CZ92999A3 - pharmaceutical preparation for treating and/or prophylaxis neurological disorders and use of compounds containing phosphorus for preparing a medicament - Google Patents

Abstract

Pharmaceutical composition for treatment and / or prophylaxis degenerative diseases like Huntington's choruses, schizophrenia, neurological disorders of uAIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (for example, Giles de la syndrome) Tourette), traumatic brain damage, tinnitus, neurology, in particular trigeminal neurology, neuropathic pain, toothache, pain in cancer, disproportionate neuronal activity leading to neurodystesis u chorobjako diabetes, multiple sclerosis (MS) aporuchy a temporomandibular joint dysfunction, contains derivatives a penzopyran sample (A) or a pharmaceutically acceptable salt thereof salts or solvates.

Description

The present invention relates to a pharmaceutical composition for the treatment and / or prophylaxis of neurological disorders and the use of phosphorus-containing compounds for the manufacture of a medicament.

BACKGROUND OF THE INVENTION

EP-A-0 126 311 describes substituted benzopyran compounds, including β-acetyl-trans-4- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, which have the effect of lowering blood pressure.

Also EP-A-0 376 524, EP-A-0 205 292, EP-A-0 250 077, EP-A-0 093 535, EP-A-0 150 202, EP-A-0 076

075 and WO89 / 05808 (Beecham Group plc) disclose certain benzopyran derivatives having antihypertensive effects.

EP-A-0 350 805 (Biersdorf); EP-A-0 277 611; EP-A-0

277,612, EP-A-0 337 179 and EP-A-0 355 565 (Hoechst Aktiengesellschaft); EP-A-0 466 131 (Nissan Chemical Industries Ltd)

EP-A-0 339 562 (Yoshitomi Pharmaceuticals), EP-A-0 415 065 (E. Merck), EP-A-0 450 415 (Squibb), EP-A-0 482 934, EP-A- No. 0 296 975, JO-2004-791 and WO89 / 07103 also disclose certain benzopyran derivatives which are believed to have an antihypertensive effect.

EP-A-0 430 621 and EP-A-0 385 584 (Beecham Group plc) disclose the decomposition of certain intermediates which are useful for preparing the compounds described in the above-mentioned patent applications.

• · · ·

EP-A-0 139 992 (Beecham Group plc) discloses certain benzopyran derivatives having cis-isomerisms at the 3 and 4 positions, their compounds being described as having an antihypertensive effect.

EP-A-0 587 645, EP-A-0 673 373, EP-A-0 673 374, EP-A-0 673 248, EP-A-0 674 519, WO95 / 34545, WO95 / 34547 and WO95 / 34546 (SmithKline Beecham plc) discloses groups of compounds which have, inter alia, anticonvulsant effects, and which are also considered to be of use in the treatment and prevention of mania, depression, and withdrawal symptoms.

It has now surprisingly been found that the compounds of the above groups have an additive effect and are believed to be useful in the treatment and / or prophylaxis of degenerative diseases such as Huntingdon's chorea, schizophrenia, AIDS-related neurological disorders, sleep disorders (including circadian disorders). rhythm, insomnia and narcolepsy), tics (eg Giles de la Tourette syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, toothache, pain in cancer, inadequate neuronal activity leading to neurodysthesia in diseases such as diabetes, multiple sclerosis (MS) and motor neuron disorders, ataxia, muscle rigidity (spasticity) and temporomandibular joint dysfunction.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition for the treatment and / or prophylaxis of degenerative diseases such as Huntington's chorea, schizophrenia, neurological disorders in AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la syndrome)

4 · · ·

4 4> 4 4

Tourette's), traumatic brain injury, tinnitus, especially neuralgia of trigemine neuralgia, neuropathic pain, toothache, pain in cancer, inadequate neuronal activity leading to neurodysthesia in diseases such as diabetes, multiple sclerosis (MS) and motor neuron disorders, ataxia, muscle rigidity (spasticity) and dysfunction of the temporomandibular joint, which comprises a compound of formula (A) (A) in which:

P is a ring system selected from the following:

R.

where

9 9999 99 99

9 9 9 9 9

9900 9 99 9

9,999,999,999

9 «99 • 9 999 99 99 where either

and the other variables are as described below

(b)

wherein either aib together represent a bond or CH 2, or aib together represents a carbonyl group, C = NOR ^F , CHOR ^f or

O

II

C-O-C-P?

> 000 0 0

00

Wherein R ^f is hydrogen or alkyl of 1 to 6 carbon atoms; or a

J

wherein either J is a nitrogen atom and J ^a is a free electron pair, M is a carbon atom and M ^a is R ₅ ; or

J is a carbon atom and M is a nitrogen atom and J ^a and M ^a are hydrogen; or

(d)

where Z is an oxygen atom or Cfe:

E)

'4

44 • · · 4

4, 44444, 4444

4 44 · 44 444444

444 444 44

444 44 444 44 44 wherein either Y is a nitrogen atom and R ₂ is a nitrogen atom, or Y is C-R 1;

wherein either one of R 1 and R ₂ is hydrogen and the other is selected from the group consisting of hydrogen, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl optionally interrupted by oxygen or hydroxy-substituted, (C 1 -C 6) alkoxy or substituted aminocarbonyl, (C 1 -C 6) alkylcarbonyl, (C 1 -C 6) alkoxycarbonyl, (C 1 -C 6) alkylcarbonyloxy, (C 1 -C 6) alkoxycarbonyl up to 6 carbon atoms, nitro, cyano, halogen, trifluoromethyl, CF 3 S or CF 3 -A-, wherein A is -CF ₂ -, -CO-, -CH ₂ -, CH (OH), SO ₂ , SO, CH 2 -O, or CONH, or CF ₂ H-A'-, wherein A 'is O, S, SO, SO ₂ , CF ₂ or CFH, trifluoromethoxy, C 1 -C 6 alkylsulfinyl, C 2 -C 6 perfluoroalkylsulfonyl 6 carbon atoms, alkylsulfo (C 1 -C 6) -alkyl, (C 1 -C 6) -alkoxysulfinyl, (C 1 -C 6) -alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy; β · ♦ ········ ¹ ······ · · · · · 9 · · · 4 9 · 9 9 • 9 99 · 99 999999

998 9 ·· ··

999 99 999 99 99, heteroarylsulfinyl, arylsulfonyl, heteroarylsulfonyl, in which any aromatic moiety is optionally substituted, C 1 -C 6 alkylcarbonylamino, C 1 -C 6 alkoxycarbonylamino, alkylthiocarbonyl C 1 -C 6 alkyl, C 1 -C 6 alkoxythiocarbonyl, C 1 -C 6 alkylthiocarbonyloxy, C 2 -C 7 1-mercaptoalkyl, formyl or aminosulfinyl, aminosulfonyl or an aminocarbonyl group, and any amino moiety thereof is optionally substituted by one or two C 1 -C 6 alkyl groups, or C 1 -C 6 alkylsulfinylamino, C 1 -C 6 alkylsulfonylamino, C 1 -C 6 alkoxysulfinylamino C 1 -C 6 alkoxy or C 1 -C 6 alkoxy, or ethylenyl terminally substituted with C 1 -C 6 alkylcarbonyl, nitro or cyano, or -C (C 1 -C 6 alkyl) NOH or C (C 1 -C 6 alkyl) NNH ₂ ;

or one of R _x and R ₂ is nitro, cyano or C 1 -C 3 alkylcarbonyl and the other is halogen, C 1 -C 4 alkyl, methoxy or amino optionally substituted with one or two; · · · · · »· · · * · * · * · · · * · · · · · · · · · · · · · · Two alkyl groups of 1 to 6 carbon atoms or alkanoyl groups of 2 to 7 carbon atoms;

or R 1 and R 2 together are - (CH ₂ ) ₄ -; (CH ₂ ) _x CO (CH ₂ ) _y , where x is

0 to 3 and y is 0 to 3 with the proviso that x + y is at least 2x; or -CH = CH-CH = CH-; or form an optionally substituted triazole or oxadiazole ring, or together form a CONR ^c CO group wherein R ^c is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an arylalkyl or a heteroarylalkyl group;

Z is a nitrogen atom only when Y is C-R 1 or

Z is CR ^a , when Y is nitrogen or C-R 1; wherein R ^a is hydrogen, halogen or nitro; (C 1 -C 4) alkylcarbonyl, (C 1 -C 4) alkyl; (C 1 -C 4) aralkyl, (C 1 -C 4) arylalkenyl, (C 1 -C 4) heteroarylalkyl or (C 1 -C 4) heteroarylalkenyl;

R ^b is hydrogen, halogen, nitro;

(C 1 -C 4) alkylcarbonyl or (C 1 -C 4) alkyl; and wherein any aryl or heteroaryl or alkyl moiety attached to R ^a or R ^b is optionally substituted;

one of R ₃ and R ₄ is hydrogen or C 1 -C 6 alkyl, and the other is C 1 -C 9 alkyl

C 9 -C 99 carbon atoms, CF ₃ or CH ₂ X ^a , where X ^a is fluorine, chlorine, bromine, iodine, C 1 -C 4 alkoxy, hydroxy, C 1 -C 4 alkylcarbonyloxy -S-C 1 -C 4 -alkyl, nitro, amino optionally substituted by one or two C 1 -C 4 -alkyl; cyano or (C 1 -C 4) alkoxycarbonyl, or R 3 and R ₄ together are a C 2 -C 5 polymethylene group optionally substituted by C 1 -C 4 alkyl;

R 8 is C 1 -C 6 alkylcarbonyloxy, benzoyloxy, ONO ₂ , benzyloxy, phenyloxy, or C 1 -C 6 alkoxy, and R 8 and R ₉ are hydrogen or R 5 is hydroxy and R 8 and R ₉ are independently a hydrogen atom or an alkyl group having 1 to 2 carbon atoms;

R ^x is (a)

where

Rii a

Rio j or

R?

·· 4 ·· 4 ·· 4 4

4 · <4 ·· • 44 ·· 4 45 4

4 44 444444 • 44 ··

4 «444 ·· ····· 4 4 •

• 4

4 4

R12 are independently selected from hydrogen, alkyl group, haloalkyl group, cycloalkyl group, aralkyl, cyano, nitro, COR _X3, CONHR, CONR ₃ R ₄ or halogen, wherein R ₁₃ and R _i4 are independently selected from hydrogen, alkyl groups, haloalkyl, aryl, aralkyl, cycloalkyl or (cycloalkyl) alkyl groups;

and hydrogen, alkyl, haloalkyl, cycloalkyl, O-R15, cyano, nitro, CF _3, halo, S-alkyl, COR15, COOR15, NRisCOalkylová group or OCOalkylová group wherein R15 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, cycloalkyl or (cycloalkyl) alkyl; m is 0 or 1;

(b) R ^x is an R ₈ -N-CO-R ₇ group wherein it is a heteroaryl or a phenyl group; both of which are optionally substituted one or more times independently of one another by a group or atom selected from chlorine, fluorine, bromine, iodine, nitro, amino, optionally substituted one or two times by C 1 -C 4 alkyl, cyano, azido, alkyl (C 1 -C 4) groups, (C 1 -C 4) alkoxy, trifluoromethoxy, trifluoromethyl; optionally substituted with aryloxy or heteroaryloxy;

Ra is C 1 -C 4 alkoxy substituted with one or more halogens (except trifluoromethoxy); amino substituted with C 1 -C 4 alkanoyl, aroyl, aryl, phenylsulfonyl or C 1 -C 4 alkylsulfonyl; (C až-C uhlíku) alkyl substituted with one or more halogens (except trifluoromethyl) or alkoxy; phenylsulfonylalkylsulfonyl groups having 1 to 4 carbon atoms in the alkylsulfonyl moiety, aminosulfonyl groups wherein the amino group is optionally substituted with a alkyl group having 1 to 4 carbon atoms; CONH 2 wherein the amino group is optionally substituted with C 1 -C 4 alkyl;

is hydrogen; (C 1 -C 6) alkyl, OR 18 or NHCOR 17, wherein R ₁₆ is hydrogen, (C 1 -C 6) alkyl, formyl, (C 1 -C 6) alkanoyl, (C 1 -C 6) aroyl or aralkyl and R 17 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 mono- or dialkylamino, amino, C 1 -C 6 aminoalkyl carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, acyloxyalkyl of 1 to 6 carbon atoms in both the acyloxy and alkyl moieties, alkoxycarbonylalkyl of 1 to 6 · · · • · «« «« · «« «« «« «· · · · · · · · · · · · · · a C 1-6 alkoxycarbonylalkyl group as in the alkoxy group parts of such alkyl, aryl or heteroaryl;

X is oxygen or NR _8, wherein R _S is hydrogen or an alkyl group having 1 to 6 carbon atoms; and the group R ^x is in the cis or trans position to the group R ₅ .

In general, cis compounds of formula (A) may be prepared from the corresponding trans compounds by procedures for their preparation, which are described in more detail.

in EP-0 126 311, EP-0 376 524, EP-205 292, EP-0 250 077 EP-0 093 535, EP-0 150 202, EP-0 076 075, WO / 89/05808 EP-0 350 805, EP-0 277 611 and EP-0 277 612, EP-0 337 179 EP-0 339 562, EP-0 355 565 and EP-A-415 065 (E. Merck), EP-A-450 415 (Squibb) EP-0 466 131 EP-A- 0 482 934

EP-A-0 296 975, JO-2004-791 and WO89 / 07103.

The cis-compounds of formula (A) may be prepared by processes analogous to those described in EP-A-0 139 992.

The cis-compounds of formula (A) may also be prepared according to the procedures described by G. Burrell et al., Tet. Letters, 31, 3649-3652 (1990) or according to the procedures described in U. Quast and E. Villhauer, Eur. J. Pharmacol., Molecular Pharmacology Section, 245, 165-171 (1993).

It should be appreciated that the racemates of the compound of formula (A) may be resolved or the enantiomerically purified compounds of formula (A) may be prepared.

AA AAAA ·· AA

ΑΑΑ AAA A A A A A A A A A A

A A AA AA AA AAAAAA

AAAAAA AA

AA AAA AA AAA AA AA

It should also be appreciated that it is preferred that compounds of formula (A) can be prepared in the desired enantiomeric form by preparing a chiral pure epoxide, using catalysts and under the conditions generally described in WO91 / 14694 or WO93 / 17026, and then the epoxides are converted to the desired compound of formula (A) using the procedures described herein.

trans compounds of formula (A) may be prepared according to the procedures disclosed in PCT / GB92 / 01045.

These procedures are incorporated herein by reference. Furthermore, the trans compounds of formula (A) may be prepared according to procedures analogous to those described in one of the aforementioned patents.

Reference is made in particular to EP-A-0 587 645,

EP-A-0 673 373, EP-A-0 673 374

EP-A-0 674 519, WO95 / 34545, WO95 / 34547 and WO95 / 34546 for compounds suitable for use in the present invention.

Preferred compounds of this invention are trans-6-acetyl-4S- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, hereinafter also compound 1 (for preparation see Example 20 in WO92 / 22293), cis-6-acetyl-4S- (3-chloro-4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3S-ol, here further compound 2 (for for preparation (see Example 17 in WO95 / 34545) and trans-6-acetyl-4S- (3,5-difluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, hereinafter also compound 3 (for preparation see Example 4 in WO95 / 34545).

···· φ φ • · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ • • • • • φ φ

The above compounds can be used in therapy as pharmacologically acceptable salts, for example hydrochlorides and pharmacologically acceptable solvates, for example hydrates.

Administration to a mammal may be by the oral, parenteral, sublingual or transdermal route.

The amount effective for the treatment of the disorders described herein depends on conventional factors such as the nature and severity of the disorders and the weight of the mammal. However, a unit dose will normally contain 1 to 5000 mg, suitably 1 to 500 mg, for example an amount in the range of 2 to 400 mg, such as 2, 5, 10, 20,

30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered one or more times per day, for example 1, 2, 3, 4, 5, and 6 times per day, more usually 1 to 4 times per day, so that the total daily dose is normally in the range of an adult weight 70 kg, 1 to 5000 mg, for example 1 to 500 mg, i.e. in the range of about 0.01 to 15 mg / kg per day, more usually 0.1 to 6 mg / kg per day, for example 1 to 6 mg / kg per day day.

It is highly preferred that the compound of formula (A) can be administered in the form of a unit dose composition, for example, a unit dose composition for oral administration, including sublingual, rectal, topical or parenteral (mainly intravenous) administration.

Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration and as such may be in the form of tablets, capsules, liquid oral preparations, powders, granules, lozenges, reconstitutable powders, solutions.

9999

9 9 • · · · Φ

Granules, lozenges, reconstitutable powders, solutions for injection and infusion or suspensions or suppositories. Orally administrable formulations are preferred, and in particular shaped oral compositions thereof, as they are more convenient for normal use.

Tablets and capsules for oral administration are generally presented in a unit dose and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricating agents, disintegrants, colorants, flavoring agents and wetting agents. The tablets may be coated according to methods well known in the art.

Suitable fillers that can be used include cellulose, mannitol, lactose and other similar formulations. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include, for example, sodium lauryl sulfate.

These solid compositions for oral administration may be prepared by conventional mixing, filling, tabletting or similar techniques. Repeated blending processes can be used to achieve appropriate distribution of the active ingredient in those compositions in which a large number of fillers are used. These procedures are, of course, conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions,

9999 ··· * 99 99 • 99 999 9 · 9 9 »9999« 9999 »99 99 99 999999

999 98 «99

999 9 «999 99 99 before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible oils, emulsifying agents, for example lecithin, monooleatsorbitan or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters such as esters of glycerin, propylene glycol, or ethyl alcohol; preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid and, if necessary, conventional flavoring and coloring agents.

Oral formulations also include conventional sustained release formulations such as enteric coated tablets or granules.

For parenteral administration, liquid unit dosage forms are prepared comprising a compound and a sterile vehicle. The compound, depending on the vehicle and concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and sterilizing it through a filter, before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anesthetic, preservatives and buffering agents are also dissolved in the vehicle. In order to increase stability, the composition can be frozen after filling into a vial and removing the water by vacuum.

Parenteral suspensions are prepared in substantially the same manner with the difference that the compound is at 0 000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 000 * 0 0 ·

The vehicle is suspended instead of being dissolved, and is sterilized by treatment with ethylene oxide prior to suspension in a sterile vehicle. Preferably, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the present invention.

Normally, the compositions will generally be accompanied by written or printed instructions for use for the intended treatment.

The invention further provides a pharmaceutical composition for use in the treatment and / or prophylaxis of degenerative diseases such as Huntington's chorea, schizophrenia, OCD, neurological deficits in AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g.

Giles de la Tourette's syndrome), traumatic brain damage, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, toothache, pain in cancer, inadequate neuronal activity leading to neurodysthesia in diseases such as diabetes, multiple sclerosis (MS) and motor neuron disorders , ataxia, muscular rigidity (spasticity) and dysfunction of the temporomandibular joint comprising a compound of formula (A), a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

In another aspect, the invention provides the use of a compound of formula (A), a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and / or prophylaxis of degenerative diseases such as Huntington's chorea, schizophrenia, neurological disorders in AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (such as Gilles de la Tourett

4 <

»4 4

4 4 <

4 4 4 4 ·

I 4 ·

AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (eg Gilles de la Tourette syndrome), traumatic brain damage, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, toothache, cancer pain, inadequate neuronal activities leading to neurodystheses in diseases such as diabetes, multiple sclerosis (MS) and motor neuron disorders, ataxia, muscle rigidity (spasticity) and temporomandibular joint dysfunction.

These compositions and medicaments may be prepared as previously described.

The present invention is particularly concerned with the treatment of neuropathic pain and trigeminal neuralgia, in particular using trans-6-acetyl-4S- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R- ol (compound 1), cis-6-acetyl-4S- (3-chloro-4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3S-ol (compound 2), and trans-6-acetyl-4S- (3,5-difluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol (Compound 3).

The following data illustrates the invention.

Model of the trigeminal nerve in anesthetized cats

Cats were general anesthetized with achloralosis (90-100 mg / kg iv) and artificially ventilated from room air. Their body temperature was maintained between 37 and 38 ° C. A cannula was inserted into the femoral artery to monitor blood pressure and heart rate. Arterial blood flow was recorded by Doppler, 0000 ^{1 V} 00000 0000 0 00 0 000000 0 000 00 «Stereotactically introduced into each of the ganglia of both trigeminal nerves. Guanethidine (3 mg / kg) was then administered

i.v.) and allowed to stabilize for 45 min. Stimulation (2 mA, 10 Hz for 2 min) of the trigeminal ganglia on the same side as the common carotid from which blood flow was measured led to increased blood flow and decreased carotid vascular resistance. The ability of drugs administered intravenously to influence this response has been used to determine their effects on the trigeminovascular system.

Intravenous administration of compound 1 (n = 3) or compound 2 (n = 4) at 3.4 μιηοΐ / h resulted in a significant inhibition of TGN-induced carotid vascular resistance reduction over 4 hours (Table 1).

Intraduodenal administration of compound 1 (n = 3) or compound 2 (10 mg / kg) also resulted in a significant reduction in TGN-induced carotid vascular resistance reduction over 3 hours (Table 2).

«9 ··· 9 9 ··

9 9 9 9 9 9 9 99 9 999999

9

999 99 99

Table 1

Effects of continuous intravenous administration of Compound 1 and Compound 2 on TGN-induced reduction of carotid vascular resistance in an anesthetized cat

n % change in TGN-decreased vascular resistance carotides in 4 hours after continuous i.v. infusion (mean ± standard deviation) Control (3.4 μπιοΐ / h) 4 11.6 ± 8.6 Control (11 μπιοΐ / hr) 3 15.7 ± 10 Compound 1 3.4 μνηοΐ / ΐι 3 -29.1 ± 3.7 * Compound 2 3.4 μΓηοΙ / h 4 -30.0 ± 6.6 * Compound 2 11 μ / h 4 -21.8 ± 14 *

P <0.05 · · · • © © © © © © © © © © © © © © © © © © © © © © · ··· ·· ··

Table 2

Effects of intraduodenal administration of compound 1 or 2 (10 mg / kg) on TGN-induced reduction of carotid vascular resistance in an anesthetized cat

n % change in TGN-induced vascular reduction carotid resistance in 3 hours (mean value ± standard deviation) Control (labrosol) 3 30.6 ± 12.2 Compound 1 (labrasol) 3 -43 ± 12.9 * Control (methylcellulose) 2 6.8 Compound 2 (methylcellulose) 2 -69

* P <0.05

Compound 3 had evident effects on TGN by stimulating induced carotid vascular resistance reduction in an anesthetized cat treated with guanethidine. In the absence of treatment with this drug, TGN stimulation usually resulted in an approximately 40 to 50% reduction in carotid vascular resistance, which could be repeated at 30 minute intervals. 2 hours after administration, the intraduodenal bolus of compound 3 (10 mg / kg) resulted in a 77% (n = 4) inhibition of trigeminal mediated responses,

ft · · · · (* · · · · · · · ·

* ·

The left sciatic nerve was exposed in anesthetized rats and dorsal 50-60% of the nerve was ligated as described by Seltzer et al., Pain, 43, 205-218 (1990). The surgical wound was then closed and the animals allowed time to recover. Thermal nociception was measured by delaying the removal of the hind paw from an infrared light source, both before surgery (8 days and 1 day before surgery) and at regular intervals after nerve ligation.

The compounds were administered as a single dose or as multiple doses in cases of induced hyperalgesia, mostly 14 days after nerve ligation. Compounds were administered as either oral or systemic, and changes in thermal nociception were recorded for 40 days.

Claims (8)

A pharmaceutical composition for the treatment and / or prophylaxis of degenerative diseases such as Huntington's chorea, schizophrenia, neurological disorders in AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcoiepsia), tics (e.g. Giles de la Tourette syndrome), traumatic brain injury , tinnitus, neuralgia, in particular trigeminal neuralgia, neuropathic pain, toothache, cancer pain, inadequate neuronal activity leading to neurodysthesia in diseases such as diabetes, multiple sclerosis (MS) and motor neuron disorders, ataxia, muscle rigidity (spasticity) and dysfunction temporomandibular joint comprising a compound of formula -fAf R ^x I (A) P in which P is a ring system selected from the following: (a) where either R ,. or 0 ^R , or and the other variables are as defined below: b) wherein either aib together represent a bond or CH ₂ , or aib together represents a carbonyl group, C = NOR ^F , CHOR ^f or COC (O) R ^F where R ^F is hydrogen or C 1 -C 6 alkyl ; or c) wherein either J is a nitrogen atom and J ^a is a free electron pair, M is a carbon atom and M ^and is R 5; or • 4 4 4 4 · · · · 444 «4 ·· ···· J is a carbon atom and M is a nitrogen atom and J ^a and M ^a are hydrogen; or d) wherein Z is oxygen or CH ₂ ; e) wherein either Y is a nitrogen atom and R ₂ is a nitrogen atom, or Y is C-R 1; wherein either one of R 1 and R ₂ is hydrogen and the other is selected from the group consisting of hydrogen, C 3 -C 8 cycloalkyl, C 1 -C 6 alkyl optionally interrupted by oxygen or hydroxy substituted, alkoxy C 1 -C 6 or substituted aminocarbonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylcarbonyloxy, C 1 -C 6 alkoxy 6 carbon atoms, nitro, cyano, halogen, trifluoromethyl, CF ₃ S and CF ₃ -A-, wherein A is -CF ₂ -, -CO-, -CH ₂ -, CH (OH), SO ₂ , SO, CH ₂ -O, or CONH, or CF ₂ H-A'-, wherein A 'is O, S, SO, SO ₂ , CF ₂ or CFH, trifluoromethoxy, C 1 -C 6 alkylsulfinyl C 2 -C 6 perfluoroalkylsulfonyl C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkoxysulfinyl, C 1 -C 6 alkoxysulfonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, heteroaryl, heteroarylsulfinyl, arylsulfonyl, heteroarylsulfonyl in which any aromatic moiety is optionally substituted, alkyl of 1 to 6 carbon atoms in the alkyl moiety, alkoxycarbonylamino of 1 to 6 carbon atoms in the alkoxy moiety, alkylthiocarbonyl of 1 to 6 carbon atoms in the alkyl moiety an alkylthiocarbonyloxy group having from 1 to 6 carbon atoms in the alkyl moiety, a 1-mercaptoalkyl group having from 2 to 7 carbon atoms, a formyl group or an aminosulfinyl group, an amine moiety; an osulfonyl group or an aminocarbonyl group, wherein any of their · jejich φ φ · · · · · φ φ φ φ φ φ φ φ The amino moiety is optionally substituted with one or two C 1 -C 6 alkyl, or C 1 -C 6 alkylsulfinylamino, C 1 -C 6 alkylsulfonylamino, alkoxysulfinylamino (C 1 -C 6) alkyl or (C 1 -C 6) alkoxy-sulfonylamino, or ethylenyl terminally substituted by C 1 -C 6 alkylcarbonyl, nitro or cyano, or -C (C _1-6 alkyl) NOH or -C (C 1-6) ₆ alkyl) NNH ₂ ; or one of R 1 and R ₂ is nitro, cyano or C 1 -C 3 alkylcarbonyl and the other is halogen, C 1 -C 4 alkyl, methoxy or amino optionally substituted with one or two C 1 alkyl groups up to 6 carbon atoms or alkanoyl of 2 to 7 carbon atoms; or R 1 and R ₂ taken together are - (CH ₂ ) ₄ -; (CH ₂ ) _x CO (CH ₂ ) _y wherein x is 0 to 3 and y is 0 to 3 with the proviso that x + y is at least 2x; or -CH = CH-CH = CH-; or form an optionally substituted triazole or oxadiazole ring, or together form a CONR ^c CO group wherein R ^c is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an arylalkyl or a heteroarylalkyl group; Z is a nitrogen atom only when Y is C-R 1 or Z is Z CR ^a , when Y is nitrogen or C-R 1; wherein R ^a is hydrogen, halogen or nitro; (C 1 -C 4) alkylcarbonyl, (C 1 -C 4) alkyl; (C 1 -C 4) aralkyl, (C 1 -C 4) arylalkenyl, (C 1 -C 4) heteroarylalkyl or (C 1 -C 4) heteroarylalkenyl; R ^b is hydrogen, halogen, nitro; (C 1 -C 4) alkylcarbonyl or (C 1 -C 4) alkyl; wherein any aryl or heteroaryl or alkyl moiety attached to R ^a or R ^b is optionally substituted; One of R ₃ and R ₄ is hydrogen or alkyl of 1 to 4 carbon atoms and the other is an alkyl group having 1 to 4 carbon atoms, CF ₃ or CH 2 X ^a where X ^a is fluorine, chlorine, bromine, iodine, , (C 1 -C 4) alkoxy, hydroxy, (C 1 -C 4) alkylcarbonyloxy, -C (C 1 -C 4) alkyl, nitro, amino optionally substituted by one or two (C 1 -C 4) alkyl groups ; cyano or (C 1 -C 4) alkoxycarbonyl, or R ₃ and R ₄ together are a C 2 -C 5 polymethylene group optionally substituted by C 1 -C 4 alkyl; R 5 is C 1 -C 6 alkylcarbonyloxy; 99 99 9 9 9 9 9 9 9 9 9 9 9 · · · · · 9 9 9 9 9 9 9 9 9 29 ..... ....... ··· 9 9 9 9 9 9 999 99 99 9999 99 99 alkyl moieties, benzoyloxy, ONO 2, benzyloxy, phenoxy or C 1 -C 6 alkoxy, and R ₆ and R ₉ are hydrogen or R 5 is hydroxy and R 8 and R 8 are independently hydrogen or C 1 -C 2 alkyl; R ^x is (a) where R 11 and R ₁₂ are independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, aralkyl, cyano, nitro, COR 13, CONHR 13, CONR 13 R ₁₄ or halogen, wherein R 13 and R ₁₄ are independently selected from hydrogen, alkyl, haloalkyl, aryl, aralkyl, cycloalkyl or (cycloalkyl) alkyl; R10 is hydrogen, alkyl, haloalkyl, cycloalkyl, O-R15, cyano, nitro, CF _3, halo, S-alkyl, ·· ·· ·· φφ · · · φ φ φ • · · · φ φ • · · φ • • • COR15 / COOR15, NR18COalkyl or OCOalkyl wherein R15 is hydrogen, alkyl, haloalkyl, aryl, aralkyl, cycloalkyl or (cycloalkyl) alkyl; m is 0 or 1; or (b) R ^x is an R ₈ -N-CO-R ₇ group, m wherein R ₇ is heteroaryl or phenyl; both of which are optionally substituted one or more times independently of one another by a group or atom selected from chlorine, fluorine, bromine, iodine, nitro, amino optionally substituted by one or two C 1 -C 4 alkyl, cyano, azido groups C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trifluoromethoxy, trifluoromethyl; optionally substituted aryloxy or heteroaryloxy; (C 1 -C 4) alkoxy substituted with one or more halogens outside of trifluoromethoxy; amino substituted with C 1 -C 4 alkanoyl, aroyl, aryl, phenylsulfonyl or C 1 -C 4 alkylsulfonyl; alkyl groups having 1 and 4 carbon atoms substituted by one or more halogens other than trifluoromethyl or alkoxy; phenylsulfonylalkylsulfonyl groups having 1 to 4 carbon atoms in the alkyl moiety, aminosulfonyl groups wherein the amino group is optionally substituted with an alkyl moiety; 9 9 ·· • 9 9 9 9 9 9 # 99 999 999 9999 999 99 99 9999 99 99 C 1 -C 4 group; CONH ₂ , wherein the amino group is optionally substituted with C 1 -C 4 alkyl; R 8 is hydrogen; (C 1 -C 6) -alkyl; OR ₁₆ or NHCOR 1, wherein R ₁₆ is hydrogen, C 1 -C 6 alkyl, formyl, C 1 -C 6 alkanoyl, C 1 -C 6 aroyl or aralkyl, and R 17 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 mono- or dialkylamino in each alkyl moiety, amino, C 1 -C 6 aminoalkyl, hydroxyalkyl C 1 -C 6 haloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 acyloxyalkyl in both the acyloxy and alkyl moieties, C 1 -C 6 alkoxycarbonylalkyl both in the alkoxy and alkyl moieties, aryl or heteroaryl; X is oxygen or NR ₁₈ , wherein R ₁₈ is hydrogen or C 1 -C 6 alkyl; and a group R ¹ is in the cis or trans position to the R ₅ group, or a pharmacologically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. • φ · φ • · · · • • • • • · • • • • • • • φ φ φ φ φ φ φ φ φ φ Use of a compound of formula (A) according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment and / or prophylaxis of degenerative diseases such as Huntingdon's chorea, schizophrenia, neurological deficits in AIDS, sleep disorders (including circadian disorders). rhythm, insomnia and narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain damage, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, toothache, pain in cancer, inadequate neuronal activity leading to neurodysthesia in diseases such as diabetes , multiple sclerosis (MS) and motor neuron disorders, ataxia, muscle rigidity (spasticity) and temporomandibular joint dysfunction. 3. A composition according to claim 1 for the treatment of trigeminal neuralgia. Use according to claim 2 for the treatment of trigeminal neuralgia. 5. A composition according to claim 1 for the treatment of neuropathic pain. Use according to claim 2 for the treatment of neuropathic pain. Composition according to claim 1, 3 or 5, characterized in that the compound of formula (A) is trans-6-acetyl-4S- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H -1-benzopyran-3R-ol, cis-6-acetyl-4S- (3-chloro-4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3S-ol or trans -6-acetyl-4S- (3,5-difluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol or a pharmaceutically acceptable salt or solvate thereof. Use according to claim 2, 4 or 5, wherein the compound of formula (A) is trans-6-acetyl-4S- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran 3R-ol, cis-6-acetyl-4S- (3-chloro-4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3S-ol or trans-6-acetyl -4S- (3,5-difluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol or a pharmaceutically acceptable salt or solvate thereof.