.000 title claims abstract description 29
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- 238000002360 preparation method Methods 0.000 claims abstract description 11
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Abstract
The invention a series of crystalline salts of (S) (+) - 8-chloro-5- (5,6-dichloro-2,3-dihydrobenzofura n-7-yl) -3-methyl-2,3,4, 5-tetrahydro-1H-3-benzacepin-7-ol, its preparation and use as therapeutic agents
Description
SALTS OF ADDITION OF ACID OF COMPOUNDS OF 2,3,4,5- TETRAHYDRO-1H-3-BENZACEPINE
DESCRIPTION OF THE INVENTION
The present invention relates to crystalline salts of (S) (+) - 8-chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2, 3, 4, 5-tetrahydro-lH-3-benzacepin-7-ol, its preparation and use as therapeutic agents. International patent application No. WO 93/17012 describes a class of compounds that exhibit strong antidopaminergic effects and thus make them useful in the treatment of central nervous system disorders related to dysfunctions of the dopamine D-1 receptor system, for example, psychosis, pain, depression and Parkinson's disease. In example 3 of the international application No. WO 93/17012 the preparation of (S) (+) - 8-chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) - is described 3-methyl-2, 3, 4, 5-tetrahydro-lH-3-benzacepin-7-ol of formula I:
ref: 27046
Due to its poor solubility, it is preferred that the compound of formula I be used as a therapeutic agent in the form of an acid addition salt. In addition, it has been found that some acid addition salts, of the compound of formula I, form alternative poly orphic forms. This is pharmaceutically undesirable because the potential for salts to occur in more than one crystalline form makes it very difficult to predict how different parts of the body will react to different crystalline forms. In general, for commercial use it is important to have a physiologically acceptable salt with good bioavailability, good handling properties, and a reproducible crystalline form. Surprisingly, it has now been found that a series of novel pharmaceutically acceptable acid addition salts of the compound of formula I can be obtained in a reproducible crystalline form.
Accordingly, the present invention provides a series of crystalline salts of (S) (+) - 8-chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2, 3, 4, 5-tetrahydro-lH-3-benzazepin-7-ol derived from organic acids such as fumaric, tartaric, maleic and mandelic acids. Preferred salts of the invention are (S) (+) - 8-chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2,3,4, 5- tetrahydro-lH-3-benzazepin-7-ol; semifumarate; (S) (+) -8-Chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine -7-ol, (+) - semitartrate; (S) (+) - 8-Chloro-5- (5,6-dichloro-2,3-dihydrobenzo-furan-7-yl) -3-methyl-2,3,4,5-tetrahydro-lH-3 -benzacepin-7-ol, maleate; (S) (+) - 8-Chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine -7-ol, (+) -mandelato. The acid addition salts of (S) (+) - 8-chloro-5- (5, β-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2, 3, 4, 5- tetrahydro-lH-3-benzazepin-7-ol, are prepared by dissolving the acid of the corresponding addition salt and the compound of formula I in a common solvent, and crystallizing the salt resulting from the solution. Examples of common solvents include lower aliphatic alcohols such as ethanol, methanol, 2-propanol, 2-butanol, 1-hexanol and solvents similar to isobutylmethyl ketone and tetrahydrofuran.
The present invention also provides pharmaceutical compositions comprising crystalline salts of (S) (+) - 8-chloro-5- (5, β-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2, 3 , 4,5-tetrahydro-lH-3-benzazepin-7-ol and a pharmaceutically acceptable carrier. The compositions of this invention are usually adapted for oral administration, but solution formulations for parenteral administration are also within the scope of this invention. The compounds are usually presented as a unit dose composition containing 0.01 mg - 1000 mg for oral dosing. Typical doses for the antipsychotic effect could vary between 0.1-400 mg, preferably between 1.0-200 mg per day divided into 2 or 3 doses when administered orally. Preferred unit dosage forms include solid forms, tablets or capsules, in liquid forms, solutions, suspensions, elixirs emulsions or capsules filled with them, or in the form of sterile injectable solutions. The composition of this invention can be formulated by conventional methods of galenic pharmacy. Conventional excipients are those pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral administration that do not react in a harmful manner with the active compound. Examples of such carriers are water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, syrup, peanut oil, olive oil, gelatin, lactose, alba, sucrose, agar, pectin, acacia, amylose, stearate. of magnesium, talc, silicic acid, stearic acid, monoglycerides and diglycerides of fatty acid, fatty acid esters of pentaerythritol, hydroxymethylcellulose and polyvinylpyrrolidone. The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as binders, lubricants, preservatives, disintegrants, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers and / or coloring substances and the like, that do not react in a harmful way with the active compound. For parenteral application, injectable solutions or suspensions are particularly suitable, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. For oral administration, tablets, dragees, or capsules having talc and / or a carbohydrate binder carrier or the like are particularly suitable, the carrier preferably being lactose and / or corn starch and / or potato starch. A syrup, elixir or the like may be used when it is desired to employ a sweetened vehicle. A typical tablet, which can be prepared by a conventional tableting technique, contains: Active compound 10 mg Lactosum 67.8 mg Pharma. Eur. Avicel® 31.4 mg Amberlite® IRP 88 1.0 mg Magnesium stearate 0.25 mg Pharma. Eur.
The invention also provides methods of treating certain central nervous system disorders related to dysfunctions of the dopamine D-1 receptor system, eg, psychosis, depression, pain and Parkinson's disease in mammals, including human, methods which comprises administering an effective amount of a pharmaceutically acceptable crystalline salt of (S) (+) - 8-chloro-5- (5,6-dichloro-2,3-dihydrobenzo-furan-7-yl) -3-methyl. -2, 3, 4, 5-tetrahydro-lH-3-benzacepin-7-ol. The invention further provides pharmaceutically acceptable crystalline salts of (S) (+) - 8-chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2, 3, 4, 5-tetrahydro-lH-3-benzazepin-7-ol for use in the treatment of central nervous system disorders related to dysfunctions of the system in the dopamine D-1 receptor, eg, psychosis, depression, pain and Parkinson's disease. The acid addition salts of (S) (+) - 8-chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2, 3, 4, 5- tetrahydro-lH-3-benzazepin-7-ol of the invention were synthesized and crystallized from common solvents as described in the following examples.
EXAMPLE 1
(S) (+) - 8-Chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2,3,5,5-tetrahydro-lH-3-benzazepin- 7-ol, semi-umarate
The (S) (+) - 8-chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2, 3, 4, 5-tetrahydro-lH- was dissolved. 3-benzazepin-7-ol, (7.97 g, 20 mmol) in 99% ethanol at 70 ° C. Fumaric acid (2.32 g, 20 mmol) was added. The solution was cooled to 0 ° C, and the resulting suspension was filtered. The filter cake was washed with 99% ethanol (3 x 20 ml) and dried at constant weight. Yield: 8.80 g (96%) of white crystalline product. P.f. by DSC: 298 ° C.
Elemental Analysis: (C2? H20Cl3N? O, 456.8 g / mol) Calculated: C 55.22 H 4.41 N 3.07% Found: C 55.30 H 4.55 N 3.94% Alternative polymorphic forms: None
EXAMPLE 2
(S) (+) -8-Chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2, 3,4,5-tetrahydro-lH-3-benzazepine -7-ol, L (+) -semitartrate
The preparation was carried out analogously to the preparation of Example 1 using L (+) - tartaric acid and 20 mmol of the compound of formula I. Yield: 7.75 g (82%) of white crystalline product. P.f. by DSC: 276 ° C. Elemental Analysis: (C2? H21Cl3N? 05, 473.8 g / mol): Calculated: C 53.24 H 4.47 N 2.96% Found: C 53.21 H 4.55 N 2.80% Alternative polymorphic forms: None
EXAMPLE 3
(S) (+) - 8-chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2, 3,4,5-tetrahydro-lH-3-benzazepine -7-ol, maleate The preparation of the compound was carried out analogously to the preparation of Example 1 using maleic acid, and 20 mmol of the compound of formula I. Yield: 7.61 g (74%) of white crystalline product Pf by DSC: 234 ° C Elemental Analysis: (C23H22Cl3N? 08 514.8 g / mol): Calculated: C 53.66 H 4.31 N 2.72% Found: C 53.79 H 4.37 N 2.56% Alternative polymorphic forms: None
E.JEMPLO 4
(S) { +) -8-chloro-5-. { 5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-ol, L (+) -mandelate
The preparation of the compound was carried out analogously to the preparation of Example 1 using L (+) - mandelic acid, and 20 mmol of the compound of formula I.
Yield: 10.35 g (94%) of white crystalline product. P.f. by DSC: 249 ° C. Elemental Analysis: (C27H26Cl3N5, 550.9 g / mol): Calculated: C 58.87 H 4.76 N 2.54% Found: C 58.97 H 4.88 N 2.50% Alternative polymorphic forms: None
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:
Claims (12)
1. Crystalline salts of (S) (+) - 8-chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2, 3, 4, 5-tetrahydrofo- lH-3-benzazepin-7-ol, characterized in that they are derived from fumaric acid, L (+) tartaric acid, maleic acid and L (+) - mandelic acid.
2. The crystalline salt according to claim 1, characterized in that it is (S) (+) - 8-chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2, 3, 5-tetrahydro-lH-3-benzazepin-7-ol, semifumarate; (S) (+) - 8-chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine -7-ol, L (+) -se itartrate; (S) (+) - 8-Chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine -7-ol, maleate; (S) (+) - 8-Chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2, 3,4,5-tetrahydro-lH-3-benzazepine -7-ol, L (+) -mandelato.
3. The use of a crystalline salt according to claims 1 or 2 as a medicament.
4. The use of a salt according to claims 1 or 2, for the preparation of the pharmaceutical composition for treating an indication related to dysfunctions of the dopamine D-1 receptor system.
5. A pharmaceutical composition, characterized in that it comprises a crystalline salt according to claim 1 or 2, together with a pharmaceutically acceptable carrier or diluent.
6. A pharmaceutical composition for use in the treatment of an indication related to dysfunctions of the dopamine D-1 receptor system, characterized in that it comprises an effective amount of a crystalline salt according to claim 1 or 2, together with a carrier or diluent pharmaceutically acceptable.
7. The pharmaceutical composition according to claim 5 6, characterized in that it is in the form of an oral dosage unit containing 0.1-400 mg of the active ingredients.
8. A process for the preparation of crystalline acid addition salts of (S) (+) - 8-chloro-5- (5,6-dichloro-2,3-dihydrobenzofuran-7-yl) -3-methyl-2, 3, 4, 5-tetrahydro-lH-3-benzazepin-7-ol according to any of claims 1 or 2, the process is characterized in that it comprises dissolving the acid of the corresponding addition salt and (S) ( +) -8-chloro-5- (5,6-dichloro-2,3-dihydro-benzofuran-7-yl) -3-methyl-2, 3, 4, 5-tetrahydro-lH-3-benzacepin-7 -ol in a common solvent, and crystallize the salt resulting from the solution.
9. A method for treating an indication related to dysfunctions of the dopamine D-1 receptor system, in a mammal, characterized in that it comprises administering an effective amount of a crystalline salt according to claim 1 or 2.
10. The method according to claim 9, characterized in that the indication is related to psychosis.
11. A method for treating an indication related to dysfunctions of the dopamine D-1 receptor system, in a mammal, characterized in that it comprises administering a pharmaceutical composition according to claim 5.
12. A process for the manufacture of a pharmaceutical composition to be used in the treatment of an indication related to dysfunctions of the dopamine D-1 receptor system, the process is characterized by placing a crystalline salt according to claim 1 or 2 in a galenical dosage form.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK1030/95 | 1995-09-15 | ||
| DK103095 | 1995-09-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MX9802000A MX9802000A (en) | 1998-08-30 |
| MXPA98002000A true MXPA98002000A (en) | 1998-11-12 |
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