Ethynyl derivatives

Abstract

The present invention relates to compounds that may be used in the treatment of Parkinson's disease, anxiety, emesis, obsessive compulsive disorder, autism, neuroprotection, cancer, depression or diabetes type 2.

Claims

1. A compound of formula IB: ##STR00010## or a pharmaceutically acceptable salt or acid addition salt or stereoisomer thereof.

2. A process for the manufacture of a compound of claim 1, wherein the process comprises: alkylating a compound of formula 12: ##STR00011## with ethyliodide; and separating of the isomers to a compound of formula IB: ##STR00012## optionally converting the compound obtained into a pharmaceutically acceptable salt or acid addition salt thereof.

3. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or acid addition salt or stereoismer thereof, and a pharmaceutically acceptable excipient.

4. A method for the treatment of Parkinson's disease in a patient, wherein the method comprises administering an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or acid addition salt or stereoisomer thereof, to the patient in need thereof.

Description

BRIEF DESCRIPTION OF THE FIGURE

(1) FIG. 1: Illustration of the experimental outline for mGlu4 PAM Ca2+ mobilization screening assay and the determination of EC.sub.50 and % Emax values.

LIST OF EXAMPLES AND DATA

(2) TABLE-US-00001 EC.sub.50 (nM) mGlu4 Eff. Structure Name PAM (%) 1 (4S)-3′-[2,6-Difluoro-4-(2- phenylethynyl)phenyl]-2-ethyl- 1′-methyl-spiro[6,7-dihydro-5H- indazole-4,6′- hexahydropyrimidine]-2′,4′- dione 77 132 2 (4S)-3′-[2,6-Difluoro-4-(2- phenylethynyl)phenyl]-1-ethyl- 1′-methyl-spiro[6,7-dihydro-5H- indazole-4,6′- hexahydropyrimidine]-2′,4′- dione 85 136

(3) The compounds of formulas IA and IB and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

(4) The compounds of formulas IA and IB and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula IA and IB, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

(5) In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

(6) As mentioned earlier, medicaments containing a compound of formulas IA and IB or pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula IA and IB or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.

(7) As further mentioned earlier, the use of the compounds of formulas IA and IB for the preparation of medicaments useful in the prevention and/or the treatment of the above recited diseases is also an object of the present invention.

(8) The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.

(9) Preparation of Pharmaceutical Compositions Comprising Compounds of the Invention:

(10) Tablets of the Following Composition are Manufactured in the Usual Manner:

(11) TABLE-US-00002 mg/tablet ingredient 5 25 100 500 Compounds of formula IA or IB 5 25 100 500 Lactose Anhydrous DTG 125 105 30 150 Sta-Rx 1500 6 6 6 60 Microcrystalline Cellulose 30 30 30 450 Magnesium Stearate 1 1 1 1 Total 167 167 167 831

(12) Manufacturing Procedure

(13) 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

(14) 2. Dry the granules at 50° C.

(15) 3. Pass the granules through suitable milling equipment.

(16) 4. Add ingredient 5 and mix for three minutes; compress on a suitable press.

(17) Capsules of the Following Composition are Manufactured:

(18) TABLE-US-00003 mg/capsule ingredient 5 25 100 500 Compound of formula IA or IB 5 25 100 500 Hydrous Lactose 159 123 148 — Corn Starch 25 35 40 70 Talk 10 15 10 25 Magnesium Stearate 1 2 2 5 Total 200 200 300 600

(19) Manufacturing Procedure

(20) 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.

(21) 2. Add ingredients 4 and 5 and mix for 3 minutes.

(22) 3. Fill into a suitable capsule.

(23) A compound of formula IA or IB, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer; the talc is added thereto and mixed thoroughly. The mixture is filled by machine into suitable capsules, e.g. hard gelatin capsules.

(24) Injection Solutions of the Following Composition are Manufactured:

(25) TABLE-US-00004 ingredient mg/injection solution. Compound of formula IA or IB 3 Polyethylene Glycol 400 150 acetic acid q.s. ad pH 5.0 water for injection solutions ad 1.0 ml

(26) Manufacturing Procedure

(27) A compound of formula IA or IB is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

(28) Experimental Section:

Example 1

(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-2-ethyl-1′-methyl-spiro[6,7-dihydro-5H-indazole-4,6′- hexahydropyrimidine]-2′,4′-dione

(29) ##STR00008##
Step 1: 2-((2-(Trimethylsilyl)ethoxy)methyl)-6,7-dihydro-2H-indazol-4(5H)-one
6,7-Dihydro-2H-indazol-4(5H)-one (CAS 912259-10-0) (1.46 g, 10.7 mmol) was dissolved in THF (15 ml) and cooled to 0-5° C. Sodium hydride (60% dispersion in mineral oil) (450 mg, 11.3 mmol, 1.05 equiv.) was added carefully in portions and the mixture was stirred for 60 minutes at room temperature. The reaction mixture was cooled again to 0-5° C. and (2-(chloromethoxy)ethyl)trimethylsilane (2.28 ml, 2.15 g, 12.9 mmol, 1.2 equiv.) was added and the mixture was stirred for 2 hours at room temperature. The reaction mixture was extracted carefully with saturated NaHCO.sub.3 solution and twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and evaporated to dryness. The desired 2-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-2H-indazol-4(5H)-one (quant. yield) was obtained as a yellow oil, MS: m/e=267.2 (M+H.sup.+).
Step 2: (NE)-2-Methyl-N-[1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol-4-ylidene]propane-2-sulfinamide
2-((2-(Trimethylsilyl)ethoxy)methyl)-6,7-dihydro-2H-indazol-4(5H)-one (Example 1, step 1) (40 g, 150.14 mmol) was dissolved in 400 ml of THF. (R)-2-Methylpropane-2-sulfinamide (CAS 196929-78-9) (27.3 g, 225.2 mmol, 1.5 equiv.) and titanium(IV) ethoxide (102.75 g, 93.4 ml, 450.42 mmol, 3.0 equiv.) were added and the mixture was stirred for 4 hours at 70° C. The reaction mixture was cooled and saturated NaHCO.sub.3 solution and ethyl acetate were added. The formed suspension was filtered through celite and the filtrate was extracted twice with ethyl acetate. The organic layers were washed brine, dried over sodium sulfate and evaporated to dryness. The desired (NE)-2-methyl-N-[1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol-4-ylidene]propane-2-sulfinamide (20.0 g, 36% yield) was obtained as a brown oil, MS: m/e=370.2 (M+H.sup.+).
Step 3: Methyl 2-[(4S)-4-[[(R)-tert-butylsulfinyl]amino]-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol-4-yl]acetate
Methyl acetate (22.25 g, 23.9 ml, 300.3 mmol, 3 equiv.) was dissolved in 370 ml of dry THF and the solution was cooled to −70° C. LDA (2.0 M in THF/heptane/ethylbenzene) (150 ml, 300.3 mmol, 3 equiv.) was added drop wise at −75° C. to −65° C. and the mixture was stirred for 45 minutes at −70° C. Chlorotitanium triisopropoxide (1.0 M in dichloromethane) (400 ml, 400 mmol, 4 equiv.) was added drop wise at −75° C. to −65° C. and the mixture was stirred for 45 minutes at −70° C. (NE)-2-methyl-N-[1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol-4-ylidene]propane-2-sulfinamide (Example 1, step 2) (37 g, 100 mmol) dissolved in 370 ml of dry THF was added drop wise at −75° C. to −65° C. and the mixture was stirred for 1 hour at −70° C. Saturated NaHCO.sub.3 solution was added and the mixture stirred for 10 minutes. Ethyl acetate was added to the formed suspension and the mixture was stirred for 10 minutes. The formed suspension was filtered through celite and the filtrate was extracted twice with ethyl acetate. The organic layers were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography. The desired methyl 2-[(4S)-4-[[(R)-tert-butyl sulfinyl]amino]-1-(2- trimethylsilylethoxymethyl)-6,7-dihydro-5H- indazol-4-yl]acetate (22 g, 40% yield) was obtained as a brown oil, MS: m/e=444.2 (M+H.sup.+).
Step 4: Methyl 2-[(4S)-4-amino-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol-4-yl]acetate
Methyl 2-[(4S)-4-[[(R)-tert-butylsulfinyl]amino]-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol-4-yl]acetate (Example 1, step 3) (20 g, 45.08 mmol) was dissolved in 500 ml of ethyl acetate and HCl (4N in ethyl acetate) (56.3 ml, 225.4 mmol, 5 equiv.) was added drop wise at 0-5° C. The mixture was stirred for 30 minutes at 0-5° C. The reaction mixture was evaporated at 0-5° C. and extracted with saturated NaHCO.sub.3 solution and three times with dichloromethane. The organic layers were combined, dried over sodium sulfate and evaporated to dryness. The desired methyl 2-[(4S)-4-amino-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol-4-yl]acetate (340 mg, 54% yield) was obtained as a yellow oil, MS: m/e=340.1 (M+H.sup.+).
Step 5: Methyl 2-[(4S)-4-[(2,6-difluoro-4-iodo-phenyl)carbamoylamino]-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol- 4-yl]acetate
2,6-Difluoro-4-iodoaniline (14.4 g, 56.56 mmol, 1.2 equiv.) was dissolved in DMF (250 ml) and CDI (9.17 g, 56.56 mmol, 1.2 equiv.) was added at room temperature. The mixture was stirred for 1 hour at 100° C. To the mixture methyl 2-[(4S)-4-amino-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol-4-yl]acetate (Example 1, step 4) (16 g, 47.13 mmol, 1.0 equiv.) dissolved in 20 ml of DMF was added at room temperature and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water and extracted three times with ethyl acetate. The organic layers were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography. The desired methyl 2-[(4S)-4-[(2,6-difluoro-4-iodo-phenyl)carbamoylamino]-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro-5H-indazol-4- yl]acetate (9.1 g, 19% yield) was obtained as a brown gum, MS: m/e=621.1 (M+H.sup.+).
Step 6: (4S)-3′-(2,6-Difluoro-4-iodo-phenyl)-1-(2-trimethylsilylethoxymethyl)spiro[6,7-dihydro-5H-indazole-4,6′- hexahydropyrimidine]-2′,4′-dione
(18 g, 29.01 mmol) Methyl 2-[(4S)-4-[(2,6-difluoro-4-iodo-phenyl)carbamoylamino]-1-(2-trimethylsilylethoxymethyl)-6,7-dihydro- 5H-indazol-4-yl]acetate (Example 1, step 5) was dissolved in THF (360 ml) and sodium hydride (60% in mineral oil) (1.74 g, 43.52 mmol, 1.5 equiv.) was added at 0-5° C. The mixture was stirred for 1 hour at room temperature. The reaction mixture was extracted with saturated NH.sub.4Cl solution and three times with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and evaporated to dryness. The desired (4S)-3′-(2,6-difluoro-4-iodo-phenyl)-1-(2-trimethyl silylethoxymethyl)spiro[6,7-dihydro-5H-indazole-4,6′- hexahydropyrimidine]-2′,4′-dione (240 mg, 86% yield) was obtained as a yellow gum, MS: m/e=589.0 (M+H.sup.+).
Step 7: (4S)-3′-(2,6-Difluoro-4-iodo-phenyl)-1′-methyl-1-(2-trimethylsilylethoxymethyl)spiro[6,7-dihydro-5H-indazole-4,6′-hexahydropyrimidine]-2′,4′-dione
(17 g, 28.9 mmol) (4S)-3′-(2,6-Difluoro-4-iodo-phenyl)-1-(2-trimethylsilylethoxymethyl)spiro[6,7-dihydro-5H-indazole-4,6′-hexahydropyrimidine]-2′,4′-dione (Example 1, step 6) was dissolved in DMF (200 ml) and cesium carbonate (14.12 g, 43.34 mmol, 1.5 equiv.) and iodomethane (4.92 g, 2.16 ml, 34.67 mmol, 1.2 equiv.) were added at room temperature. The mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water and extracted three times with ethyl acetate. The organic layers were washed with water and brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an petroleum:ethyl acetate 10:1 to 1:1 gradient. The desired (4S)-3′-(2,6-difluoro-4-iodo-phenyl)-1′-methyl-1-(2- trimethylsilylethoxymethyl)spiro[6,7-dihydro-5H-indazole-4,6′-hexahydropyrimidine]-2′,4′-dione (15.7 g, 90% yield) was obtained as a yellow gum, MS: m/e=603.2 (M+H.sup.+).
Step 8: (4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-1-(2-trimethylsilylethoxymethyl)spiro[6,7-dihydro-5H-indazole-4,6′-hexahydropyrimidine]-2′,4′-dione
(4S)-3′-(2,6-Difluoro-4-iodo-phenyl)-1′-methyl-1-(2-trimethylsilylethoxymethyl)spiro[6,7-dihydro-5H-indazole-4,6′- hexahydropyrimidine]-2′,4′-dione (Example 1, step 7) (12 g, 19.9 mmol) and phenylacetylene (3.05 g, 3.32 ml, 29.9 mmol, 1.5 equiv.) were dissolved in 120 ml of THF. Triethylamine (10.1 g, 13.9 ml, 99.6 mmol, 5 equiv.), bis-(triphenylphosphine)-palladium(II)dichloride (420 mg, 0.6 mmol, 0.03 equiv.), triphenylphosphine (313 mg, 1.2 mmol, 0.06 equiv.) and copper(I)iodide (114 mg, 0.6 mmol, 0.03 equiv.) were added and the mixture was stirred for 3 hours at 60° C. The reaction mixture was evaporated with isolute®. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane 30:70 to 100:0 gradient. The desired (4S)-3′-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-1-(2- trimethylsilylethoxymethyl)spiro[6,7-dihydro-5H-indazole-4,6′-hexahydropyrimidine]-2′,4′-dione (11.2 g, 98% yield) was obtained as a brown foam, MS: m/e=577.3 (M+H.sup.+).
Step 9: (4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[1,5,6,7-tetrahydroindazole-4,6′- hexahydropyrimidine]-2′,4′-dione
The title compound was obtained as a white foam, MS: m/e=447.2 (M+H.sup.+), using chemistry similar to that described in Example 1, step 4 by stirring the reaction for 2 hours at 80° C. starting from (S)-1′-(2,6-difluoro-4-(phenylethynyl)phenyl)-3′-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,5,6,7-tetrahydro-1′H-spiro[indazole- 4,4′-pyrimidine]-2′,6′(3′H,5′H)-dione (Example 1, step 8).
Step 10: (4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-2-ethyl-1′-methyl-spiro[6,7-dihydro-5H-indazole-4,6′- hexahydropyrimidine]-2′,4′-dione
The title compound was obtained as a white solid, MS: m/e=475.4 (M+H.sup.+), using chemistry similar to that described in Example 1, step 7 starting from (4S)-3′-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[1,5,6,7-tetrahydroindazole-4,6′-hexahydropyrimidine]-2′,4′-dione (Example 1, step 9) and iodoethane. The desired (4S)-3′-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-2-ethyl-1′-methyl-spiro[6,7-dihydro-5H-indazole-4,6′-hexahydropyrimidine]-2′,4′-dione was obtained by separation of the two formed isomers using a Reprosil Chiral NR® column with heptane:ethanol 60:40 mixture as eluent collecting peak A.

Example 2

(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1-ethyl-1′-methyl-spiro[6,7-dihydro-5H-indazole-4,6′- hexahydropyrimidine]-2′,4′-dione

(30) ##STR00009##
The title compound was obtained as a white solid, MS: m/e=475.4 (M+H.sup.+), using chemistry similar to that described in Example 1, step 7 starting from (4S)-3′-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[1,5,6,7-tetrahydroindazole-4,6′-hexahydropyrimidine]-2′,4′-dione (Example 1, step 9) and iodoethane. The desired (4S)-3′-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1-ethyl-1′-methyl- spiro[6,7-dihydro-5H-indazole-4,6′-hexahydropyrimidine]-2′,4′-dione (Example 1, step 9) and iodoethane. The desired (4S)-3 ′-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1-ethyl-1′-methyl-spiro[6,7-dihydro-5H-indazole-4,6′-hexahydropyrimidine]-2′,4′-dione was obtained by separation of the two formed isomers using a Reprosil Chiral NR® column with heptane:ethanol 60:40 mixture as eluent collecting peak B.