JPS5865280A - Depression disease therapy - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a therapeutic agent for human depression comprising a specific 5-(aminoalkyl)-11-phenyl-5H-dibenzo[bμ)(1,4]diazepine. Some of these are new.

Wander, A., UK Pat. No. 907,646 describes the preparation of certain of the dibenzodiazepines used in the present invention, such as the active ingredient of the compound of Example 1 in the form of the maleate salt. is disclosed.

Wanderney (A.) discloses the use of reductants in British Patent No. 959994.

For example, 5-(aminoalkyl)-11-7enyl-10°11-dihydro-5H as a sympatholytic agent, antihistamine, antispasmodic, tranquilizer, and psychoactive agent.
-dibenzo[bμI][1,4) diazepine.

Greigzem E ((:, retq, M, I'
: , ) et al. J.

y, ec5 Cht, 14. A2.153 pages (19
71) in mice, 2-chloro-5-(dimethylamineethyl)-1
1-phenyl-5H-dibenzoCb, el(1,4]
discloses the anaphylactic activity of diazepines.

Compounds useful as a therapeutic agent for depression according to the present invention are those represented by the following general formula and pharmaceutically acceptable acid addition salts thereof.

(R, R are selected from the group consisting of H and methyl;
, CL By, F), both of which are H, or one of which is methyl and the other is H, is novel.

Pharmaceutically acceptable acid addition salts are physiologically compatible salts such as those formed with strong or weak acids.

Typical examples of strong acids are hydrochloric acid, sulfuric acid, and phosphoric acid. Representative examples of weak acids include fumaric acid, maleic acid, succinic acid, oxalic acid, and cyclohexanoic acid.

For the purpose of demonstrating the antidepressant use of the compound represented by the general formula
d, t, E, L,) etc. are J6Met, Ghtrn,
1(2):325 (1968) (conventional method demonstrating the utility of compounds for the treatment of depression in humans)
was used as follows.

9 test compounds were administered to 5 adult female mice (I
C: R-DUB species), amount of ptosis (62η/Kg,
30 minutes before the administration of tetrabenazine (methane sulfonate) (P, ), it was administered intraperitoneally. Thirty minutes later, each animal was examined for complete eyelid closure (blepharoptosis). Litchfield et al. J, Pha
rmacol, Exp, Therap, 9 (5,9
9-1, p. 13 (1949), the ED5o (median effective dose) of each test compound that inhibits tetrabenazine-induced depression in mice can be established. Preferred among the dibenzodiazepines useful as therapeutic agents of the present invention are the active agents of Example 1, namely 5-(6-dimetelaminobyl)-11-phenyl-5H-dibenzo[b,
g] (1,4) diazebinte.

Therefore, the first objective of the present invention is to provide a therapeutic agent for depression.

Other objects and advantages of the present invention will be apparent to those skilled in the art, and will become apparent from the description herein.

The therapeutic agent of the present invention consists of an active ingredient represented by the general formula (2) and a suitable pharmaceutical carrier as an optional ingredient, and is used in the form of a solution, syrup, elixir, tablet, capsule, suppository, powder, etc. .

For the compound of the general formula (1) in which the 5th position is substituted with 6-dimethylaminoprobyl, a dehydration condensation catalyst, such as an oxyhalide of phosphorus pentoxide (the latter is preferred), and a suitable solvent, such as 1.1.2 Using 2-tetrachloroethane, <N-(3
-dimethylamitube)-0-inzamide is produced by cyclodehydration of diphenylamine. Reaction formula % formula % (X is defined the same as in general formula I) A new compound of general formula phthalimide)propyl']
-O-Inzamide diphenylamine (II l)
is produced by cyclodehydration and then converting the phthalimi F moiety to amino (NH2) with hydrazine and acid. The reaction formula is as follows.

(8) The compound represented by the general formula (1) (where X is defined in the same manner as in the case of the general formula (2)) is also new.

-4' New compounds of formula l in which the 5-position is substituted with 3-monomethylpropylamine are prepared by reacting a 3-aminopropyl compound with triethyl orthoformate and then with sodium borohydride [Grockett &Blanton's method, 1
974 (11:55-6 Synthesis). Reaction formula % Formula % The starting compound xnzamide I'l (lα, 1b) is prepared by an improved method of the method described in British Patent No. 907,646. Diphenylamine is first converted to β-
Reductive alkylation with a solution of chloropropyldimethylamine or 6-(1-phthalimido)-1-chloropropane,
Next, hydrogen reduction is performed using nitro moiety Pd, /G to obtain the corresponding ortho-amino compound. Then, the amino group at the ortho position is reacted with a halogenated benzoyl or a substituted halogenated benzoyl.

The reaction formula is as follows.

■ (CH2)3■ Q = -N(OH3) 2 or 1-phthalimide Production Example 1 N-(3-dimethylaminozolobyl)-〇-aminodiphenylamine 32.0.9 (0,107 mol) of N- (3-dimethylaminopropyl)-〇-nitrodiphenylamine (AP
I55°10.4~174°C10.33 Dragon) and 100m
t of 200 proof ethyl alcohol and 1.5g of 10
The mixture with %Pct/G catalyst was shaken under hydrogen atmosphere at room temperature for 1 hour. After a theoretical amount of hydrogen had been absorbed, the catalyst was removed through a Celite filter and the solvent was removed under reduced pressure. The residue was distilled under high vacuum as follows.

Fraction 1 80-130°10.2 tons
4.02 130-137VD, 2ix 7.
03 137-142'10.2 Sushi 15.520
% methyl alcohol/80% benzene, thin layer chromatography on silica gel showed that fraction 6 was extremely pure.

Production Example 2 Bipyridine 10 of N-(3-dimethylaminopropyl)-〇-aminodiphenylamine [15,59 (0,0575 mol)] cooled to about 5°C and under nitrogen atmosphere
Add 17.89 (0,063 mol) of benzoyl chloride to the 0#It) solution. A small amount of benzene was used to flush residual benzoyl chloride into the reaction vessel. After stirring for 1 hour, the container was stopped and the mixture was placed in the refrigerator. The solvent was then evaporated under reduced pressure. The residual oil was dissolved in 100% methylene chloride and diluted with 150 ml (r) 3N NaOH.
Washed 6 times with 2,507 liters of water. The methylene chloride layer was dried over magnesium sulfate, evaporated under reduced pressure and residual pyridine was removed under high vacuum (0.2 mmHg) until the next morning. The weight of the residual oil, free base, was 24.9 g.

To a hot solution of the free base of oxalate 4, Oy in isopropyl alcohol was added 1.359 (0.0107 mol) of oxalic acid dihydrate. The precipitated oxalate salt of the title compound is 6.
It weighed 5g and was melted at 162-5°C.

This salt was heated to 97-98°C (refluxing propyl alcohol) for 1
It was dried overnight at room temperature and 0.1 gmHg, and analyzed as follows.

Analysis Calculated value (026H29N305): C, 67, 3
7; ) (,lls,!+1; N, 9.06 measurement value: C,67,42; H,6,35; N,
9.01 Production Example 6 In the method of Production Example 2, 2-chlorobenzoyl chloride was used instead of nzoyl.

6-chlorobenzoyl chloride.

2-fluorobenzoyl chloride.

jA-3-fluorobenzoyl.

2-bromobenzoyl chloride.

3-bromobenzoyl chloride.

N-(3-dimethylaminopropyl)-〇-(2-chlorobenzamido)diphenylamine using 4-chlorobenzoyl chloride.

N-(3-dimethylaminopropyl)l-(3-chlorobenzamido)diphenylamine.

N-(6-dimethylaminopropyl)i-(2-fluorobenzamido)diphenylamine.

N-(6-dimethylaminopropyl)-〇-(3-fluorobenzamido)diphenylamine.

N-(3-dimethylaminopropyl)-O-(2-bromobenzamido)diphenylamine.

N-(6-dimethylaminopropyl)-0-(3-bromobenzamido)diphenylamine.

N-(6-dimethylaminopropyl)-o-(3-chlorobenzamido)diphenylamine.

I read it.

Production Example 4 0-Nitrodiphenylamine was mixed with sodium hydride, 3-
(1-phthalimido)-1-chloropropane was reacted with N-3-(1-7thalimido)propyl-〇-nitrodiphenylamine, which was then hydrogen-reduced in ethanol using Pd/G. The irradiated compound was obtained.

Preparation Example 5 Method of Preparation Example 2 - C'N-3-(1-phthalimido)propyl-0-aminodiphenylamine in excess of the following acyl chloride: 2-chlorobenzoyl chloride.

3-chlorobenzoyl chloride.

2-fluorobenzoyl chloride.

3-fluorobenzoyl chloride.

2-bromobenzoyl chloride.

3-bromobenzoyl chloride.

4-Chlorochloride is reacted with each of the Nzoyl to give N-3-(1-7thalimido)propyl-〇-(2-chlorothalimido)diphenylamine.

N-3-(1-7talimido)propyl-0-(3-chlorobenzamido)diphenylamine.

N-3-(1-7talimido)propyl-〇-(2-fluorobenzamido)diphenylamine.

N-3-(1-phthalimido)propyl-〇-(6-fluorobenzamido)diphenylamine.

N-3-(1-7talimido)propyl-0-(2-bromobenzamido)diphenylamine.

N-3-(1-phthalimido)propyl-0-(3-promoinzamido)diphenylamine.

N-3-(1-phthalimido)propyl-〇-(4-chlorobenzamido)diphenylamine was obtained.

The following examples are four illustrative of compounds useful in the present invention.

Example 1 Salt [1:1] 18.9 g (0.05 mol) of N-(6-dimethylaminopropyl)-o-benzamide diphenylamine and 3
2.19 g (0.2 mol) of phosphorus oxychloride and 50 m
t of 1.1.2.2-tetrachloroethane was stirred and heated at 150° C. under a nitrogen atmosphere for 1.5 hours. Cool slightly and pour over crushed ice at approximately 10100O to a final volume of 1O
Diluted with enough water to make ooIRt. The resulting aqueous suspension was extracted twice with methylene chloride and the methylene chloride layer was discarded.

Make the aqueous layer basic with 3 N NaOH and add 250 #L each.
Extracted six times with methylene chloride (Z). These six methylene chloride extracts were combined, dried over magnesium sulfate, and dried in vacuo to yield 13.8 g of the free base of the irradiated compound as a residual oil. This oil was dissolved in hot inpropyl alcohol and reacted with 4.5 g (0,039 mol) of fumaric acid. Take 1 piece of fumarate and dry it to 13F.
I prayed. mP 168-1700C.

Di U1 = Calculated value (C28H29N304): 0, 71.
32; H, 6, 20; N, 8.91 Measured value: C, 7
1,19; H, 6,19; N, 8.89 Example 2 N-(3-dimethylaminopropyl) by the method of Example 1
-〇-inzami1diphenylamine in place of equimolar amount of N-(3-dimethylaminozolobyl)-〇-(2-chlorobenzamido)diphenylamine.

N-(6-dimethylaminopropyl 1O-(3-chlorobenzamido)diphenylamine.

N-(6-dimethylaminozolobyl 1 l)-(2-fluorobenzamido)diphenylamine.

N-(3-dimethylaminozolobyl)-〇-(3-fluorobenzamido)diphenylamine.

N-(3-dimethylaminopropyl)-0-C2-bromobenzamido)diphenylamine.

N-(6-dimethylaminozolobyl)-O-(3-bromohanzumido)diphenylamine.

1l-(2-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[: b, e] using N-(6-dimethylaminozorobyl)-O-(4-chlorobenzamido)diphenylamine c'
+, 4':l diazepine, fumarate.

1l-(I-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzoCb,e'](1,
4] Diazepine, fumarate.

1l-(2-fluorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzoCb+ g:)cl
,,.

Diazepine, fumarate.

1l-(3-fluorophenyl)-5-(3-dimethylaminozolobyl)-5H-dihanzo[b, gl(:1
．． 41 diazepine, fumarate.

1l-(2-bromophenyl)-5-(3-dimethylaminopropyl)-5H-diphenolj,g][11,4
) diazepine, fumarate.

1l-(3-bromophenyl)-5-(5-dimethylaminopropyl)-5H-dibenzoCh, e][1,4
] Diazepine, fumarate.

1l-(4-chlorophenyl)-5-(3-dimethylaminopropyl)-5H-dibenzo[A,gl(1,4]
Diazepine, fumarate was obtained.

Example 6 N-3-(1-phthalimido)furopyru-0-benzamide diphenylamine instead of N-(3-dimethylaminopropyl)-0-benzamide diphenylamine in the method of Example 1 before addition of fumaric acid.

N-3-(1-phthalimido)propyl-〇-(2-chlorobenzamido)diphenylamine.

N-3-(1-phthalimido)propyl-□-(3-chlorobenzamido)diphenylamine.

N-3-(1-phthalimido)propyl-〇-(2-fluorobenzamido)diphenylamine.

N-3-(1-phthalimido)propyl-〇-(3-fluoro4dzamido)diphenylamine.

N-3-(1-phthalimido)pro1-0-(2-bromobenzamido)diphenylamine.

N-3-(1-phthalimido)propyl-〇-(6-bromohanzumido)diphenylamine.

5-14-(1-phthalimido)propyl]-11-phenyl-5H-dibenzo[bμ][1,43 diazepine using N-3-(1-phthalimido)propyl-〇-(4-chlorobenzamido)diphenylamine .

5-(3-(1-phthalimido)propyl]-11-(
2-chlorophenyl)-5H-dibenzo[A, gXl.

4] Diazepine.

5-[3-(1-phthalimido)propyl]-11-(
6-chlorophenyl)-58-dibenzoCA, el[1
゜4〕Diazepine.

5-(3-41-phthalimido)propyl]-11-(
2-fluorophenyl)-5H-dibenzo[h,e][
1,4':] diazepine.

5-C3-(,1-phthalimido)propyl]-11
-(ro-fluorophenyl)-5H-dibenzo[b,e
] [1,4) Diazepine.

5-[3-(1-phthalimido)propyl]-11-
(2-Bromophenyl)-5H-dibenzo[bμ)[1
, 4] Diazepine.

5-(3-(1-phthalimido)propyl]-11-(
3-Bromophenyl)-5H-dibenzo[A,e,][
1゜4〕Diazepine.

5-i-(1-7talimido)propyl]-11-(4
-chlorophenyl)-5H-dibenzo[A,g][1°4]diazepine.

Example 4 0.035 mol of 5-[3-(1-phthalimido)propyl-11-phenyl-5H-dibenzo[b.

A mixture of ']C1,4] diazepine, 0.039 moles of hydrated hydrazine, and 190 proof ethyl alcohol was refluxed for 2.5 hours and allowed to stand for 7 hours. 10 ml of concentrated hydrochloric acid was dissolved in 5'[1 mt of water and added to the above mixture;
Stir for hours. It was filtered and the P solution was evaporated under reduced pressure.

The resulting hydrochloride salt was isolated by recrystallization from a suitable solvent and dried under reduced pressure.

Example 5 5-[3-(1-phthalimido)furovir]-11-phenyl-5H-dibenzoCh,e]c by the method of Example 4
1.4] Instead of diazepine, equimolar amount of 1l-(2-
Chlorophenyl)-5-(3-(1-phthalimido)probilco5H-diinzo[bμ][1°4]diazepine.

1'1-(3-chlorophenyl)-5-(3-(1-phthalimido)propyl]-50-dibenzo[bμ][
1゜4〕Diazepine.

1l-(2-fluorophenyl)-5-[3-(1-phthalimido)propyl]-58-diinzo[6,e][
1,4:] diazepine.

11-(Ri-fluorophenyl)-5-[3-(1-phthalimido)propyl-5H-dibenzo[b,J[1
, 4] Diazepine.

1l-(2-bromophenyl)-5-[3-(1-phthalimido)propyl]-5H-dibanzo[A,g)[1
゜4〕Diazepine.

1l-(3-bromophenyl)-5-[3-('l-phthalimi)')propyl]-5H-dihanzocb,g'
:+ci.

4] Diazepine.

5-(6-Aminozorobyl)-11-(2-chlorophenyl) using 1l-(4-chlorophenyl)-5-[3-(1-phthalimido)propyl-5H-dibenzo[bμ][1°4] diazepine -5H-dibenzo[Ib, g][1,4]diazepine hydrochloride.

5-(3-Aminopropyl)-11-(5-chlorophenyl)-5H-dibenzo[b,J(1,4]diazepine hydrochloride.

5-(3-aminopropyl)-11-(2-fluorophenyl)-5H-dibenzo[bμ'3C1,4'3dilyze2ine hydrochloride.

5-(3-aminozorobyl)-11-(3-fluoro
7e: #) -5H-dihanzoIj', g] [1,
4] Diazepine hydrochloride.

5-(3-Aminopropyl)-11-(2-bromophenyl)-58-Z! Nzo[bμ][1,4]diazepine hydrochloride.

5-(6-aminozolobyl)-11-(3-bromo7
-5H-diA7zo[b,g][1,4]diazepine hydrochloride.

5-(6-Aminozorobyl)-11-(4-chlorophenyl)-5t(-divanzo[jμ][1,4]dirisevin hydrochloride.

The state was

Example 6 5-(3-7mi/propyl)-11-phenyl-5H-
Partitioning the hydrochloride of dibenzo[hμ][1,4]diazepine between dilute NaOH and methylene chloride, drying the degraded methylene layer, concentrating to dryness, adding dry benzene, and removing the benzene by reconcentration. The free base was converted to the free base. The resulting free base was dissolved in a large excess of freshly distilled triethyl orthoformate and refluxed for several hours. The mixture was concentrated in vacuo, ethanol was added and reconcentrated. The resulting imidate was dissolved in ethanol and sodium borohydride was added until thin layer chromatography showed the absence of a substantial amount of starting material.
It was added with stirring at 20°C. After cooling, water was slowly poured into the mixture and then extracted with ethyl acetate. The ethyl acetate layer was washed neutral, salted out, filtered with f+ and evaporated. The crude free base was isolated by column chromatography, reacted with HCz ether solution and recrystallized to skim off the irradiated compound.

Example 7 5-(3-aminopropyl)-11- by the method of Example B
Hue=#-5H-dibenzo[A,tcoC1,4E Instead of diazepine, equimolar amount of 5-(6-aminopropyl)-11-(2-chlorophenyl)-5H-dibenzo[bμ][1,4 ]Diazepine hydrochloride.

5-(6-aminopropyl)-11-(2-chlorophenyl)-5H-dibenzo[A,g][1,4)diazepine hydrochloride.

5-(6-aminopropyl)-11-(2-fluorophenyl)-58-dibenzo[bμ][1,4]diazepine salt "acid acid.

5-(6-Aminopropyl)-11-(3-fluorophenyl)-5H-dibenzo[bμ][1,4')diazepine hydrochloride.

5-(6-aminopropyl)-11-(2-bromophenyl)-5H-di4inzo[bμ'][1,4)diazepine hydrochloride.

5-(6-aminopropyl)-11-(3-bromophenyl)-5H-dibenzo[1! ', gXl, 4) diazepine hydrochloride.

Using 5-(6-aminopropyl)-11-(4-chlorophenyl)-5H-dibenzo[blt][1,4]diazepine hydrochloride, 1l-(2-chlorophenyl)-N-methyl-5H-dibenzo [bμ][1,4]Diazepine-5-propanamine hydrochloride.

11-(3-chlorophenyl)-N-methyl-5H-diinzoCI), eJcl, 4J diazepine-5-propanamine hydrochloride.

1l-(2-fluorophenyl)-N-methyl-5H-
Dibenzo[bμ[1,41 diazepine-5-propanamine hydrochloride.

1l-(3-fluorophenyl)-N-methyl-5H-
dibenzoCb,e]c1.4) diazepine-5-pro,
Gunamine hydrochloride.

11-(2-bromophenyl)-N-methyl-5H-dibenzoCb, g][1,4]diazepine-5-propanamine hydrochloride.

11-(3-bromophenyl)-N-methyl-5H-dimenzoCb,e]c1,4]diazepine-5-propanamine hydrochloride.

11-(4-chlorophenyl)-N-methyl-5H-dibenzo[bμ[1,4')diazepine-5-propanamine hydrochloride was obtained.

Prescription and Administration Effective amounts of the above-mentioned pharmacologically active compounds of general formula I can be administered in the usual manner, e.g., orally, in solutions, emulsions, suspensions, pills, tablets, capsules. It can also be administered parenterally to humans for therapeutic purposes in the form of a sterile solution in a pharmaceutically acceptable carrier.

An example of a solid carrier for oral administration is lactose.

These include magnesium, stearate, terra alba, sucrose, Merck, stearic acid, gelatin, agar, pectin, and gum acacia.

Examples of liquid carriers for oral administration are vegetable oils and water.

The carrier or excipient for intramuscular administration may be a sterilized parenterally acceptable liquid, such as water or a parenterally acceptable oil (eg, fallen beef oil), contained in an ampoule.

When administering to patients with mild symptoms or low body weight, the active acid of the present invention is effective in very small doses, but the unit dose is usually 5 tnq or more, preferably 10°25.50 to 10°25.50 tnq. 100 or more, preferably administered 6 to 4 times a day, but this will, of course, depend on the condition, the compound used, and the individual desired result. 25-200 and seems to be optimal as a unit dose; the usual wider range is about 10-500.
It is assumed that η/unit dose. The daily dose usually required is from about 0.5 to about 20/Kf/day, preferably 0.5
~10+11R/Kf. The active ingredients of the invention can be used in combination with other pharmacologically active agents such as those mentioned above. It is only necessary that the active ingredient be present in an effective amount, ie, a suitable effective dose is selected to be consistent with the dosage form used. Obviously, several unit dosage forms can be administered at about the same time. The exact individual dose and daily dose will, of course, be established according to standard pharmaceutical principles under the direction of a physician or veterinarian.

The following formulation examples are representative for pharmacologically active compounds of the invention.

Formulation Example 1: Capsules were made containing 50 mq of active ingredient, 10 capsules per capsule. When increasing the amount of active ingredient, the amount of lactose can be decreased.

Active ingredient (as salt) 10
50 Lactose 259 219
Starch 126 126 Magnesium stearate 4
4 Total 399 399 Another capsule contained more active ingredient. The prescription was as follows.

Active ingredient, as salt 100 250 5
00 Lactose 214 163
95 starch 87
81 47 Magnesium stearate 4
6 8 total 399 500 65
0 In each case, the selected active ingredients were homogeneously blended with lactose, starch, magnesium stearate and the resulting blend was encapsulated.

2. A typical formulation of tablets containing 5.01 JU// tablet of active ingredient was as follows: This formulation could be used with other levels of active ingredient by adjusting the weight of dicalcium phosphate.

In97 tablet 1, active ingredient 10.02, cornstarch 15. .

3. Cornstarch (yeast)
12.04, lactose 35
．． .

5. Dicalcium phosphate 132.0
6. Calcium stearate 2
．． 0 Total 202.0 Ingredients 1.2.4.5 were homogeneously blended. ingredient 6 to 10
% water as a 4-st. The blend was granulated with starch yeast and the resulting wet mass was passed through an 8 mesh screen. The wet granules were dried and sized using a 12 mesh screen. The dried granules were friended with calcium stearate and compressed.

3. Active ingredient per 1 CC of 2% sterile legal solution 2o ~ Preservative (e.g. chlorobutahal) 0.5 w/v% water for injection Prepare the residual solution, sterilize it with JlA, fill it into a vial,
Seal and autoclave.

It will be apparent to those skilled in the art that various changes and modifications can be made without departing from the scope and spirit of the invention.
Incoholated Pco', J (2 others)

Claims (1)

[Scope of Claims] Item 1: A therapeutic agent for depression comprising a compound represented by the following general formula and/or a pharmaceutically acceptable acid addition salt thereof. (CH2)3NRIR2 (R, R are selected from the group consisting of H and methyl;
, GISBf, F), the second term compound is 5-(6-dimethylaminopropyl)-11-
The therapeutic agent according to claim 1, which is phenyl-5H-dibenzo[6μ)[1,4)diazepine. The compound of Item 6 is 5-c3-dimethylaminopropyl)-11-
Claim 1, which is phenyl-5H-dibenzo[bμ)[1,4)diazepine, fumarate C1:1]
Therapeutic agents listed in section. Item 4: Compounds represented by the following general formula and pharmaceutically acceptable acid addition salts thereof. (X is selected from the group consisting of H, cz, By, F;
R' and R2 are both H, or R1 when R is methyl
is H) Compound J represented by the fifth term following general formula (CH2)3 (X is selected from the group consisting of H, CJ, BT, and F)