RU2806046C1 - COCRYSTALLINE FORM OF 2,8-DIMETHYL-5-PHENETHYL-2,3,4,5-TETRAHYDRO-1H-PYRIDO[4,3-b]INDOLE - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a method of producing a cocrystalline form of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole with nicotinic acid of formula II at a molar ratio of 2,8- dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and nicotinic acid in a 1:1 cocrystal and the following parameters: orthorhombic cells, C₂₇H₂₉N₃O₂ at 20°C:

F(000) = 913, unit cell parameters and intensities of 19,604 reflections measured (6.32° ≤ 2Θ ≤ 49.98°), 4002 independent (R _int = 0.1028, R_sigma = 0.0964), final R ₁ = 0.0625 (I>=2σ (I)) and wR ₂ = 0.1882, taking into consideration that 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride is treated with equimolar aqueous alkali solution NaOH and the resulting free base 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole is mixed with an equimolar amount of nicotinic acid, Ethyl acetate is added to the mixture as a solvent and subjected to mechanical activation by grinding, followed by evaporation of the solvent residue.

EFFECT: method of obtaining a cocrystalline form of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole with nicotinic acid which can find its application in medicine for the production of pharmaceuticals for the treatment of neurodegenerative diseases and associated depressive episodes, including in the treatment of Alzheimer's disease.

1 cl, 3 dwg, 2 tbl, 2 ex

Description

The invention relates to the pharmaceutical industry, namely to a new co-crystal of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (CD-008-0045) and nicotinic acid, suitable for the production of pharmaceuticals for the treatment of neurodegenerative diseases, including the treatment of Alzheimer's disease, as well as associated depressive and anxiety states.

Cocrystals are supramolecular systems that can be considered both in the context of improving the pharmacokinetic properties of the main active component (CD-008-0045) and in the context of creating new two-component pharmaceutical compositions with synergistic pharmacological effects. In addition, obtaining individual cocrystal forms makes it possible to impart special properties to active pharmaceutical ingredients, such as improved solubility, thermal stability, improved mechanical properties, etc. At the same time, the ability to select cocrystal components greatly facilitates the “fine-tuning” of the physical properties of the cocrystal.

In particular, from the point of view of pharmaceutical development of solid dosage forms, the high hygroscopicity of the active substance can adversely affect the storage stability of a drug based on it, which creates serious, and sometimes insoluble, problems when choosing excipients in the composition of the finished drug. Therefore, reducing the hygroscopicity of the most active component is an important applied problem that can be solved by obtaining new cocrystalline forms that are less hygroscopic than previously known ones.

Known is 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride, salt of CD-008-0045 and a strong inorganic acid, formula (I)

a physiologically active compound belonging to the class of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles, which is an antagonist of 5-HT6 serotonin receptors and is active in the treatment of neurodegenerative diseases and disorders of the central nervous system [Pat . RU 2334747 C1, RF, SUBSTITUTED 2,3,4,5-TETRAHYDRO-1H-PYRIDO[4,3-b]INDOLES, METHOD OF THEIR PREPARATION AND APPLICATION / Ivashchenko, A.V., Kravchenko D.V. application 04/05/2007; publ. 09/27/2008 - 87 pp., ill.].

Pharmacological profile of compound CD-008-0045.

Compound CD-008-0045 is a new multi-target clinical candidate for the treatment of anxiety, depressive episodes and cognitive dysfunction in various pathologies, including Alzheimer's disease, post-Covid syndrome, etc.

Compound CD-008-0045 has multitarget activity, in particular the ability to inhibit several groups of receptors, including adrenergic, dopamine, serotonin and histamine, which suggests that CD-008-0045 has broad therapeutic potential. CD-008-0045 has very high affinity for 5HT7 receptors and lower affinity for 5HT6, 5HT2A and 5HT2C receptors. CD-008-0045 inhibits histamine H1 receptors and alpha-adrenergic receptors (α2A, α2B and α2C). According to preclinical studies, it was demonstrated that the compound has a positive effect on cognitive functions and also has anxiolytic and antipsychotic potential, which gave impetus to its further research as an agent for leveling anxiety symptoms in generalized anxiety disorder, as well as for correcting cognitive deficits in the disease Alzheimer's and other diseases.

It seems appropriate to modify the efficacy and safety profile of the compound CD-008-0045, as well as improve its pharmacotechnological properties by developing new binary compositions with other pharmacologically active or auxiliary components. Nicotinic acid was chosen as such a component.

Nicotinic acid, which is converted in the body into nicotinamide, which binds to coenzymes codehydrogenase I and II (NAD and NADP), which transport hydrogen, is involved in the metabolism of fats, proteins, amino acids, purines, tissue respiration, glycogenolysis and synthetic processes. In particular, it has a vasodilating effect at the level of small vessels (including the brain), improves microcirculation, and has a weak anticoagulant effect (increases the fibrinolytic activity of the blood). Shown ([Morris M C.; Evans D A.; Bienias J L.; Scherr P A.; Tangley CC. Dietary niacin and the risk of incident Alzheimer's disease and of cognitive decline // J Neurol Neurosurg Psychiatry. - 2004. - No. 75. - P. 1093-1099]) that regular use of niacin (nicotinic acid, nicotinamide and its derivatives) leads to a statistically significant slowdown in the progression of Alzheimer's disease and age-related cognitive impairment in a group of 6158 patients aged over 65 years.

A key positive factor when introducing cocrystals of CD-008-0045 and nicotinic acid into the body is potentially a synergistic enhancement of the vasodilating effect. Compound CD-008-0045 has a powerful (K _i level of 0.4-30 nmol/l) and highly selective inhibitory effect on alpha-adrenergic receptors (α2A, α2B and α2C). It is known that the alpha subtype is the predominant subtype of adrenergic receptors in the smooth muscles of arterioles and veins, and that inhibition of these receptors leads to relaxation of these blood vessels and a decrease in blood pressure [Docherty JR. The pharmacology of alpha(1)-adrenoceptor subtypes. Eur J Pharmacol. 2019 Jul 15;855:305-320]. Thus, we can assume a synergistic effect of these components, which allows us to consider the cocrystal of the compound CD-008-0045 with nicotinic acid as a potential effective vasodilating and antihypertensive drug in the complex treatment of generalized anxiety disorders, as well as in the correction of cognitive deficits in Alzheimer's disease and others diseases.

Nicotinic acid is a weak organic acid, unlike hydrochloric acid. This made it possible to assume that in cocrystalline form with nicotinic acid, compound CD-008-0045 will exist in a non-ionized form, and therefore have less hygroscopicity compared to the previously known hydrochloride of formula (I).

No patent documents containing descriptions of cocrystal forms of compounds based on 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole were found. In addition, a literature and patent search did not reveal alternative crystalline forms of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and pharmaceutical compositions containing this compound in its composition. Thus, the closest analogue of the claimed cocrystal is the form of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole in the form of hydrochloride.

The following are definitions of terms that are used in the description of this invention.

"Azaheterocycle" means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in the ring. An azaheterocycle may have one or more "cyclic" system substituents.

"Alkyl" means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. Alkyl may have one or more of the same or different substituents ("alkyl substituents"), including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonylheteroaralkyloxy, annelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl , annulated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl or R _k ^a R _k+1 ^a N-, R _k ^a R _k+1 ^a NC(=O)-, R _k ^a R _k+1 ^a NC(=S)-, R _k ^a R _k+1 ^a NSO ₂ -, where R _k ^a and R _k+1 ^a are independently "amino group substituents" as defined in this section, for example, hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, heterocyclyl or heteroaryl, or R _k ^a and R _k+1 ^a together with an N atom , with which they are connected, form through R _k ^a and R _k+1 ^a 4 - 7-membered heterocyclyl or heterocyclenyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylmethyl and pyridylmethyloxycarbonylmethyl. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, heteroaralkyloxycarbonyl or R _k ^a R _k+1 ^a N- , R _k ^a R _k+1 ^a NC(=O)-, annulated arylheterocyclenyl, annulated arylheterocyclyl.

"Alkoxy" means an alkyl-O-group, where alkyl is defined in this section. Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy.

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. Aryl may contain one or more "ring system substituents", which may be the same or different. Representatives of aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl may be annealed to a non-aromatic ring system or heterocycle.

"Aryloxycarbonyl"means aryl-O-C(=O)- group, in which the meaning aryl is defined in this section. Representatives aryloxycarbonyl groups are phenoxycarbonyl and 2-naphthoxycarbonyl.

An "aromatic" radical means a radical obtained by removing a hydrogen atom from an aromatic C-H bond. The "aromatic" radical includes aryl and heteroaryl rings as defined in this section. Aryl and heteroaryl rings may additionally contain substituents - aliphatic or aromatic radicals, as defined in this section. Representative aromatic radicals include aryl, fused cycloalkenyl aryl, fused cycloalkylaryl, fused heterocyclyl aryl, fused heterocyclenyl aryl, heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl, and annelated heterocyclylheteroaryl.

"Heteroaralkyl" means a heteroaryl-alkyl group, in which heteroaryl and alkyl are defined in this section. Representatives of heteroarylalkyls are pyridylmethyl, thienylmethyl, furylmethyl, imidazolylmethyl, pyrazinylmethyl, etc.

"Heteroaryl" means an aromatic monocyclic or polycyclic system containing from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are replaced by a heteroatom or heteroatoms such as nitrogen, sulfur or oxygen. The prefix “aza,” “oxa,” or “thia” before “heteroaryl” denotes the presence of a nitrogen atom, an oxygen atom, or a sulfur atom in the cyclic system, respectively. The nitrogen atom present in the heteroaryl can be oxidized to an N-oxide. Hetaryl may have one or more "ring system substituents", which may be the same or different. Representatives of heteroaryls are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, isooxazolyl, isothiazolyl, tetrazolyl, ochazolyl, thiazolyl, pyrazolyl, furazanyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2 -a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridine, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazine silt , thienopyrrolyl, furopyrrolyl, etc.

"Pharmaceutically acceptable salt" means the relatively non-toxic organic and inorganic salts of the acids and bases claimed in the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of compounds, or specially prepared. In particular, base salts can be prepared specifically starting from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like. (A detailed description of the properties of such salts is given in Berge SM, et al., “Pharmaceutical Salts” J. Pharm. Sci. 1977, 66: 1-19.) Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, whereby metal and amine salts can be synthesized. Metallic salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be prepared include sodium hydroxide, carbonate, bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. The organic bases from which salts of the claimed acids can be obtained are amines and amino acids that are sufficiently basic to form a stable salt and suitable for use for medical purposes (in particular, they must have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris(hydroxymethyl)aminomethane and the like. In addition, tetraalkylammonium hydroxides, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. The basic amino acids that can be used as amino acids are lysine, ornithine and arginine.

The purpose of the invention is to obtain a co-crystal of the compound CD-008-0045 with nicotinic acid as a potential effective drug for complex therapy of generalized anxiety disorders, as well as for the correction of cognitive deficits in Alzheimer's disease and other diseases, which has a vasodilating and antihypertensive effect.

The technical result of the invention is to obtain a cocrystalline form of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, suitable for use in the pharmaceutical industry for the production of drugs for treatment of various neurodegenerative diseases and associated depressive episodes, including in the treatment of Alzheimer's disease.

The specified technical result is achieved as follows: Co-crystalline form of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole with nicotinic acid, formula II, where the molar ratio 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole with nicotinic acid is 1:1, having the following crystal lattice parameters: orthorhombic cells, C27H29N3O2 at 20°С: a = 26.4708 Å, b = 5.8756 Å, c = 14.7574 Å, α = 90°, β = 90°, γ = 90° V = 2295.26 Å3, Mr = 427.55, Z = 4, space group Pca21, dcal = 1.237 g/cm3, μ(MoKα) = 0.079 mm-1, F(000) = 913. Unit cell parameters and intensity of 19604 reflections measured (6.32 ≤ 2Θ ≤ 49.98), 4002 independent (Rint = 0.1028, Rsigma = 0.0964 ). Final R1 = 0.0625 (I>=2σ(I)) and wR2 = 0.1882 (for all data). The measurements were carried out on a Xcalibur-3 diffractometer (MoKα radiation, CCD detector, graphite monochromator, ω-scanning, 2θmax = 50°).

Cocrystal form (formula II)

The structure was deciphered by the direct method using the SHELXTL software package. The positions of hydrogen atoms were determined objectively from difference electron density synthesis and refined using the “rider” model with U _iso = nU _eq ( n = 1.5 for methyl groups and n = 1.2 for other hydrogen atoms). The structure was refined by F ² by full-matrix least squares in the anisotropic approximation for non-hydrogen atoms to wR ₂ = 0.180 for 3346 reflections (R ₁ = 0.079 for 1569 reflections with F>4σ(F), S = 1.025).

The new cocrystal is a solid crystalline stable substance that does not disintegrate and is not affected by moisture (in a comparative study of the moisture content in samples of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4, 3-b]indole (formula I) and a cocrystal of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole with nicotinic acid (1:1 ) (formula II)) when stored under conditions of accelerated aging - temperature (40 ± 2) ° C, relative humidity (60 ± 5) %, a twofold decrease in the moisture content of the sample according to Fischer after 6 months of storage is shown. Thus, the new cocrystal with nicotinic acid is convenient for the preparation of stable pharmaceuticals.

The structure of the new cocrystal was proven by two methods, which together are sufficient to confirm the formation of a new compound:

• measuring X-ray diffraction by powder,

• single crystal diffractometry.

Table 1. Intensity and position of peaks for a sample of the cocrystal of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole with nicotinic acid (1:1) .

Angle(°) dValue(Å) Rel. Intensity 1 6,737 13.11059 22.5% 2 9,012 9.80435 11.8% 3 13,491 6.55821 22.0% 4 13,785 6.41865 12.7% 5 14,753 5.99967 100.0% 6 16,621 5.32947 10.7% 7 17,627 5.02741 22.9% 8 18.113 4.89377 9.9% 9 19,213 4.61576 21.6% 10 20,228 4.38647 57.1% eleven 21,107 4.20580 64.7% 12 23,585 3.76921 6.9% 13 24,595 3.61658 5.0% 14 25,748 3.45730 25.0% 15 26,038 3.41937 27.0% 16 27,739 3.21340 5.4% 17 30,713 2.90872 8.2%

Table 2. Parameters of the diffraction pattern observed in the reference sample of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole with nicotinic acid (1:1) - orthorhombic cell.

R-Values

Rexp: 2.06 Rwp: 9.00 Rp: 6.34 GOF: 4.37

Rexp`: 3.03 Rwp`: 13.26 Rp`: 10.73 DW: 0.66

Quantitative Analysis - Rietveld

Phase 1 : hkl_Phase 0.000%

Background

Chebychev polynomial, Coefficient 0 800(300)

1 300(500)

2 -200(500)

3 0(500)

4 0(400)

5 0(400)

6 0(400)

7 0(300)

8 0(300)

9 0(200)

10 0(200)

11 10(170)

12 10(140)

13 30(120)

14 10(90)

15 9(70)

16 10(60)

17 0(40)

18 1(30)

19 -20(20)

20 -3(11)

Instrument

Primary radius (mm) 300

Secondary radius (mm) 300

Linear PSD 2Th angular range (°) 2.5

FDS angle (°) 3

Beam spill, sample length (mm) 9(3)

Intensity corrected

Full Axial Convolution

Filament length (mm) 16

Sample length (mm) 33.0718

Receiving Slit length (mm) 17

Primary Sollers (°) 2.4

Secondary Sollers (°) 2.5

Tube_Tails

Source Width (mm) 0.09575778

Z1 (mm) -1.407527

Z2 (mm) 1.474325

Fraction 0.001094931

Corrections

Zero error 0

Specimen displacement -0.150(2)

LP Factor 0

hkl Phase - 1 Pawley method

Phase name hkl_Phase

R-Bragg 1.363

Spacegroup Pca21

Cell Mass 0.000

Cell Volume (Å^3) 2289.8(3)

Wt% - Rietveld 0.000

Double-Voigt|Approach

Cry size Lorentzian 350(60)

Cry size Gaussian 183(12)

k: 1 LVol-IB (nm) 112(8)

k: 0.89 LVol-FWHM (nm) 125(8)

Strain

Strain L 0.01(2)

Strain G 0.10(4)

e0 0.00024(8)

Lattice parameters

a (Å) 26.4078(16)

b (Å) 5.8775(4)

c (Å) 14.7526(12)

The following are specific examples that illustrate, but do not limit, the present invention.

The invention is illustrated by drawings:

Fig. Figure 1 shows the spatial structure of the cocrystalline form of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole with nicotinic acid (1:1) - 2,8- Dimethyl 5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indolium-2 nicotinate (molecular weight: 427.55), obtained by single crystal diffractometry. Ellipsoids of thermal vibrations are given with a probability of 50%.

Fig. Figure 2 shows a comparison of the theoretical (red line) and experimental (blue line) diffraction patterns of a sample of the cocrystalline form of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole with nicotinic acid and their difference (gray line). Blue dashes indicate calculated peak positions.

Fig. Figure 3 shows a) the Hirschfeld surface of the N2…H2…O2 bond in a crystal of the cocrystalline form of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole with nicotinic acid (1:1). b) space-filled model of the N2…H2…O2 fragment, which determines the intermolecular interaction of the cocrystal components (van der Waals atomic radii are used).

General method for preparing co-crystal of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole with nicotinic acid (1:1).

To obtain the claimed cocrystal, the following substances were used.

- 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride was synthesized at IIHR LLC (Moscow region, Khimki). The purity of the compound is 98%. The degree of purity was confirmed by NMR, IR and HPLC methods.

- Anhydrous nicotinic acid - manufacturer "Acros organics", lot 128290025, CAS 59-67-6, purity 99%.

- Sodium hydroxide (0.1 mol/l aqueous solution) - manufacturer "PanReac AppliChem", code 303125, Batch 12610739, purity Class A.

- Ethyl acetate (for UV, IR, HPLC, ASC) - manufacturer “PanReac AppliChem”, code 361318, Batch 0001792752, purity 99.9%.

A new cocrystal of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole with nicotinic acid (1:1) is significantly characterized by the XRD results shown in Fig. 1 and in Table. 1 and the diffraction pattern data presented in FIG. 2.

The cocrystal can be obtained as follows.

Example 1

A sample of 100.00 mg (0.293 mmol) of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride was treated with an equimolar solution of aqueous alkali NaOH 11.70 mg (0.293 mmol ). The precipitate that formed was dried in air to obtain 89.00 mg (0.293 mmol) of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole free base. It was mixed with 36.07 mg (0.293 mmol) of nicotinic acid, placed in an agate cell for grinding in a planetary micromill, and 0.06 ml of ethyl acetate was added to the mixture (according to the ratio of 0.5 μl of solvent per 1 mg of mixture). 10 agate balls with a diameter of 3 mm were placed in the cell. The process of mechanical activation (grinding) was carried out for 1 hour at a speed of 500 rpm. After the process was completed, the cell was left in a fume hood until the remaining solvent completely evaporated. The powder thus obtained was a cocrystal of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: nicotinic acid (1:1), which was confirmed SAR and XRF data. The resulting XRD profile of the final product was substantially consistent with that shown in FIG. 1 and in Table. 1. The resulting diffraction pattern of the final product was substantially consistent with that shown in FIG. 2.

Example 2

A sample weighing 50 mg of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: nicotinic acid (1:1) was ground in a mortar for 1 -2 minutes, after which a thin layer was applied to a special silicon sample holder. For application, a suspension of the ground sample in anhydrous heptane was created. After the sample dried, the diffraction pattern was measured for 2 hours. The obtained diffraction patterns were used for calculations without making additional corrections. The search for crystalline phases was carried out using d(hkl) values using the Cambridge structural database and open literature sources. To take into account the background, linear polynomials up to order 20 were used. The instrumental contribution to the broadening of the diffraction maxima is described using preliminary measurements of the standard (LaB6). All X-ray diffraction studies were performed on a Bruker D8 Advance diffractometer equipped with variable slits, a Ni filter (λ[CuKα]=1.5418 Å) and a position-sensitive LynxEye detector, in an angular range of 4-50° with a step of 0.02° over an angle of 2θ s using Bragg-Brentano geometry. Calculations were carried out using the EVA program [Bruker AXS GmbH, DIFFRAC.EVA, Bruker AXS GmbH, Karlsruhe, Germany, 2011.] and TOPAS 4.2 [Coelho, A. TOPAS 4.2, Bruker AXS GmbH, Karlsruhe, Germany; 2009].

Claims (5)

Method for obtaining co-crystalline form of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole with nicotinic acid of formula II at a molar ratio of 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and nicotinic acid in the cocrystal of 1:1, and the following parameters: orthorhombic cells, C ₂₇ H ₂₉ N ₃ O ₂ at 20°C: F(000) = 913, unit cell parameters and intensities of 19604 measured reflections (6.32° ≤ 2Θ ≤ 49.98°), 4002 independent ( R _int = 0.1028, R _sigma = 0.0964), final R ₁ = 0.0625 (I>=2σ( I)) and wR ₂ = 0.1882, which consists in the fact that 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride is treated with an equimolar solution of aqueous alkali NaOH and the resulting free base 2,8-dimethyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole are mixed with an equimolar amount of nicotinic acid, ethyl acetate is added to the mixture as solvent and subjected to mechanical activation by grinding followed by evaporation of the solvent residue.