HK1071133B - Citric acid salt of a therapeutic compound and pharmaceutical compositions thereof - Google Patents

Description

Citrate salts of therapeutic compounds and pharmaceutical compositions thereof

The present invention relates to polymorphs of the citrate salt of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholine 3-one of the formula:

the compound 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene]The thiomorpholin-3-one is 5-hydroxytryptamine-1D (5-HT)_1D) Receptor antagonists and are useful in the treatment of a number of conditions, diseases and disorders of the central nervous system. The compounds are particularly useful in the treatment of the following diseases in mammals, particularly humans: hypertension, all forms of depression, depression in cancer patients, depression in parkinson's disease patients, post-myocardial infarction depression, sub-syndrome symptomatic depression (subsyndromal depressive disorder), depression in infertile women, infantile depression, major depressive disorder, individual episode depression, recurrent depression, child abuse induced depression, post partum depression (post partum depression), thymic dysfunction; mild, moderate, or major depression with or without atypical features, melancholic features, psychiatric features, stress features; seasonal affective disorder, depression in the middle and old aged, chronic depression; adjustment disorders with depressed mood or with anxiety and depressed mood; mixed anxiety and depression; substance-induced affective disorders; and affective disorders secondary to general medical conditions, bipolar disorder-depressive phase, general anxiety disorder, phobias, agoraphobia, social anxiety, social phobia, simple phobia, separation anxiety disorder, post-traumatic stress response syndrome, avoidant personality disorder, premature ejaculation, eating disorder, binge eating disorder, anorexia nervosa, bulimia nervosa, obesity; chemical dependence and addiction to alcohol, cocaine, heroin, phenobarbital, nicotine, marijuana, and benzodiazepines; cluster headacheMigraine, pain, alzheimer's disease, obsessive-compulsive disorder, panic disorder with agoraphobia, memory disorders, dementia, amnesia and age-related cognitive decline (ARCD), parkinson's disease dementia, neuroleptic-induced parkinsonism and tardive dyskinesia, endocrine disorders, hyper-prolactin, vasospasm, cerebral vasculature vasospasm, cerebral ataxia; gastrointestinal disorders, including altered motility and secretion; negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress urinary incontinence, tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer, small cell lung cancer, chronic migraine attacks, headache associated with vascular disease, autism, generalized central nervous system delay of development, Asperger's disorder, selective mutism, chronic motor or vocal tic disorder, somatization disorder, insomnia, intermittent explosive disorder, pyromania, pathological gambling, impulse-control disorder, premenstrual dysphoric disorder, and attention deficit/hyperactivity disorder (ADHD). The citrate salts of the present invention may also be used in pharmaceutical compositions in combination with a 5-hydroxytryptamine reuptake inhibiting antidepressant (SRI) in order to treat many of these diseases.

WO 98/14433 published at 9/4/1998 (corresponding to U.S. application Ser. No. 09/254,999,2000 filed at 12/8/1997, 09/733346 filed at 12/8/2001, and PCT/IB01/02139 filed at 11/12/2001) relates to compounds which are 5-hydroxytryptamine-1D receptor antagonists, including 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one, particularly the hydrochloride salt thereof. The above applications, which are the same as the present application and are incorporated herein by reference in their entirety, generally describe pharmaceutically acceptable acid addition salts of the compounds referred to therein.

The citrate salt of the present invention exhibits the following characteristics: including solid state stability and compatibility with certain pharmaceutical product formulating excipients, which make them superior to the above-mentioned known salts of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one.

Brief Description of Drawings

FIG. 1 is a Differential Scanning Calorimetry (DSC) trace (trace) of the citrate salt of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one.

FIG. 2 is an X-ray powder diffraction pattern of the citrate salt of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one observed (y-axis is linear counts per second; X-axis is 2 θ in degrees).

FIG. 3 is a calculated X-ray powder diffraction pattern of the citrate salt of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one (y-axis is linear counts per second; X-axis is 2 θ in degrees).

FIG. 4 is an X-ray crystal structure of the citrate salt of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one.

FIG. 5 is 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene as determined by cross-polarized magic angle spin (CPMAS) using a Bruker 7mm wide aperture magic angle spin (WBMAS) probe in a Bruker Avance DRX 500MHz NMR spectrometer at 295K]Process for preparing (E) -thiomorpholin-3-one citrate¹³C NMR spectrum.

Summary of The Invention

The present invention relates to the citrate salt of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one. The citrate salt of the present invention is an anhydrous or near anhydrous polymorph.

This citrate salt of the invention is also characterized by the major X-ray diffraction pattern peaks expressed in terms of 2 theta and d-spacing (within the error limits shown) as measured using copper radiation:

angle 2 theta (± 0.2)	d-spacing (_) (+ -0.2)
		13.0	6.8
17.4	5.1
		18.0	4.9
18.9	4.7
		20.0	4.4
21.2	4.2
		22.2	4.0
24.0	3.7
		27.1	3.3
32.4	2.8

The compounds of the invention have the following X-ray diffraction patterns, which are characterized primarily by: an X-ray diffraction pattern peak with a 2 θ of about 17.4 as measured using copper radiation.

The compounds of the invention have the following X-ray diffraction patterns, which are characterized primarily by: an X-ray diffraction pattern peak with a 2 θ of about 20.0 as measured using copper radiation.

The compounds of the invention have the following X-ray diffraction patterns, which are characterized primarily by: x-ray diffraction pattern peaks at 2 θ of approximately 17.4 and 20.0 as measured using copper radiation.

The citrate salt of the present invention is characterized in that it is generally formed into a sheet. In addition, the citrate is characterized in that it forms monoclinic crystals belonging to the Pc space group. The citrate salt is also characterized as having a melting/decomposition point as determined by Differential Scanning Calorimetry (DSC) that begins at about 198-. In addition, the citrate salt of the present invention is also characterized by having a water solubility of 1.3mg/ml and a natural pH of 3.37 in aqueous solution. In addition, the citrate salt has a hygroscopicity of about 1.27% at 90% relative humidity.

The citrate salt of the present invention is also characterized by the solid state when used¹³When examined by the C NMR cross-polarized magic angle spinning method, it shows the following major resonance peaks (. + -. 0.1 ppm; relative to 29.5ppm adamantane standard) in a low field, in 100 parts per million: δ 179.3, 177.0, 171.6, 164.0, 151.0 and 144.1.

The compounds of the invention are characterized by the fact that they are in the solid state when used¹³When examined by the C NMR cross-polarized magic angle spinning technique, it shows the following main resonance peaks: delta 179.3.

The compounds of the invention are characterized by the fact that they are in the solid state when used¹³When examined by the C NMR cross-polarized magic angle spinning technique, it shows the following main resonance peaks: δ 177.0.

The compounds of the invention are characterized by the fact that they are in the solid state when used¹³When examined by the C NMR cross-polarized magic angle spinning method, it shows the following main resonance peaks: δ 171.6.

Another embodiment of the present invention relates to a pharmaceutical composition comprising the citrate salt of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one and a pharmaceutically acceptable carrier or excipient, in particular to the use of the pharmaceutical composition for the treatment of the following diseases in mammals, preferably humans: hypertension, all forms of depression, depression in cancer patients, depression in parkinson's disease patients, post-myocardial infarction depression, sub-syndrome symptomatic depression (subsyndromal depressive disorder), depression in infertile women, infantile depression, major depressive disorder, individual episode depression, recurrent depression, child abuse induced depression, post partum depression (post partum depression), thymic dysfunction; mild, moderate, or major depression with or without atypical features, melancholic features, psychiatric features, stress features; seasonal affective disorder, depression in the middle and old aged, chronic depression; adjustment disorders with depressed mood or with anxiety and depressed mood; mixed anxiety and depression; substance-induced affective disorders; and affective disorders secondary to general medical conditions, bipolar disorder-depressive phase, general anxiety disorder, phobias, agoraphobia, social anxiety, social phobia, simple phobia, separation anxiety disorder, post-traumatic stress response syndrome, avoidant personality disorder, premature ejaculation, eating disorder, binge eating disorder, anorexia nervosa, bulimia nervosa, obesity; chemical dependence and addiction to alcohol, cocaine, heroin, phenobarbital, nicotine, marijuana, and benzodiazepines; cluster headache, migraine, pain, alzheimer's disease, obsessive-compulsive disorder, panic disorder with agoraphobia, memory disorders, dementia, amnesia and age-related cognitive decline (ARCD), parkinson's disease dementia, neuroleptic-induced parkinsonism and tardive dyskinesia, endocrine disorders, hyper-prolactin, vasospasm, cerebral ataxia; gastrointestinal disorders, including altered motility and secretion; negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress urinary incontinence, tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer, small cell lung cancer, chronic migraine attacks, headache associated with vascular disease, autism, generalized central nervous system delay of development, Asperger's disease, selective mutism, chronic motor or vocal tic disorders, somatization disorders, insomnia, intermittent explosive disorders, pyromania, pathological gambling, impulse-control disorders, premenstrual dysphoric disorder, and attention deficit/hyperactivity disorder (ADHD).

The present invention also relates to a method of treatment of a mammalian, preferably human, disease which comprises administering to a subject in need thereof a citrate salt of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one, said disease being: hypertension, all forms of depression, depression in cancer patients, depression in parkinson's disease patients, post-myocardial infarction depression, sub-syndrome symptomatic depression (subsyndromal depressive disorder), depression in infertile women, infantile depression, major depressive disorder, individual episode depression, recurrent depression, child abuse induced depression, post partum depression (post partum depression), thymic dysfunction; mild, moderate, or major depression with or without atypical features, melancholic features, psychiatric features, stress features; seasonal affective disorder, depression in the middle and old aged, chronic depression; adjustment disorders with depressed mood or with anxiety and depressed mood; mixed anxiety and depression; substance-induced affective disorders; and affective disorders secondary to general medical conditions, bipolar disorder-depressive phase, general anxiety disorder, phobias, agoraphobia, social anxiety, social phobia, simple phobia, separation anxiety disorder, post-traumatic stress response syndrome, avoidant personality disorder, premature ejaculation, eating disorder, binge eating disorder, anorexia nervosa, bulimia nervosa, obesity; chemical dependence and addiction to alcohol, cocaine, heroin, phenobarbital, nicotine, marijuana, and benzodiazepines; cluster headache, migraine, pain, alzheimer's disease, obsessive-compulsive disorder, panic disorder with agoraphobia, memory disorders, dementia, amnesia and age-related cognitive decline (ARCD), parkinson's disease dementia, neuroleptic-induced parkinsonism and tardive dyskinesia, endocrine disorders, hyper-prolactin, vasospasm, cerebral ataxia; gastrointestinal disorders, including altered motility and secretion; negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress urinary incontinence, tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer, small cell lung cancer, chronic migraine attacks, headache associated with vascular disease, autism, generalized central nervous system delay of development, Asperger's disorder, selective mutism, chronic motor or vocal tic disorder, somatization disorder, insomnia, intermittent explosive disorder, pyromania, pathological gambling, impulse-control disorder, premenstrual dysphoric disorder, and attention deficit/hyperactivity disorder (ADHD).

The present invention also relates to a process for the preparation of the citrate salt of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one comprising the steps of:

(i) contacting 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one in a suitable solvent with citric acid; and

(ii) the crystals formed were collected.

In a preferred embodiment, said suitable solvent is selected from (C)₁-C₆) Alkanol, (C)₁-C₆) Alkyl ketone or (C)₁-C₆) Alkyl ethers. More preferably, the suitable solvent is 2-propanol. In the process of the invention, preference is given to using 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene in the solution phase]-thiomorpholin-3-one is contacted with a citric acid solution to carry out the contacting step (i). More preferably by adding solid citric acid to 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene]-thiomorpholin-3-one in solution.

Preferably, the contacting step is carried out for 1 to 24 hours, more preferably 10 to 20 hours, and this step comprises stirring or mixing the resulting mixture. In a preferred embodiment of the process, step (i) is carried out at ambient temperature-the reflux temperature of the solvent; more preferably at ambient temperature-the reflux temperature of 2-propanol, i.e. about 80 ℃; most preferably the process is carried out at 30-60 ℃. Preferably, once the step of adding citric acid is complete, the reaction mixture is cooled to ambient temperature and the remaining reactants are stirred for a period of time.

The invention also relates to the citrate salt of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one prepared according to the process of the invention.

Detailed Description

The compound 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene]The thiomorpholin-3-one is 5-hydroxytryptamine-1D (5-HT)_1D) Receptor antagonists and are useful in the treatment of a number of CNS disorders, diseases and conditions. The free base of this compound and its hydrochloride salt can be prepared as described in international patent publication No. WO 98/14433, published on 9/4 of 1998, the entire contents of which are incorporated herein by reference.

The citrate salt may be prepared under a variety of different conditions. However, according to the invention, preference is given to using 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene]The free base of thiomorpholin-3-one is dissolved in a suitable solvent until complete dissolution, whereupon citric acid is added to the solution thus prepared to form the citric acid addition salt of the present invention. Preferably said suitable solvent is selected from (C)₁-C₆) Alkanol, (C)₁-C₆) Alkyl ketone or (C)₁-C₆) Alkyl ethers; more preferably (C)₁-C₆) An alkanol; most preferred is 2-propanol. In the process of the invention, preference is given to using 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene in the solution phase]-thiomorpholin-3-one is contacted with citric acid in solution or in solid form to carry out the contacting step (i).

Preferably, the contacting step is carried out for 1 to 24 hours, more preferably 10 to 20 hours, and this step comprises stirring or mixing the resulting mixture. In a preferred embodiment of the process, step (i) is carried out at ambient temperature-the reflux temperature of the solvent; more preferably at ambient temperature-the reflux temperature of 2-propanol, i.e. at about 80 ℃; most preferably the process is carried out at 30-60 ℃. Preferably, once the step of adding citric acid is complete, the reaction mixture is cooled to ambient temperature and the remaining reactants are stirred for a period of time.

The citrate salt of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one is only slightly hygroscopic and has high water solubility. The combination of these properties with their relative inertness to common excipients used in pharmaceutical formulations makes it highly suitable for pharmaceutical formulation applications.

Although the generally known acid addition salts of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one are crystalline, most of these salts are hygroscopic making them difficult candidates for pharmaceutical formulation applications. The citrate salt of the present invention exhibits a hygroscopicity of about 1.27% wt/wt when contacted with a relative humidity of 90% in a humidity chamber. The citrate has a water solubility of 1.3mg/ml at a pH of 3.37. In addition, the citrate salt of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one exhibits excellent solid state stability under light and high temperature and humidity.

Differential scanning calorimetry

The solid state thermal properties of the citrate salt of the present invention were studied by Differential Scanning Calorimetry (DSC). The trace (trace) of the salt is shown in figure 1. Using a Mettler Toledo DSC 821^e(STAR^eSystem) obtained DSC thermograms. Generally, 1-10mg samples were prepared using a crimped aluminum pan with small pinholes. The measurement is carried out at a heating rate of 5 ℃/min in the range of 30-300 ℃.

As shown in fig. 1, the citrate salt begins a melting transition at about 198-. However, the person skilled in the art notes that in DSC measurements there is a certain degree of variability in the starting values of the actual measurement and the peak temperatures which occur depending on the rate of heating, the crystal form and the purity and other measurement parameters.

X-ray powder diffraction pattern

Using CuK with copper radiation_αFixed slits (1.0, 0.6mm) and Kevex solid state detectorAn X-ray powder diffractogram of the citrate salt of the invention was taken with a Bruker D5000 diffractometer (Bruker AXS, Madison, Wisconsin). Data was collected from 3.0-40.0 degrees 2 θ using a step size of 0.04 degrees and a step time of 1.0 second.

X-ray powder diffraction pattern measurements of this citrate were performed using a copper anode (relative intensity: 0.500) with wavelength 1 at 1.54056 and wavelength 2 at 1.54439. The 2 theta range is 3.0-40.0 degrees, the step size is 0.04 degrees, the step time is 1.00 seconds, the smoothing width is 0.300 and the threshold is 1.0.

Diffraction peaks at diffraction angles (2 θ) measured in an X-ray powder diffraction analysis of the salt are shown in table I. However, the relative intensities may vary depending on the crystal size and morphology. The actually measured powder diffractogram is shown in FIG. 2.

Table i X-ray powder diffraction pattern of citrate with diffraction line intensity and peak position.

2 theta angle	d-value (_)	I (relative)	2 theta angle	d-value (_)	I (relative)	2 theta angle	d-value (_)	I (relative)
									8.2	10.7	3.7	23.1	3.9	13.6	32.4	2.8	18.6
11.5	7.7	4.9	24.0	3.7	33.5	32.8	2.7	7.4
									13.0	6.8	14.5	24.7	3.6	5.3	33.6	2.7	3.3
13.7	6.5	5.6	25.1	3.5	9.9	34.5	2.6	6.3
									14.9	5.9	9.8	26.2	3.4	6.9	34.9	2.6	4.7
16.3	5.4	7.0	26.6	3.4	11.2	35.8	2.5	4.1
									16.6	5.3	13.1	27.1	3.3	20.4	36.3	2.5	7.5
17.4	5.1	100.0	27.7	3.2	6.2	36.8	2.4	4.3
									18.0	4.9	40.2	28.3	3.2	6.3	37.3	2.4	5.7
18.9	4.7	17.3	29.6	3.0	10.7	38.3	2.4	6.3
									20.0	4.4	71.6	30.4	2.9	8.3	38.9	2.3	4.3
21.2	4.2	23.4	31.0	2.9	3.4
									22.2	4.0	20.0	31.6	2.8	2.8

The 2 theta, d-spacing and relative intensities and peak positions of the X-ray powder diffraction patterns of representative citrate salts are listed in table II. The numbers listed are computer generated.

Table ii X-ray powder diffraction intensities and peak positions for representative citrate salts.

2 theta angle	d-value (_)	I (relative)
			13.0	6.8	14.5
17.4	5.1	100.0
			18.0	4.9	40.2
18.9	4.7	17.3
			20.0	4.4	71.6
21.2	4.2	23.4
			22.2	4.0	20.0
24.0	3.7	33.5
			27.1	3.3	20.4
32.4	2.8	18.6

Single crystal X-ray analysis

Single crystals of the citrate salt of the present invention were obtained and studied by X-ray diffraction. Representative crystals were observed and a 1_ data set (max sin θ/λ ═ 0.5) was collected using a Siemens R4RA/v diffractometer. FromInternational Tables for X-Ray CrystallographyAtomic scattering factors were obtained from Vol.I.V, pp.55, 99, 149 (Birmingham: Kynoch Press, 1974). The X-ray powder diffraction pattern was calculated from the data collected for the single crystal to provide a comparison with the actually measured diffraction pattern.

The structure was resolved using a direct method. SHELXTL supplied by Bruker AXS, Inc^TMComputer libraries facilitate all the requisite crystallographic calculations and molecular display (SHELXTL)^TMReference Manual, Version 5.1, Bruker AXS, Madison, Wis 1997). The relevant crystals, data acquisition and processing are summarized in table III.

The test structures were obtained by direct methods and then processed by conventional means. The hydrogen location is calculated if possible. Methyl hydrogens and hydrogens on nitrogen and oxygen were located by difference fourier method. Hydrogen parameters were added to the structure factor calculation, but no processing was performed. Respective criteria for calculated displacements less than 0.1 in the final cycle of least squares machiningAnd (4) deviation. The final R-index was 4.72%. The final difference fourier method showed no missing or misplaced electron density. Using SHELXTL^TMThe drawing software package draws the processing structure and is shown in fig. 4.

The atomic coordinates (x 10) of the salt are listed in Table IV⁴) And equivalent isotropic substitution parameter (\ u)²x10³). The bond length [ \ u observed for the citrate salt is listed in Table V]Angle of harmony [ °]. In Table VI, the anisotropic substitution parameter (\\ u) of the citrate salt is listed²x10³) In order to calculate an anisotropic substitution factor index having the formula: -2 pi²[h²a^*2U₁₁+...+2hka^*b^*U₁₂]. Finally, the hydrogen coordinates (x 10) of the salts are listed in Table VII below⁴) And isotropic substitution parameter (\ u)²x10³)。

Table iii crystal structure data and measurement parameters of said citrate salt

Parameter(s)	Citric acid salt
		Empirical formula weight temperature wavelength crystal system space group unit cell size	CHNOSClCHO640.52293(2)K1.54178_ monoclinic Pca (6.5940 (10) _ α (90 °))

Bulk Z density (calculated) absorption coefficient F (000) crystal size collected reflection independent reflection θ degree of completeness 49.98 ° absorption corrected process data/constraints/parameters using FGoodness of fit final R index [ | > ε (I)]Maximum diffraction peak and cavity of extinction coefficient of absolute structural parameter

b＝15.257(2)_β＝101.440(10)°c＝15.099(2)_γ＝90°1488.9(4)_21.429Mg/m3.081mm6680.24x0.04x0.04mm17071707[R(int)＝0.0000]100.0% of no use FFull matrix least squares 1707/0/3911.065R 1-0.0472 wR 2-0.1028-0.01 (3)0.0038(6)0.223 and-0.268 e

Table iv. atomic coordinates (x 10) of the citrate salt⁴) And equivalent isotropic substitution parameter (\ u)²x10³). (U defines (eq) as orthogonal U_ijOne third of the tensor trace. )

	x	y	x	U(eq)
					S(1X)CI(1X)CI(2X)N(1)C(2)C(3)N(4)	1 6007950(8)11404(8)8720(15)9164(19)7216(19)6189(14)	3502(2)4063(2)2613(2)1936(5)2836(7)3358(7)3417(5)	840113244(3)13403(3)6037(6)5723(7)5475(7)6246(5)	53(1)83(1)73(1)42(2)50(3)48(3)37(2)

C(5)C(6)C(7)C(8)C(9)C(10)C(11)C(12)C(13)C(14)C(15)N(16)C(17)C(18)C(19)C(20)C(21)C(22)C(23)C(24)C(25)C(26)C(1X)O(2X)O(3X)C(4X)C(5X)O(6X)C(7X)O(8X)O(9X)

5665(19)7568(18)4480(17)3464(19)1780(20)1145(19)2141(19)3874(17)5020(16)4255(15)5686(18)5221(14)3520(20)1591(19)6643(17)8123(17)9521(19)9542(18)8029(19)6611(19)7262(14)10622(18)10057(19)11060(17)10378(16)8610(18)6358(19)5754(14)6105(16)5421(15)6600(14)

2527(6)1994(7)4015(6)4335(7)4884(8)5140(7)4849(7)4282(6)4044(6)3731(6)3625(7)3032(5)2409(8)2834(8)2904(7)2257(7)2151(7)2713(7)3353(7)3453(7)4069(6)1388(7)-243(7)-820(6)-38(6)320(6)214(6)-675(5)491(8)-95(6)1254(5)

6513(7)6786(6)6160(6)5318(7)5270(8)6041(9)6862(7)6954(6)7850(6)8528(6)9400(7)10007(5)9721(10)9378(8)10837(6)10928(7)11710(7)12428(7)12367(6)11563(7)9602(5)6296(8)3822(8)3541(6)4658(6)3209(6)3317(7)3152(5)4257(6)4709(5)4507(5)

44(3)41(3)34(3)45(3)57(4)55(3)47(3)36(3)35(3)32(3)41(3)38(2)77(4)58(3)33(3)40(3)51(3)45(3)43(3)45(3)70(3)57(3)53(3)100(4)84(3)40(3)35(3)52(2)39(3)75(3)55(2)

C(10X)C(11X)O(12X)O(13X)

4897(18)4463(19)2826(13)5938(13)

794(7)533(6)708(5)140(6)

2640(6)1651(6)1170(5)1372(5)

46(3)32(2)50(2)64(3)

Table v. bond length and angle observed for citrate.

S(1X)-C(14)S(1X)-C(18)CI(1X)-C(23)CI(2X)-C(22)N(1)-C(6)N(1)-C(2)N(1)-C(26)C(2)-C(3)C(3)-N(4)N(4)-C(7)N(4)-C(5)C(5)-C(6)C(7)-C(8)C(7)-C(12)C(8)-C(9)C(9)-C(10)C(10)-C(11)C(11)-C(12)C(12)-C(13)C(13)-C(14)C(14)-C(15)C(15)-O(25)C(14)-S(1X)-C(18)C(6)-N(1)-C(2)

1.758(10)1.794(11)N1.719(10)1.727(10)1.486(12)1.500(12)1.493(13)1.495(16)1.461(12)1.435(13)1.478(12)1.483(14)1.402(13)1.398(13)1.384(16)1.369(15)1.357(14)1.418(15)1.458(13)1.317(12)1.470(14)1.227(12)100.9(5)110.3(8)

C(15)-N(16)(16)-C(19)N(16)-C(17)C(17)-C(18)C(19)-C(20)C(19)-C(24)C(20)-C(21)C(21)-C(22)C(22)-C(23)C(23)-C(24)C(1X)-O(2X)C(1X)-O(3X)C(1X)-C(4X)C(4X)-C(5X)C(5X)-O(6X)C(5X)-C(7X)C(5X)-C(10X)C(7X)-O(9X)C(7X)-O(8X)C(10X)-C(11X)C(11X)-O(12X)C(11X)-O(13X)C(18)-C(17)-N(16)C(17)-C(18)-S(1X)

1.365(12)1.422(12)1.470(13)1.429(17)1.375(13)1.385(14)1.356(14)1.380(14)1.386(14)1.386(14)1.227(13)1.278(13)1.468(14)1.534(15)1.423(11)1.522(14)1.537(14)1.247(12)1.261(12)1.517(13)1.205(11)1.283(11)112.7(10)114.1(9)

C(6)-N(1)-C(26)C(2)-N(1)-C(26)N(1)-C(2)-C(3)N(4)-C(3)-C(2)C(7)-N(4)-C(3)C(7)-N(4)-C(5)C(3)-N(4)-C(5)N(4)-C(5)-C(6)C(5)-C(6)-N(1)C(8)-C(7)-C(12)C(8)-C(7)-N(4)C(12)-C(7)-N(4)C(9)-C(8)-C(7)C(10)-C(9)-C(8)C(11)-C(10)-C(9)C(10)-C(11)-C(12)C(7)-C(12)-C(11)C(7)-C(12)-C(13)C(11)-C(12)-C(13)C(14)-C(13)-C(12)C(13)-C(14)-C(15)C(13)-C(14)-S(1X)C(15)-C(14)-S(1X)

111.3(8)112.9(9)110.8(9)110.2(8)116.6(8)112.8(8)109.3(8)110.4(9)110.7(8)120.7(10)121.9(9)117.4(8)119.6(10)120.3(10)120.6(11)121.6(11)117.1(9)122.6(10)120.2(9)127.1(9)117.4(11)120.9(7)121.6(8)

C(20)-C(19)-C(24)C(20)-C(19)-N(16)C(24)-C(19)-N(16)C(21)-C(20)-C(19)C(20)-C(21)-C(22)C(21)-C(22)-C(23)C(21)-C(22)-CI(2X)C(23)-C(22)-CI(2X)C(24)-C(23)-C(22)C(24)-C(23)-CI(1X)C(22)-C(23)-CI(1X)C(23)-C(24)-C(19)O(2X)-C(1X)-O(3X)O(2X)-C(1X)-C(4X)O(3X)-C(1X)-C(4X)C(1X)-C(4X)-C(5X)O(6X)-C(5X)-C(7X)O(6X)-C(5X)-C(4X)O(7X)-C(5X)-C(4X)O(6X)-C(5X)-C(10X)C(7X)-C(5X)-C(10X)C(4X)-C(5X)-C(10X)O(9X)-C(7X)-C(8X)

118.5(9)121.2(9)120.3(9)121.3(10)120.6(10)119.4(10)120.6(9)119.9(8)119.2(9)119.1(9)121.6(8)120.9(10)121.5(11)122.0(11)116.1(10)113.2(9)110.4(9)109.0(8)110.9(8)108.4(8)106.9(8)111.1(8)126.8(9)

O(25)-C(15)-N(16)O(25)-C(15)-C(14)N(16)-N(15)-C(14)C(15)-N(16)-C(19)C(15)-C(16)-C(17)C(19)-N(16)-C(17)

119.5(11)121.5(10)119.0(10)119.1(9)119.5(9)120.1(9)

O(9X)-C(7X)-C(5X)O(8X)-C(7X)-C(5X)C(11X)-C(10X)-C(5X)O(12X)-C(11X)-C(13X)O(12X)-C(11X)-C(10X)O(13X)-C(11X)-C(10X)

118.0(10)115.2(10)118.4(8)123.6(9)120.4(9)116.0(9)

TABLE VI Anisotropic substitution parameter (\ u) for citrate²x10³). The anisotropic substitution factor index assumes the following formula: -2 pi²[h²a^*2U₁₁+...+2hka^*b^*U₁₂]。

	U	U	U	U	U	U
							S(1X)CI(1X)CI(2X)N(1)C(2)C(3)N(4)C(5)C(6)C(7)C(8)C(9)C(10)C(11)C(12)C(13)C(14)C(15)N(16)C(17)C(18)	40(2)128(3)81(2)53(6)53(8)56(8)45(6)61(8)63(8)43(7)51(8)64(10)49(9)55(8)47(7)38(7)35(6)35(7)53(6)77(10)46(8)	76(2)69(2)82(2)44(6)57(8)56(7)45(6)39(6)41(6)37(6)49(7)52(7)43(7)46(7)27(6)43(6)39(6)51(7)28(5)58(8)56(8)	39(2)46(2)47(2)30(5)46(7)35(6)23(5)36(6)22(6)21(6)33(7)45(8)66(9)36(7)33(7)24(6)19(5)38(7)30(5)78(9)71(8)	6(2)-17(2)7(2)-11(4)-9(6)1(5)-1(4)15(5)2(5)3(5)6(5)22(6)11(7)10(5)6(5)0(5)-6(5)-5(5)6(4)22(7)18(7)	2(1)1(2)-13(2)10(5)28(6)16(6)12(4)24(6)17(6)4(5)6(6)-15(7)-5(7)-1(6)5(5)6(5)2(5)5(6)-1(5)-26(8)7(7)	-14(2)24(2)13(2)-16(5)-22(7)-14(6)-2(5)-7(6)-2(6)-23(6)-15(7)-17(8)-1(6)4(6)-9(6)-4(5)-12(5)-8(6)-8(5)-39(8)-22(7)

C(19)C(20)C(21)C(22)C(23)C(24)C(25)C(26)C(1X)C(2X)C(3X)C(4X)C(5X)O(6X)C(7X)O(8X)O(9X)C(10X)C(11X)O(12X)O(13X)

39(7)51(8)61(8)49(8)70(8)60(9)60(6)57(9)54(8)106(9)99(8)53(8)49(8)71(6)38(7)106(8)75(6)54(8)40(7)43(5)68(6)

35(6)41(7)50(7)45(7)47(7)35(7)104(7)55(7)41(7)93(7)107(7)30(6)31(6)43(5)62(8)108(7)51(5)60(7)33(6)75(5)104(7)

22(6)29(6)45(7)39(7)14(6)41(7)39(4)60(8)61(9)87(7)35(5)34(6)24(5)40(5)15(6)18(4)34(4)23(6)27(6)28(4)19(4)

5(5)-1(5)10(6)18(6)-2(5)-2(6)29(4)-12(6)-9(6)-21(6)-7(5)-1(5)1(5)-4(3)-7(6)-7(4)-18(4)-4(5)10(5)-12(4)9(4)

-2(5)9(6)22(7)3(6)12(6)13(7)-6(4)14(7)2(7)-13(6)-21(5)4(6)7(5)8(4)-2(5)29(5)0(4)9(5)13(6)-7(4)5(4)

-1(6)7(6)19(6)19(6)1(7)1(6)-35(6)2(7)4(7)43(7)52(6)14(6)3(6)-5(4)9(6)-51(6)10(5)18(6)6(6)15(4)44(5)

TABLE VII hydrogen coordinates of citrate (x 10)⁴) And isotropic substitution parameter (\ u)²x10³)。

	x	y	z	U(eq)
					H(1X)H(2A)H(2B)H(3A)H(3B)H(5A)H(5B)	7880(190)9814101187538629847534944	1710(70)278931343942308222462564	5570(80)520261995290497160117013	80808080808080

H(6A)H(6B)H(8)H(9)H(10)H(11)H(13)H(17A)H(17B)H(18A)H(18B)H(20)H(21)H(24)H(26A)H(26B)H(26C)H(3XX)H(4XA)H(4XB)H(6XX)H(10A)H(10B)H(13X)

71998445392310652316756447385933731235524816710473562311422114321023411700(300)869990206600(200)358254655480(180)

1410225841795080551850264120202820453198239118861695389515951429789-220(100)184927-1000(80)8221382190(70)

6952731047964711600273777953925710232985192261044411764115126859583563615150(100)259133213490(80)28342683610(80)

8080808080808080808080808080808080140(60)808080808080

By using as SHELXTL^TMXFOG and XPOW computer programs provided in the computer program library component calculate X-ray powder diffraction patterns from single crystal data collected for the citrate. The calculated powder pattern is shown in fig. 3.

Solid state NMR

The citrate salt was characterized using a solid state NMR method. Approximately 300mg of the sample was pressed tightly into a 7mm ZrO rotator. Acquisition using a Bruker 7mm WBMAS probe in a Wide aperture Bruker Avance DRX 500MHz NMR spectrometer at 295K using the Cross-polarized magic Angle spinning (CPMAS) method¹³C NMR spectrum. The sample was rotated at 15.0 kHz. The cross-polarization contact time was set at 1 ms. A total of 512 scans were required for most samples yielding acquisition times of about 30 minutes. The position spectrum was determined using an external sample of adamantane (. delta.29.5 ppm) with the highest magnetic field set at 29.5ppm methyl signal.

Process for preparing citrate salt¹³The C NMR CPMAS spectrum is shown in FIG. 5. The citrate sample is considered to work quite well from the point of view of the solid state spectral properties. The resolution is excellent and the sensitivity is acceptable.

The main resonance peaks of the solid state carbon spectrum of the citrate salt of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one from a low magnetic field of 100ppm are listed in table VIII.

TABLE VIII main solid state of citrate¹³C NMR peak (adamantane standard 29.5 ppm).

13C(ppm)
	179.3
177.0
	171.6
164.0
	151.0
144.1

The citrate salts (hereinafter "active salts") of the present invention may be administered by the oral, transdermal (e.g. by use of a patch), intranasal, sublingual, rectal, parenteral or topical routes. Transdermal and oral administration are preferred. Most desirably, the active salt is administered in a dosage range of about 0.01mg to about 1500mg per day, preferably about 0.1 to about 300mg per day, in single or divided doses, although variations will necessarily occur depending on the weight and condition of the subject being treated and the particular route of administration chosen. Most desirably, however, dosage levels in the range of about 0.001mg to about 10mg per kg of body weight per day are employed. However, it will vary with the weight and condition of the person being treated and the individual response to the drug and the type of pharmaceutical formulation selected and the time period and interval over which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be higher than adequate, while in other instances larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.

The active salts may be administered by any of the several routes described above, alone or in combination with a pharmaceutically acceptable carrier or diluent. More specifically, the active salts may be administered in a variety of different dosage forms, for example, they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermal patches, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injections, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, oral pharmaceutical compositions may be suitably sweetened and/or flavored. Generally, the active salt is present in such dosage forms at a concentration level of about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients, such as microcrystalline cellulose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, as well as disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia, may be used. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting purposes. Solid compositions of a similar type may also be used as fillers in capsules; preferred materials in this regard also include lactose and high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavouring agents, colouring matter and, if desired, emulsifying and/or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof.

For parenteral administration, solutions of the active salts in sesame or peanut oil or in aqueous propylene glycol may be used. The aqueous solution should be suitably buffered (preferably to a pH greater than 8) and the liquid diluent first rendered isotonic, if necessary. These aqueous solutions are suitable for intravenous injection purposes. The oil solution is suitable for intra-articular, intramuscular and subcutaneous injection purposes. These solutions are readily prepared under sterile conditions by standard pharmaceutical techniques well known to those skilled in the art.

The active salts can also be administered topically and can be administered using creams, patches, jellies, gels, pastes, ointments and the like in accordance with standard pharmaceutical practice.

Examples

The following examples illustrate the methods and compounds of the present invention. It should be understood, however, that the intention is not to limit the invention to the particular embodiments described.

Lemon of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl-benzylidene) -thiomorpholin-3-one Acid salts

In a 1-liter round-bottom flask equipped with an overhead mechanical stirrer, the free base of 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one (30.14 g; 0.067 mol; prepared according to the procedure described in International patent publication No. WO 98/14433) was dissolved in 525ml of 2-propanol. The solution was stirred and heated to 50 ℃. Citric acid (16.2 g; 0.084mol) was added in portions to the resulting clear solution and the reaction mixture was granulated cold and at room temperature for 18 hours. A sample of the precipitated solid was examined by DSC to determine if any unreacted free base was present, after which the white crystalline solid product was collected. After filtration, the solid product was washed with 2-propanol (100ml) and dried under vacuum at 45 ℃ under a nitrogen purge. The title citrate was obtained in 94% yield (40.6 g; 0.063 mol).

Claims (12)

1. A compound which is the citrate salt of the compound 4- (3, 4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene ] -thiomorpholin-3-one of the formula

2. The compound of claim 1 having an X-ray diffraction pattern characterized primarily by: an X-ray diffraction pattern peak with a 2 θ of about 17.4 as measured using copper radiation.

3. The compound of claim 1 having an X-ray diffraction pattern characterized primarily by: an X-ray diffraction pattern peak with a 2 θ of about 20.0 as measured using copper radiation.

4. The compound of claim 1 having an X-ray diffraction pattern characterized primarily by: x-ray diffraction pattern peaks at 2 θ of approximately 17.4 and 20.0 as measured using copper radiation.

5. The compound of claim 1 having an X-ray diffraction pattern characterized primarily by: major X-ray diffraction pattern peaks, as measured using copper radiation, expressed in terms of the following 2 θ and d-spacings:

angle 2 theta (± 0.2) d-value (_) 0.2 13.0 6.8 17.4 5.1 18.0 4.9 18.9 4.7 20.0 4.4 21.2 4.2 22.2 4.0 24.0 3.7 27.1 3.3 32.4 2.8 。

6. The compound of claim 1, characterized by an onset of melting/decomposition transition at 198-.

7. The compound of claim 1, characterized by the fact that it is in the solid state¹³When examined by the C NMR cross-polarized magic angle spinning technique, it shows the following main resonance peaks: delta 179.3.

8. The compound of claim 1, characterized by the fact that it is in the solid state¹³When examined by the C NMR cross-polarized magic angle spinning technique, it shows the following main resonance peaks: δ 177.0.

9. The compound of claim 1, characterized by the fact that it is in the solid state¹³When examined by the C NMR cross-polarized magic angle spinning technique, it shows the following main resonance peaks: δ 171.6.

10. The compound of claim 1, characterized by the fact that it is in the solid state¹³When examined by the C NMR cross-polarized magic angle spinning technique, it shows the following main resonance peaks: δ 179.3, 177.0, 171.6, 164.0, 151.0 and 144.1.

11. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

12. The use of a compound of claim 1 for the manufacture of a medicament for the treatment of a mammalian disease state selected from the group consisting of: hypertension, all forms of depression, depression in cancer patients, depression in parkinson's disease patients, post-myocardial infarction depression, sub-syndrome symptomatic depression, depression in infertile women, infantile depression, major depressive disorder, single episode depression, recurrent depression, abuse-induced depression in children, post-partum depression, thymic dysfunction; mild, moderate, or major depression with or without atypical features, melancholic features, psychiatric features, stress features; seasonal affective disorder, depression in the middle and old aged, chronic depression; adjustment disorders with depressed mood or with anxiety and depressed mood; mixed anxiety and depression; substance-induced affective disorders; and affective disorders secondary to general medical conditions, bipolar disorder-depressive phase, general anxiety disorder, phobias, agoraphobia, social anxiety, social phobia, simple phobia, separation anxiety disorder, post-traumatic stress response syndrome, avoidant personality disorder, premature ejaculation, eating disorder, binge eating disorder, anorexia nervosa, bulimia nervosa, obesity; chemical dependence and addiction to alcohol, cocaine, heroin, phenobarbital, nicotine, marijuana, and benzodiazepines; cluster headache, migraine, pain, alzheimer's disease, obsessive-compulsive disorder, panic disorder with agoraphobia, memory disorders, dementia, amnestic disorders and age-related cognitive decline, parkinson's disease dementia, neuroleptic-induced parkinsonism and tardive dyskinesia, endocrine disorders, hyper-prolactin, vasospasm, cerebral vasculature vasospasm, cerebral ataxia; gastrointestinal disorders, including altered motility and secretion; negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress urinary incontinence, tourette's syndrome, trichotillomania, kleptomania, male impotence, cancer, small cell lung cancer, chronic migraine attacks, headache associated with vascular disease, autism, generalized central nervous system development retardation, asperger's disease, selective mutism, chronic motor or vocal tic disorders, disorders of locomotion, insomnia, intermittent explosive disorders, pyromania, pathological gambling, impulse-control disorders, premenstrual dysphoric disorder, and attention deficit/hyperactivity disorder.