PENTACYCLIC PYRIDOINDOLOBENZO[b,e]DIAZEPINES AND THIAZEPINES FOR TREATING CNS DISORDERS
20170174708 ยท 2017-06-22
Assignee
Inventors
Cpc classification
International classification
Abstract
The present invention discloses pyridoinolobenzo[b,e]diazepine and thiazepine derivatives of Formula 1,
##STR00001##
wherein X is NR.sup.10, S, S(O), or S(O).sub.2. Y is a single bond or no bond. A and B are independently (CH.sub.2).sub.m and (CH.sub.2).sub.n respectively; and the subscripts m and n independently vary from 1 to 4. R.sup.1 to R.sup.9 are various electron donating, electron withdrawing, hydrophilic, or lipophilic groups selected to optimize the physicochemical and biological properties of compounds of Formula I.
Claims
1. A compound of Formula I, wherein ##STR00019## X is NR.sup.10, S, S(O), or S(O).sub.2; the dotted line, Y, is a single bond or no bond; A is (CH.sub.2).sub.m; B is (CH.sub.2).sub.n; and subscripts m and n form an ordered pair (m,n), wherein (m,n) is (1,1), (1,2), (2,1), (1,3), (2,2), (3,1), (1,4), (2,3), (3,2), or (4,1); R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 hydroxyalkyl, C.sub.1-C.sub.10 alkoxycarbonylalkyl, C.sub.1-C.sub.10 carbamoylalkyl, C.sub.5-C.sub.10 aryl, C.sub.5-C.sub.10 arylalkyl, and C.sub.1-C.sub.15 aroylalkyl; each of R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, hydroxy, C.sub.1-C.sub.10 alkoxy, NR.sup.11R.sup.12, C.sub.1-C.sub.10 hydroxyalkyl, halogen, trihaloalkyl, cyano, carboxy, C.sub.1-C.sub.10 acyl, C.sub.1-C.sub.10 alkoxyalkyl, C.sub.1-C.sub.10 alkoxycarbonyl, C.sub.5-C.sub.10 aryl, and C.sub.5-C.sub.10 arylalkyl; and each of R.sup.10, R.sup.10 and R.sup.12 is independently hydrogen or C.sub.1-C.sub.10 alkyl.
2. The compound of claim 1, represented by formula II, wherein Y is a single bond: ##STR00020##
3. The compound of claim 2, wherein X is NR.sup.10, S; and R.sup.2 is hydrogen.
4. The compound of claim 3, wherein R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 hydroxyalkyl, C.sub.5-C.sub.10 arylalkyl, and C.sub.1-C.sub.10 carbamoylalkyl; each of R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, hydroxy, C.sub.1-C.sub.10 alkoxy, and halogen; each of R.sup.7, R.sup.8, and R.sup.9 is independently hydrogen; and R.sup.10 is hydrogen or C.sub.1-C.sub.6 alkyl.
5. The compound of claim 3, wherein R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 hydroxyalkyl, C.sub.5-C.sub.10 arylalkyl, and C.sub.1-C.sub.10 carbamoylalkyl; each of R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently hydrogen; each of R.sup.7, R.sup.8, and R.sup.9 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, hydroxy, C.sub.1-C.sub.10 alkoxy, and halogen; and
6. The compound of claim 4, wherein R.sup.1 is hydrogen, C.sub.1-C.sub.10 alkyl, CH.sub.2Ph, CH.sub.2CH.sub.2OH, or CH.sub.2CONH.sub.2; and each of R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently hydrogen, CH.sub.3, hydroxy, OCH.sub.3, F, or Cl.
7. The compound of claim 5, wherein R.sup.1 is hydrogen, C.sub.1-C.sub.10 alkyl, CH.sub.2Ph, CH.sub.2CH.sub.2OH, or CH.sub.2CONH.sub.2; and each of R.sup.7, R.sup.8, and R.sup.9 is independently hydrogen, CH.sub.3, hydroxy, OCH.sub.3, F, or Cl.
8. The compound of claim 7, wherein R.sup.1 is hydrogen or CH.sub.3; each of R.sup.7, R.sup.8, and R.sup.9 is independently hydrogen; and R.sup.10 is hydrogen or methyl.
9. The compound of claim 1, represented by formulas IIIa or IIIb, wherein Y is no bond: ##STR00021##
10. The compound of claim 9, wherein X is NR.sup.10, S; and R.sup.2 is hydrogen.
11. The compound of claim 10, wherein R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 hydroxyalkyl, C.sub.5-C.sub.10 arylalkyl, and C.sub.1-C.sub.10 carbamoylalkyl; each of R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, hydroxy, C.sub.1-C.sub.10 alkoxy, and halogen; and each of R.sup.7, R.sup.8, and R.sup.9 is independently hydrogen.
12. The compound of claim 10, wherein R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 hydroxyalkyl, C.sub.5-C.sub.10 arylalkyl, and C.sub.1-C.sub.10 carbamoylalkyl; each of R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently hydrogen; and each of R.sup.7, R.sup.8, and R.sup.9 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, hydroxy, C.sub.1-C.sub.10 alkoxy, and halogen.
13. The compound of claim 11, wherein R.sup.1 is hydrogen, C.sub.1-C.sub.10 alkyl, CH.sub.2Ph, CH.sub.2CH.sub.2OH, or CH.sub.2CONH.sub.2; and each of R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently hydrogen, CH.sub.3, hydroxy, OCH.sub.3, F, or Cl.
14. The compound of claim 12, wherein R.sup.1 is hydrogen, C.sub.1-C.sub.10 alkyl, CH.sub.2Ph, CH.sub.2CH.sub.2OH, or CH.sub.2CONH.sub.2; and each of R.sup.7, R.sup.8, and R.sup.9 is independently hydrogen, CH.sub.3, hydroxy, OCH.sub.3, F, or Cl.
15. The compound of claim 14, wherein R.sup.1 is hydrogen or CH.sub.3; each of R.sup.7, R.sup.8, and R.sup.9 is independently hydrogen; and R.sup.10 is hydrogen or methyl.
16. The compound of claim 15, wherein R.sup.1 is CH.sub.3.
17. The compound of claim 1, represented by formulas IVa or IVb, wherein Y is no bond: ##STR00022##
18. The compound of claim 17, wherein X is NR.sup.10, S; and R.sup.2 is hydrogen.
19. The compound of claim 18, wherein R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 hydroxyalkyl, C.sub.5-C.sub.10 arylalkyl, and C.sub.1-C.sub.10 carbamoylalkyl; each of R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, hydroxy, C.sub.1-C.sub.10 alkoxy, and halogen; and each of R.sup.7, R.sup.8, and R.sup.9 is independently hydrogen.
20. The compound of claim 18, wherein R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 hydroxyalkyl, C.sub.5-C.sub.10 arylalkyl, and C.sub.1-C.sub.10 carbamoylalkyl; each of R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently hydrogen; and each of R.sup.7, R.sup.8, and R.sup.9 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, hydroxy, C.sub.1-C.sub.10 alkoxy, and halogen.
21. The compound of claim 19, wherein R.sup.1 is hydrogen, C.sub.1-C.sub.10 alkyl, CH.sub.2Ph, CH.sub.2CH.sub.2OH, or CH.sub.2CONH.sub.2; and each of R.sup.3, R.sup.4, R.sup.5, and R.sup.6 is independently hydrogen, CH.sub.3, hydroxy, OCH.sub.3, F, or Cl.
22. The compound of claim 20, wherein R.sup.1 is hydrogen, C.sub.1-C.sub.10 alkyl, CH.sub.2Ph, CH.sub.2CH.sub.2OH, or CH.sub.2CONH.sub.2; and each of R.sup.7, R.sup.8, and R.sup.9 is independently hydrogen, CH.sub.3, hydroxy, OCH.sub.3, F, or Cl.
23. The compound of claim 22, wherein R.sup.1 is hydrogen or CH.sub.3; and each of R.sup.7, R.sup.8, and R.sup.9 is independently hydrogen.
24. The compound of claim 22, wherein R.sup.1 is hydrogen or CH.sub.3; each of R.sup.7, R.sup.8, and R.sup.9 is independently hydrogen; and R.sup.10 is hydrogen or methyl.
25. A pharmaceutical formulation comprising (a) the compound of claim 1 and (b) a pharmaceutically acceptable buffer, diluent, carrier, adjuvant, preservative, or excipient.
26. The pharmaceutical formulation of claim 24, in which the formulation is pharmaceutically acceptable for oral administration.
27. The pharmaceutical formulation of claim 24, in which the formulation is pharmaceutically acceptable for topical administration.
Description
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)
[0017]
[0018]
DETAILED DESCRIPTION OF THE INVENTION
[0019] The present invention relates to pentacyclic compounds of Formula I, wherein
##STR00005##
X is NR.sup.10, S, S(O), or S(O).sub.2;
[0020] the dotted line, Y, is a single bond or no bond;
[0021] A is (CH.sub.2).sub.m;
[0022] B is (CH.sub.2).sub.n; and [0023] subscripts m and n form an ordered pair (m,n), wherein (m,n) is (1,1), (1,2), (2,1), (1,3), (2,2), (3,1), (1,4), (2,3), (3,2), or (4,1); [0024] R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 hydroxyalkyl, C.sub.5-C.sub.10 aryl unsubstituted or substituted with electron donating groups (EDG) or electron withdrawing groups (EWG), C.sub.1-C.sub.15 aroylalkyl, and C.sub.1-C.sub.10 alkoxycarbonylalkyl, C.sub.1-C.sub.10 carbamoylalkyl, C.sub.5-C.sub.10 arylalkyl unsubstituted or substituted with EDG or EWG; [0025] R.sup.2 to R.sup.9 are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.10 alkyl, hydroxyl, C.sub.1-C.sub.10 alkoxyl, NR.sup.11R.sup.12, C.sub.1-C.sub.10 hydroxyalkyl, halogen, trihaloalkyl, cyano, carboxyl, C.sub.1-C.sub.10 acyl, C.sub.1-C.sub.10 alkoxyalkyl; C.sub.1-C.sub.10 alkoxycarbonyl; C.sub.5-C.sub.10 aryl unsubstituted or substituted with EDG or EWG, and C.sub.5-C.sub.10 arylalkyl unsubstituted or substituted with EDG or EWG; and [0026] R.sup.10, R.sup.11, and R.sup.12 are independently hydrogen or C.sub.1-C.sub.10 alkyl, and R.sup.11 and R.sup.12 may optionally be tethered together from a ring.
[0027] The phrase, electron donating group (EDG) and electron withdrawing group (EWG) are well understood in the art. EDG comprises alkyl, hydroxyl, alkoxyl, amino, acyloxy, acylamino, mercapto, alkylthio, and the like. EWG comprises halogen, acyl, nitro, cyano, carboxyl, alkoxycarbonyl, and the like.
[0028] The first embodiment of the present invention is represented by Formula I, wherein
[0029] X is NR.sup.10;
[0030] Y is a single bond; and
[0031] (m,n) is (1,1), (1,2), (2,1), (2,2), or (2,3).
[0032] The second embodiment is represented by Formula I, wherein
[0033] X is NR.sup.10;
[0034] Y is no bond with cis-fused B|C rings; and
[0035] (m,n) is (1,1), (1,2), (2,1), (2,2), or (2,3).
[0036] The third embodiment is represented by Formula I, wherein
[0037] X is NR.sup.10;
[0038] Y is no bond with trans-fused B|C rings; and
[0039] (m,n) is (1,1), (1,2), (2,1), (2,2), or (2,3).
[0040] The fourth embodiment is represented by Formula I, wherein
[0041] X is S, SO, or SO.sub.2;
[0042] Y is a single bond; and
[0043] (m,n) is (1,1), (1,2), (2,1), (2,2), or (2,3).
[0044] The fifth embodiment is represented by Formula I, wherein
[0045] X is S, SO, or SO.sub.2;
[0046] Y is no bond with cis-fused B|C rings; and
[0047] (m,n) is (1,1), (1,2), (2,1), (2,2), or (2,3).
[0048] The sixth embodiment is represented by Formula I, wherein
[0049] X is S, SO, or SO.sub.2;
[0050] Y is no bond with trans-fused B|C rings; and
[0051] (m,n) is (1,1), (1,2), (2,1), (2,2), or (2,3).
[0052] The compounds belonging to Formula I can be synthesized by the well-known Fisher indole condensation of known tricyclic dibenodiazepines 7a and dibenzothiazepines 7b [14, 15] and azacycloalkanones 9a-h as outlined in
##STR00006##
bond in B|C ring junction in formula II (8a or 8b) can be accomplished by NaBH.sub.3CN/TFA or with BH.sub.3 to give the cis- and trans-reduced compounds of formulas III and IV respectively. Compounds of the present invention may exist as a single stereoisomer or as mixture of enantiomers and diastereomers whenever chiral centers are present. Individual enantiomers can be isolated by resolution methods or by chromatography using chiral columns, and the diastereomers can be separated by standard purification methods such as fractional crystallization or chromatography.
[0053] As is well known in the pharmaceutical industry, the compounds of the present invention represented by Formula I, commonly referred to as active pharmaceutical ingredient (API) or drug substance, can be prepared as a pharmaceutically acceptable formulation. In particular, the drug substance can be formulated as a salt, ester, or other derivative, and can be formulated with pharmaceutically acceptable buffers, diluents, carriers, adjuvants, preservatives, and excipients. The phrase pharmaceutically acceptable means those formulations which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts include, but are not limited to acetate, adipate, citrate, tartarate, benzoate, phosphate, glutamate, gluconate, fumarate, maleate, succinate, oxalate, chloride, bromide, hydrochloride, sodium, potassium, calcium, magnesium, ammonium, and the like. The formulation technology for manufacture of the drug product is well-known in the art, and are described in Remington, The Science and Practice of Pharmacy [16], incorporated herein by reference in its entirety.
[0054] The final formulated product, commonly referred to as drug product, may be administered enterally, parenterally, or topically. Enteral route includes oral, rectal, topical, buccal, ophthalmic, and vaginal administration. Parenteral route includes intravenous, intramuscular, intraperitoneal, intrasternal, and subcutaneous injection or infusion. The drug product may be delivered in solid, liquid, or vapor forms, or can be delivered through a catheter for local delivery at a target. Also, it may be administered alone or in combination with other drugs if medically necessary.
[0055] Formulations for oral administration include capsules (soft or hard), tablets, pills, powders, and granules. Such formulations may comprise the API along with at least one inert, pharmaceutically acceptable ingredients selected from the following: (a) buffering agents such as sodium citrate or dicalcium phosphate; (b) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (d) humectants such as glycerol; (e) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (f) solution retarding agents such as paraffin; (g) absorption accelerators such as quaternary ammonium compounds; (h) wetting agents such as cetyl alcohol and glycerol monostearate; (i) absorbents such as kaolin and bentonite clay and (j) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (k) coatings and shells such as enteric coatings, flavoring agents, and the like.
[0056] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the API, the liquid dosage forms may contain inert diluents, solubilizing agents, wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents used iii the art.
[0057] Compositions suitable for parenteral injection may comprise physiologically acceptable, sterile aqueous or nonaqueous isotonic solutions, dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions. The compositions may also optionally contain adjuvants such as preserving; wetting; emulsifying; dispensing, and antimicrobial agents. Examples of suitable carriers, diluents, solvents, vehicles, or adjuvants include water; ethanol; polyols such as propyleneglycol, polyethyleneglycol, glycerol, and the like; vegetable oils such as cottonseed, groundnut, corn, germ, olive, castor and sesame oils, and the like; organic esters such as ethyl oleate and suitable mixtures thereof; phenol, parabens, sorbic acid, and the like.
[0058] Injectable formulations may also be suspensions that contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
[0059] Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, these compositions release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Thus, the rate of drug release and the site of delivery can be controlled. Examples of embedding compositions include, but are not limited to polylactide-polyglycolide poly(orthoesters), and poly(anhydrides), and waxes. The technology pertaining to controlled release formulations are described in Design of Controlled Release Drug Delivery Systems, [17] incorporated herein by reference in its entirety.
[0060] Formulations for topical administration include powders, sprays, ointments and inhalants. These formulations include the API along with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
[0061] Compounds of the present invention can also be administered in the form of liposomes. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together. Methods to form liposomes are known in the art and are described in Liposomes, [18], which is incorporated herein by reference in its entirety.
[0062] The compounds of the present invention can also be administered to a patient in the form of pharmaceutically acceptable prodrugs. Prodrugs are generally used to enhance the bioavailabilty, solubility, in vivo stability, or any combination thereof of the API. They are typically prepared by linking the API covalently to a biodegradable functional group such as a phosphate that will be cleaved enzymatically or hydrolytically in blood, stomach, or GI tract to release the API. A detailed discussion of the prodrug technology is described in Prodrugs: Design and Clinical Applications, [19] incorporated herein by reference.
[0063] The dosage levels of API in the drug product can be varied so as to achieve the desired therapeutic response for a particular patient. The phrase therapeutically effective amount of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated, the severity of the disorder; activity of the specific compound employed; the specific composition employed, age, body weight, general health, sex, diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed, and the duration of the treatment. The total daily dose of the compounds of this invention administered may range from about 0.0001 to about 1000 mg/kg/day. For purposes of oral administration, more preferable doses can be in the range from about 0.001 to about 5 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for optimal therapeutic effect.
[0064] The following examples illustrate specific embodiments and utilities of the invention, and are not meant to limit the invention. As would be apparent to skilled artisans, various modifications in the composition, operation, and method are possible, and are contemplated herein without departing from the concept and scope of the invention as defined in the claims.
Example 1: Proposed Synthesis of Compound of Formula I, Wherein X is NR.SUP.10., Y is a Single Bond, (m,n) is (1,2), R.SUP.1 .and R.SUP.10 .are CH.SUB.3., and R.SUP.2 .to R.SUP.9 .are Hydrogens (11a)
[0065] ##STR00007##
Step 1. 11-Methyl-dibenzo[b,e]diazepine (10 mmol) in ethanol (25 mL), and acetic acid (10 mL) is gently stirred to dissolved all the solids. Thereafter, the solution is cooled to 0 C. in ice bath and treated with a concentrated, aqueous solution of NaNO.sub.2 (15 mmol) in water (5 mL) added dropwise over a period of 2-5 minutes. The reaction is stirred at ambient temperature for 1.5 hours and treated with water (30 mL). The crude product is collected by filtration, washed with water, and dried to give the N-nitroso compound. The material is used as such for the next step.
Step 2. A stirring mixture of nitroso compound from Step 1 (1.5 mmol) and 1-methyl-4-piperidone hydrochloride (1.8 mmol) in ethanol (4.5 mL) and acetic acid (1.5 mL) is treated with zinc dust (6.0 mmol) added in three equal portions allowing 5-10 minutes between the additions. The reaction is then stirred at ambient temperature for 2-24 hours. The reaction mixture is cooled to about 0-5 C., and treated with concentrated ammonium hydroxide (5 mL). The reaction mixture is extracted with dichloromethane (330 mL). The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated in vacuo. The crude material may be used as such for the next step or can be purified by flash chromatography to furnish the hydrazine intermediate.
Step 3. A suspension of the hydrazone from Step 2 (1.3 mmol) in isopropyl alcohol (5 mL) is treated with 2 mL of 2 M solution of hydrogen chloride in dioxane (2.6 mmol), and the entire mixture is heated under reflux for 2 hours. The reaction mixture was cooled to ambient temperature, treated with 10% NaOH (4 mL), and extracted with dichloromethane (330 mL). The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated in vacuo. The crude product is purified by flash chromatography to obtain the desired product 11a.
Example 2: Proposed Synthesis of Compound of Formula I, Wherein X is NR.SUP.10., Y is a Single Bond, (m,n) is (1,1), R.SUP.1 .and R.SUP.10 .are CH.SUB.3., and R.SUP.2 .to R.SUP.9 .are Hydrogens (11b)
[0066] ##STR00008##
Step 1. The same nitroso compound from Step 1, Example 1 is used herein.
Step 2. The procedure is nearly identical to that of Step 2, Example 1 except that 1-methyl-3-pyrrolidone is used instead of 1-methyl-4-piperidone.
Step 3. The procedure is identical to that of Step 3, Example 1 to give 11b.
Example 3: Proposed Synthesis of Compound of Formula I, Wherein X is NR.SUP.10., Y is a Single, (m,n) is (2,2), R.SUP.1 .and R.SUP.10 .are CH.SUB.3., and R.SUP.2 .to R.SUP.9 .are Hydrogens (11c)
[0067] ##STR00009##
Step 1. The same nitroso compound from Step 1, Example 1 is used herein.
Step 2. The procedure is nearly identical to that of Step 2, Example 1 except that 1-aza-1-methylcycloheptan-4-one is used instead of 1-methyl-4-piperidone.
Step 3. The procedure is identical to that of Step 3, Example 1 to give 11c. Using the same procedure outlined in Steps 1-3 above, other derivatives wherein (m,n) is (1,3) can be prepared by using 1-aza-1-methylcycloheptan-3-one.
Example 4: Proposed Synthesis of Compound of Formula I, Wherein X is NR.SUP.10., Y is a Single Bond, (m,n) is (2,3), R.SUP.1 .and R.SUP.10 .are CH.SUB.3., and R.SUP.2 .to R.SUP.9 .are Hydrogens (11d)
[0068] ##STR00010##
Step 1. The same nitroso compound from Step 1, Example 1 is used herein.
Step 2. The procedure is nearly identical to that of Step 2, Example 1 except that 1-aza-1-methylcyclooctan-5-one is used instead of 1-methyl-4-piperidone.
Step 3. The procedure is identical to that of Step 3, Example 1 to give 11d. Using the same procedure outlined in Steps 1-3 above, other derivatives wherein (m,n) is (1,4) or (2,3) can be prepared by using 1-aza-1-methylcyclooctan-3-one or 1-aza-1-methylcyclooctan-4-one.
Example 5: Proposed Synthesis of Compound of Formula I, Wherein X is S, Y is a Single Bond, (m,n) is (1,2), R.SUP.1 .is CH.SUB.3., and R.SUP.2 .to R.SUP.9 .are Hydrogens (12a)
[0069] ##STR00011##
Step 1. Dibenzo[b,e]thiazepine (10 mmol) in ethanol (25 mL), and acetic acid (10 mL) is gently stirred to dissolved all the solids. Thereafter, the solution is cooled to 0 C. in ice bath and treated with a concentrated, aqueous solution of NaNO.sub.2 (15 mmol) in water (5 mL) added dropwise over a period of 2-5 minutes. The reaction is stirred at ambient temperature for 1.5 hours and treated with water (30 mL). The crude product is collected by filtration, washed with water, and dried to give the N-nitroso compound. The material is used as such for the next step.
Step 2. A stirring mixture of nitroso compound from Step 1 (1.5 mmol) and 1-methyl-4-piperidone hydrochloride (1.8 mmol) in ethanol (4.5 mL) and acetic acid (1.5 mL) is treated with zinc dust (6.0 mmol) added in three equal portions allowing 5-10 minutes between the additions. The reaction is then stirred at ambient temperature for 2-24 hours. The reaction mixture is cooled to about 0-5 C., and treated with concentrated ammonium hydroxide (5 mL). The reaction mixture is extracted with dichloromethane (330 mL). The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated in vacuo. The crude material may be used as such for the next step or can be purified by flash chromatography to furnish the hydrazine intermediate.
Step 3. A suspension of the hydrazone from Step 2 (1.3 mmol) in isopropyl alcohol (5 mL) is treated with 2 mL of 2 M solution of hydrogen chloride in dioxane (2.6 mmol), and the entire mixture is heated under reflux for 2 hours. The reaction mixture was cooled to ambient temperature, treated with 10% NaOH (4 mL), and extracted with dichloromethane (330 mL). The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated in vacuo. The crude product is purified by flash chromatography to obtain the desired product 12a.
Example 6: Proposed Synthesis of Compound of Formula I, Wherein X is S, Y is a Single Bond, (m,n) is (1,1), R.SUP.1 .is CH.SUB.3., and R.SUP.2 .to R.SUP.9 .are Hydrogens (12b)
[0070] ##STR00012##
Step 1. The same nitroso compound from Step 1, Example 5 is used herein.
Step 2. The procedure is nearly identical to that of Step 2, Example 5 except that 1-methyl-3-pyrrolidone is used instead of 1-methyl-4-piperidone.
Step 3. The procedure is identical to that of Step 3, Example 5 to give 12b.
Example 7: Proposed Synthesis of Compound of Formula I, Wherein X is S, Y is a Single Bond, (m,n) is (2,2), R.SUP.1 .is CH.SUB.3., and R.SUP.2 .to R.SUP.9 .are Hydrogens (12c)
[0071] ##STR00013##
Step 1. The same nitroso compound from Step 1, Example 5 is used herein.
Step 2. The procedure is nearly identical to that of Step 2, Example 5 except that 1-aza-1-methylcycloheptan-4-one is used instead of 1-methyl-4-piperidone.
Step 3. The procedure is identical to that of Step 3, Example 5 to give 12c. Using the same procedure outlined in Steps 1-3 above, other derivatives wherein (m,n) is (1,3) can be prepared by using 1-aza-1-methylcycloheptan-3-one.
Example 8: Proposed Synthesis of Compound of Formula I, Wherein X is S, Y is a Single Bond, (m,n) is (2,3), R.SUP.1 .is CH.SUB.3., and R.SUP.2 .to R.SUP.9 .are Hydrogens (12d)
[0072] ##STR00014##
Step 1. The same nitroso compound from Step 1, Example 5 is used herein.
Step 2. The procedure is nearly identical to that of Step 2, Example 5 except that 1-aza-1-methylcyclooctan-5-one is used instead of 1-methyl-4-piperidone.
Step 3. The procedure is identical to that of Step 3, Example 5 to give 12d. Using the same procedure outlined in Steps 1-3 above, other derivatives wherein (m,n) is (1,4) or (2,3) can be prepared by using 1-aza-1-methylcyclooctan-3-one or 1-aza-1-methylcyclooctan-4-one.
Example 9: Proposed Synthesis of Compound of Formula I, Wherein X is SO.SUB.2., Y is a Single Bond, (m,n) is (1,2), R.SUP.1 .is CH.SUB.3., and R.SUP.2 .to R.SUP.9 .are Hydrogens (12e)
[0073] ##STR00015##
[0074] The sulfide 12a from Example 5 (10 mmol) in dichloromethane (15 mL) is treated with a solution of 4-chloroperoxybenzoic acid (MCPBA) (11 mmol) in dichloromethane (15 mL). The reaction is stirred under reflux for 2-8 hours and treated with 1 M NaOH (15 mL). The organic layer is separated, washed with saturated sodium bicarbonate solution (220 mL) and water, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated in vacuo. The crude compound is purified by flash column chromatography to give the sulfone 12e.
Example 10: Proposed Synthesis of Compound of Formula I, Wherein X is SO.SUB.2., Y is a Single Bond, (m,n) is (1,2), R.SUP.1 .is CH.SUB.3., and R.SUP.2 .to R.SUP.9 .are Hydrogens (12f)
[0075] ##STR00016##
[0076] The procedure is identical to Example 9, except that two molar equivalents of MCPBA (22 mmol) is used to give the sulfone 12e
Example 11: Proposed General Procedure for the Synthesis of Compound of Formula III, Wherein X is NR.SUP.10 .or S, Y is a No with Cis-Fused B|C Rings, (m,n) is (1,2), R.SUP.1 .and R.SUP.11 .are CH.SUB.3., and R.SUP.2 .to R.SUP.9 .are Hydrogens (13, 14)
[0077] ##STR00017##
[0078] A stirred cold solution of compound 11a or 12a from (2 mmol) in trifluoroacetic acid (6.5 mL) at 5 C., is carefully treated with solid sodium cyanoborohydride (2.4 mmol). The reaction mixture is then stirred at ambient temperature for 3 h, treated with 6N HCl solution, and heated under reflux for 30 minutes. The solution is cooled to ambient temperature, and excess trifluoroacetic acid is removed in vacuo. The residue is rendered alkaline with 25% NaOH solution (12 mL), and the solution is extracted with chloroform. The combined organic layers are washed with water and brine, and dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated in vacuo. The crude compound is purified by flash column chromatography to give the enantiomeric mixtures of 13 or 14 respectively. Using the procedure outlined about, all other compounds of formula II can be reduced sterospecifically to the corresponding cis-fused stereoisomers.
Example 12: Proposed General Procedure for the Synthesis of Compound of Formula IV, Wherein X is NR.SUP.10 .or S, Y is a No with Trans-Fused B|C Rings, (m,n) is (1,2), R.SUP.1 .and R.SUP.10 .are CH.SUB.3., and R.SUP.2 .to R.SUP.9 .are Hydrogens (15, 16)
[0079] ##STR00018##
The compound 11a or 12a from (1 mmol) is treated with borane-THF (10 mL, 1.0 M) at ambient temperature, and the mixture is heated under reflux for 1 hour. After cooling to ambient temperature, the solution is treated with water to quench excess reagent borane reagent. The solvents are removed under reduced pressure, and the residue is treated with conc. HCl (7 mL). The mixture is heated to reflux for 3 hours and evaporated to dryness in vacuo, and treated with 10% NaOH solution (10 mL). The product is then extracted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to dryness under reduced pressure. The crude compound is purified by flash column chromatography to give the enantiomeric mixtures of 15 or 16 respectively. Using the procedure outlined about, all other compounds of formula II can be reduced sterospecifically to the corresponding trans-fused stereoisomers.
REFERENCES
[0080] 1. Fox, R. B.; Powell, W. H. Nomenclature of Organic Compounds: Principles and Practice, Second Edition. Oxford University Press, Oxford, 2001. [0081] 2. Hellwinkel, D. Systematic Nomenclature of Organic Chemistry: A Directory of Comprehension and Application of its Basic Principles. Springer-Verlag, Berlin, 2001. [0082] 3. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4.sup.th Edition. Washington, D.C., Association, A. P., 1994. [0083] 4. Roth, B. L. Ed. The Serotonin Receptors. Human Press, Totowa, N.J., 2006. [0084] 5. Nichols, D. E.; Nichols, C. D. Serotonin Receptors. Chem. Rev. 2008, 108, 1614. [0085] 6. Micale, V.; Leggio, G. M.; Mazzola, C.; Drago, F. Brain Res. 2006, 112, 207. [0086] 7. Jongen-Relo, A. L.; Bespalov, A. Y.; Rueter, L. E.; Freeman, A. S.; Decker, M. W.; Gross, G.; Schoemaker, H.; Sullivan, J. P.; Van Gaalen. M. M.; Wicke, K.; Zhang, M.; Amberg, W.; Garcia-LaDona, J. Soc. Neurosci. Annual Meet, Atlanta, Ga. 2006, 526, 29. [0087] 8. King, M. V.; Marsden, C. A.; Fone, K. C. A role for the 5-HT.sub.1A, 5-HT.sub.4 and 5-HT.sub.6 in learning and memory. Trends Pharmacol. Sci. 2008, 29, 482. [0088] 9. Brenchat, A. et al. Pain 2010, 149, 483-494. [0089] 10. Mnie-Filali, O.; Lambas-Senas, L.; Zimmer, L.; Haddjeri, N. Drug News Perspect. 2007, 20, 613. [0090] 11. Doly, S., Valjent, E., Setola, V., Callebert, J., Herve, D.; Launay, J.-L., and Maroteaux, L. J. Neurosci. 2008, 28, 2933. [0091] 12. Rajagopalan, P. U.S. Pat. No. 4,438,120; 1984. [0092] 13. Rajagopalan, P. U.S. Pat. No. 4,219,550; 1980. [0093] 14. Adams, C. W. U.S. Pat. No. 3,983,123; 1976. [0094] 15. Bandyopadhyaya, A.; Rajagopalan, D. R.; Rath, N. P., Herrold, A., Rajagopalan, R., Napier, C. T., Tedford, C. E., and Rajagopalan, P. Medicinal Chemistry Communications 2012, 3, 580-583. [0095] 16. Nandakumar, M. V.; Verkade, J. G. Pd.sub.2dba.sub.3/P(i-BuNCH.sub.2CH.sub.2).sub.3N: Tetrahedron 2005, 61, 9775-9782. [0096] 17. Pharmaceutical Manufacturing. In Remington: The Science and Practice of Pharmacy. Lippincott Williams & Wilkins, Philadelphia, 2005, 691-1058. [0097] 18. Weissig, V. Liposomes: Methods and Protocols Volume 1: Pharmaceutical Nanocarriers. Humana Press, New York, 2009. [0098] 19. Li, X. Design of Controlled Release Drug Delivery Systems. McGraw-Hill, New York, 2006. [0099] 20. Rautio, J. et al. Prodrugs: Design and Clinical Applications. Nature Reviews Drug Discovery 2008, 7, 255.