CA2175287A1

CA2175287A1 - Tricyclic derivatives, compositions and methods of use

Info

Publication number: CA2175287A1
Application number: CA002175287A
Authority: CA
Inventors: Pauline C. Ting; Daniel M. Solomon; Richard J. Friary; Frank J. Villani; John J. Piwinski; Joe F. Lee; Vera A. Seidl; James P. Jakway; Dhiru B. Vashi
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme Corp
Priority date: 1996-04-29
Filing date: 1996-04-29
Publication date: 1997-10-30

Abstract

Disclosed are compounds of Formula I:

(I) or a pharmaceutically acceptable salt or solvate thereof, wherein:
R3 is alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, cycloalkyl, acyloxymethyl, alkoxy, alkoxymethyl, or alkyl substituted with cycloalkyl;
R4 is H, alkyl, alkenyl, alkoxy, or -OH.

Also disclosed are pharmaceutical compositions containing compounds of Formula I, methods for inhibiting tumor necrosis factor-.alpha.
and methods for treating septic shock, inflammation, or allergic disease by administering a compound of Formula I.

Description

217~ 7 .

TRTCYCLIC DERlVATlVES. COMPOSITIONS
AND METHODS OF USE

FELD OF THE INVENTION

The present invention relates to tricyclic derivatives, pharmaceutical compositions and methods of using such derivatives.
20 The compounds of the present invention inhibit tumor necrosis factor a ("TNF-a").

BACKGROUND OF THE INVENTION

Tumor necrosis factor a ("TNF-a") is a polypeptide cytokine known to induce a variety of inflammatory and metabolic processes i n vivo. See, e.g.,Ann. Rev. Immunol. 7:625 (1989). However, overproduction or inappropriate production of TNF-a has been shown to be involved in several pathological conditions, including septic shock and various allergic diseases and inflammatory conditions. See, e.g., Immunol Res. 10:122 (1991), Science 229:869 (1985) and Proc. Natl.
Acad. Sci. 89:7375 (1992). Thus, compounds that could inhibit TNF-a would be quite valuable in treating these conditions.

In view of the substantial interest in agents that inhibit TNF-a, the identification of compounds having anti-TNF-a activity would be a valuable contribution to the art. This invention provides just such a 7 ~
. , contribution by providing novel compounds having anti-TNF-a activity.
In addition, this invention provides methods of using such compounds.

SUMMARY OF THE INVENTION

We have now unexpectedly found that compounds having the general formula I (set forth below) provide surprisingly good activity as inhibitors of tumor necrosis factor oc (TNF-a). More specifically, we believe that the compounds of formula I provide this 10 activity by inhibiting the biosynthesis of TNF-a. In view of this surprising anti-TNF-a activity, it is believed that compounds of formula I are useful in the relief of septic shock, allergic diseases, and inflammatory conditions.
Formula I is as follows:

~R1 R3 ~

R7/ \R8 or a pharmaceutically acceptable salt or solvate thereof, wherein:
one of T and U represents N and the other represents =CH; or each of T and U represents =CH-;
one of V and W represents oxygen and the other represents -CH2-;
or each of V and W represents -CH2-;

Rl and R2 are each independently selected from the group consisting of H and halogen;

J 2t7~2~J7 ~ . .

R3 is alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, cycloalkyl, acyloxymethyl, alkoxy, alkoxymethyl, or alkyl substituted with cycloalkyl;
R4 is H, alkyl, alkenyl, alkoxy, or-OH;
S Z-----N represents an optional double bond; when 7-----N is adouble bond, Z represents -CH=, or -CH2C(RS)=~ wherein Rs is H or lower alkyl; and R7 and R8 together represent OR9;
when Z-----N represents a single bond, Z represents a direct bond, -CH2-, -CH=CH-, or -CH2C(R5)(R6)-, wherein RS and R6 are independently H or lower alkyl (provided that, when R3 is -CH3, Z is not -(CH2)2-); and R7 and R8 are independently H, alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, cycloalkyl, -OR9; -C(O)OR10; -CH2C(O)OR9;
-C(O)Rl0; -SO2Rl~; -CO-4-pyridyl-N-oxide; -(CH2)n-N(CH3)2, where n is 2 to 4; -(CH2)mO(CH2)jOH, where m and j are independently 2 or 3;
C(o)~
C(O)OR; or R7 and R8 together form either a five-membered or a six-membered ring optionally substituted with COOR9; a six-membered ring containing NRl0; or a five-membered ring fused to a benzene ring;
R9 is H or lower alkyl; and Rl~ is alkyl or aryl.

More preferred compounds of this invention are represented by Formula I wherein R3 is alkoxy, and more preferably wherein R3 is ethoxy.
More preferred compounds also include those of Formula I
wherein R3 is alkyl. When R3 is alkyl, R3 is preferably an alkyl group other than -CH3, more preferably an alkyl group having from two to six carbon atoms, and more preferably still, R3 is propyl.

~ ~ 7 .~ 2 ~ 7 More preferred compounds also include those of Formula I
wherein R3 is cyclopropylmethyl, and more preferred compounds also include those of Formula I wherein R3 is allyl.
More preferred compounds also include those of Formula I
5 wherein each of T and U represent =CH-.

Preferably, R7 and R8 are independently H, alkyl, alkenyl, alkynyl, aryl, alkaryl, or aralkyl. When R7 and R8 and N taken together form either a five-membered ring, a six-membered ring, or a five-10 membered ring fused to a benzene ring, the portion of the S- or 6-membered ring represented by R7 and R~ is preferably carbocyclic optionally having a nitrogen atom substituted for one of the carbon atoms .
Representative compounds of this invention include, but are 15 not limited to:

H3CJ N(CH~)2 H3c--J N(CH3)2 (IA) (IB) H3C N(CH3)2 H3C N(CH~2 (Ic) (ID) H2~N(CH3)2 N(cH3)2 (IE) (IF) - ~- 217~237 ~ ~3 H3C N(CH3,~ H3C NH2 (IG) (IH) C(O)CH:l H3CJ NHCH3 (IJ) (IK) (IL) (IM) so2cH3 H~

(IN) (IO) 175?~
-H~ ~?N~CH3 ( IP ) (IQ) ~NR CH3 ~CI
CH3 H3C N(CH3)2 (IR) (I S ) ~ ~
H3CJ N' C 3 ~

N ' o H3C NHCH 3 (IT) (IU) ~ 7~'7 H3CJ N,CH3 H3CJ N,CH3 C(O) O C2 H5 S ~2 (IV) (IW) , ~ NHC(O)CH 3 C2H 5~ NH 2 C2H s (IX) (IY) C2H5 N(CH3)2 H2C NHCH3 (IZ) (IAA) ~ ~~
o H2C N Oc2H5 C2H5' NHCH 3 CH3 (IBB) (ICC) 2 1 7 3 ~ 7 , H5C2~N(CH 3)2 (IDD) (IEE) ,CH3 H~N,CHa o~O ~~0 (IFF) (IGG) H3CJ ,CH3 H3CJ N,CH3 CH 2C(O)OC2H 5 (CH2)20(CH2)20 H

(IHH) (IJJ) CHzCO~ H H~NHCH 3 (IKK) (ILL) -- 2 1 7 ~ 7 g H2C N(CH3)2 H2C N(CH 3)2 (IMM) (INN) ~CI
N(CH3)2 H2C N(CH 3)2 (IOO) (IPP) ~CI ~
H3C N(CH 3)2 ~ N-OH

(IQQ) (IRR) ~CI ~
H3C N(CH 3)2 H3C N'OH

(ISS) (ITT) ~ 1 7 r~

H2C N CH 3H2C ~ ~ N~

(IUU) (IVV) HN NMe2 \~COOH
(IWW) IXX

EtO
NMe2 (IYY) ~ 1 2 1 7~ 7 This invention also provides a pharmaceutical composition comprising an effective amount of a compound of Formula I in combination with a pharmaceutically acceptable carrier.

In addition, this invention provides a method for inhibiting TNF-a in a mammAl comprising ~dministering to the mAmmal an amount of a compound of Formula I effective to inhibit TNF-a.

In view of the surprising anti-TNF-a activity of compounds of formula I, this invention provides the following methods of treatment:

- a method for treating inflammation in a mamm~l comprising administering to the mammal an effective anti-inflammatory 15 amount of a compound of Formula I;

- a method for treating septic shock in a m~mmal comprising administering to the mammal an effective anti-septic shock amount of a compound of Formula l; and - a method for treating allergic reaction in a m~mmal comprising administering to the mammal an effective anti-allergic amount of a compound of Formula I.

The present invention will be described in detail below in connection with several preferred embodiments. However, additional embodiments of the present invention will be apparent to those having ordinary skill in the art.

DETALED DESCRIPTION OF THE INVENTION

As used herein, the following terms are used as defined below unless otherwise indicated:

alkyl - (including the alkyl portions of alkoxy and cycloalkyl) - represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms;

7 c~ 2 8 ~

alkenyl - (including the alkenyl portions of cycloalkenyl) represents straight and branched carbon chains having at least one carbon to carbon double bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms;
alkynyl - represents straight and branched carbon chains having at least one carbon to carbon triple bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms;
aryl - represents a carbocyclic group (preferably phenyl or substituted phenyl) containing from 6 to 14 carbon atoms and having at least one phenyl or fused phenylene ring, with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, cyano, cycloalkyl, -alkenyloxy, alkynyloxy, -SH, -S(O)eR12 (wherein e is 1 or 2 and R12 is alkyl or aryl), -CF3, amino, alkylamino, dialkylamino, -COOR12 or-NO2;
acyl - (including the acyl portions of acyloxy) represents -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkynyl, -C(O)-cycloalkyl, -C(O)-cycloalkenyl or -C(O)-cycloalkynyl;
alkaryl - represents an aryl group, as defined above, in which an alkyl group, as defined above, is substituted for one of the aryl H atoms;
alkoxy - represents an alkyl group, as defined above, attached to a molecule through an oxygen molecule (-O-alkyl);
alkoxymethyl - represents an alkoxy group as defined above attached to a molecule through a methylene group;
aralkyl - represents an alkyl group, as defined above, in which an aryl group, as defined above, is substituted for one of the alkyl H atoms;
and halo - represents fluoro, chloro, bromo and iodo.
Certain compounds of the invention may exist in different isomeric (e.g., enantiomers and diastereoisomers) as well as conformational forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Tautomeric forms are also included.

~ ~17~Q7 The compounds of Formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated 5 forms for purposes of the invention.

Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.

Certain compounds of the invention will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts.
Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed 15 with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.

Certain basic compounds of the invention also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, 20 the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other 25 mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium 30 hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and -= -. 3 2~752ù i all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

The invention disclosed herein is exemplified by the :~ following preparative examples, which should not be construed to limit the scope of the disclosure. Alternative synthetic pathways and analogous structures within the scope of the invention may be apparent to those of ordinary skill in the art. Further, those skilled in the art will recognize that the reactions are conducted under conditions, e.g., 10 temperature, that will allow the reaction to proceed at a reasonable rate to completion. Unless indicated otherwise, the substituents for the formulas given hereinafter have the same definition as those of Formula I.

~_ ~ 1 7 ~ 7 PREPARATIVE METHODS AND REACTION SCHEMES
Scheme 1 U~
CN
\ step 1 V--W~ R2 V--W~ R2 U~ R1 ~ R1 R CN ~
\ step 2 ~ ~ step 3 step 4 ~FR1 OTH P
step 5 ~ ~ ~ step 6 ~ ~ R1 N~ RR87 Step 1: This step is preferably carried out by first adding a strong base (e.g. lithium diisopropylamide, potassium bis(trimethylsilyl)amide, sodium hydride, or potassium hydride) in an inert solvent (e.g. ether 10 such as diethyl ether, tetrahydrofuran, or dioxane) with a cosolvent if necessary (e.g. N,N-dimethylformamide, 1,3-dimethyl-3,4,5,6-- ~17~2~7 tetrahydro-2(1H)-pyrimidinone, or hexamethylphosphoramide) under an inert atmosphere (nitrogen or argon). Subsequently, the alkylating agent R3L is added wherein L represents a good leaving group, e.g. L can be chloride, bromide, iodide, mesylate, or tosylate. Any suitable 5 temperature can be used with preferable temperatures for the deprotonation between -78~C and 0~C and for the alkylation between 25~C and 70~C.

Step 2: This step is preferably carried out with any suitable reducing 10 agent (e.g. diisobutylaluminum hydride, lithium triethoxyaluminum hydride, or sodium aluminum hydride) in an inert solvent such as ether (e.g. diethyl ether, tetrahydrofuran, or dioxane) at temperatures preferably between -78~C and 25~C under an inert atmosphere (nitrogen or argon).
Step 3: This step is preferably carried out with the reagent diethyl N-benzylidenaminoalkylphosphonate and two equivalents of n-butyl lithium in an inert solvent such as ether (e.g. diethyl ether, tetrahydrofuran, or dioxane) under an inert atmosphere (nitrogen or 20 argon) to generate a metalloenamine. The metalloenamine is alkylated at temperatures preferably between -78"C and 25~C with R3L wherein L
represents a good leaving group, e.g. L can be chloride, bromide, iodide, mesylate, or tosylate. Subsequent acid hydrolysis of the enamine gives the aldehyde product.
Step 4: This step is preferably carried out with the reagent diethyl [(2-tetrahydropyranyloxy)methyl]phosphonate and lithium diisopropylamide in an inert solvent such as ether (e.g. diethyl ether, tetrahydrofuran, or dioxane) under an inert atmosphere (nitrogen or 30 argon). Preferred temperature range is -78~C to 0~C for addition of the phosphonate reagent and 25"C to 70"C for elimination of the phosphonate reagent.

Step 5: This step is preferably carried out with acid (e.g.
35 hydrochloric acid, acetic acid, or tosic acid) in an inert solvent such as ether (e.g. diethyl ether, tetrahydrofuran, or dioxane) with water.
Preferred temperature range is 25~C to 70~C.

2 ~ ~
-Step 6: This step is preferably carried out with a suitably substituted amine (usually as its acid salt e.g. hydrochloride or maleate) and sodium cyanoborohydride in a solvent mixture of ether (e.g. diethyl 5 ether, tetrahydrofuran, or dioxane) and protic solvent (e.g. methanol or ethanol) with 3A sieves. Preferred temperature range is 25~C to 70~C.

Scheme 2 U~"( )~~step 7 ~ ~ step 8 ~T~/ R1 ~ T--/ R1 O
COOMe step 10 ~ step 9 ~$~R

step 11 U~ step 6 U~, Step 7: This step is preferably carried out with the reagent trimethyl phosphonoacetate and sodium hydride in a polar aprotic solvent (e.g.
N,N-dimethylformamide, N,N-dimethylacetamide, or dimethylsulfoxide) 15 under an inert atmosphere (nitrogen or argon). Preferred temperature range is 25~C to 80"C.

~ 1 7 ~ 7 Step 8: This step is preferably carried out with any suitable reducing agent (e.g. diisobutylaluminum hydride, aluminum hydride, or lithium trimethoxyaluminum hydride) in an inert solvent such as ether (e.g.
diethyl ether, tetrahydrofuran, or dioxane) at temperatures preferably 5 between -78~C and 25~C under an inert atmosphere (nitrogen or argon).

Step 9: This step is preferably carried out with N-bromosuccinimide and R3 as a nucleophile such as methanol, ethanol, or propanol in an inert solvent such as chlorinated hydrocarbons (e.g. dichloromethane, 10 1,2-dichloroethane, or chloroform) at temperatures between 0~C and 25~C.

Step 10: This step is preferably carried out with a suitable reducing agent such as tri-n-butyl tin hydride or triphenyl tin hydride and a 15 radical initiator such as azobisisobutyronitrile in an inert solvent (e.g.
benzene or toluene). Preferred temperature range is between 80~C and 110~C.

Step 11 : This step is preferably carried out with a suitable oxidizing 20 agent (e.g. pyridinium chlorochromate, chromium trioxide-pyridine, pyridinium dichromate, oxalyl chloride-dimethylsulfoxide, acetic anhydride-dimethylsulfoxide, dicyclohexylcarbodiimide-dimethylsulfoxide, or periodinane) in an inert solvent such as chlorinated hydrocarbons (e.g. dichloromethane, 1,2-dichloroethane, or 25 chloroform). Preferred temperature range is between -78~C and 25~C.

Step 6: This step is described above for Scheme 1.

2~7~2~7 ._ Scheme 3 V--V~( R2 V--V~l R2 u~ ~ step 12 U~ step 13 o ~ R1 ~--T~J~ R1 step 15 ~~( ~ step 14 ~
--T~ R

~, NHR R7 u~ )~~/~ step 16 U/~ )~~~
--T~ R1 ' Q_ ~ R1 N_R N - R7 5 Step 12: This step is preferably carried out with the reagent ' methyltriphenylphosphonium bromide and base (e.g. sodium hydride or potassium hydride) in dimethylsulfoxide with a temperature range of 50~C to 80~C under an inert atmosphere (nitrogen or argon). This step can also be carried out by addition of a Grignard reagent (e.g. methyl 10 magnesium chloride, bromide, or iodide) in an inert solvent such as ether (e.g. diethyl ether, tetrahydrofuran, or dioxane) with preferable temperatures between O"C and 25~C. Elimination to give the alkene is catalyzed by a crystal of iodine with sublimation or carried out with acetic anhydride, acetyl chloride, and acetic acid with preferable 15 temperatures between 60~C and IOO"C.

Step 13: This step is preferably carried out with a suitably substituted hydroxylamine, paraformaldehyde, (and a base (e.g.
triethylamine or 1 ,8-diazabicyclo- [5 .4 .0]undec-7-ene) if the 20 hydroxylamine exists as a salt) in a protic solvent (e.g. ethanol, isopropanol, or butanol) with preferable temperatures between 80~C and 1 20~C.

- -- - 2 1 ~ 7 _ Step 14: This step is preferably carried out with zinc in acetic acid or with zinc and ammonium chloride in an inert solvent (e.g. ether such as tetrahydrofuran or dioxane) with water at a preferred temperature 5 range of 50~C to 90~C. Alternatively, this step can be carried out with aluminum-nickel alloy and aqueous base (sodium hydroxide or potassium hydroxide) in a protic solvent (e.g. methanol, ethanol, or isopropanol) or by hydrogenation with ammonium formate and palladium on carbon in a protic solvent (e.g. methanol, ethanol, or 10 isopropanol) at a preferred temperature of 25"C.

Step 15: This step is preferably carried out with an alkylating or acylating agent R8L wherein L represents a good leaving group (e.g. L
can be chloride or R8L can be an anhydride) and a base (e.g. pyridine, 15 triethylamine, collidine, or 1,8-diazabicyclo-[5.4.0]undec-7-ene) in an inert solvent such as chlorinated hydrocarbons (e.g. dichloromethane, 1,2-dichloroethane, or chloroform) under an inert atmosphere (nitrogen or argon). Preferred temperature range is 25"C to 80~C.

20 Step 16: This step is preferably carried out by first adding a base (e.g.
sodium hydride or potassium hydride) in an inert solvent (e.g. ether such as tetrahydrofuran, dioxane, diglyme) under an inert atmosphere (nitrogen or argon). Subsequently, the alkylating agent R9L is added wherein L represents a good leaving group, e.g. L can be chloride, 25 bromide, iodide, mesylate, or tosylate. Preferred temperature range is 70~C to 160~C.

GENERAL PROCESSES

Additional general processes for making compounds of the present invention are as follows:

Preparation of a compound of formula I wherein Z-----N represents a double bond:

~17~,8~

U ~ + H2NoR9 U~

R3 R4 (C \ R6)0 or 1 R3 R4 (CR5R6~
CHO \~ N
A. OR9 The process is preferably carried out by treating the aldehyde with a hydroxyl amine derivative in an inert solvent such as 5 chlorinated hydrocarbons (e.g. dichloromethane, 1,2-dichloroethane, or chloroform) at ambient temperature. If the hydroxyl amine derivative exists as a salt, the acid can be neutralized by the addition of an amine base such as pyridine, collidine, or triethylamine.

Preparation of a compound of formula I wherein 7-----N
represents a single bond:

U~ R8 ~Z

The process is preferably carried out by first adding a strong base (e.g. n-butyl lithium, sec-butyl lithium, sodium amide, potassium amide, lithium diisopropylamide, or potassium bis(trimethylsilyl)amide) to the tricyclic compound in an inert solvent (e.g. ether such as diethyl 20 ether, tetrahydrofuran, or dioxane, or polar solvent such as ammonia, N,N-dimethylformamide, or N,N-dimethylacetamide) under an inert atmosphere (nitrogen or argon). Subsequently, the alkylating agent is added wherein L represents a good leaving group, e.g. L can be chloride, bromide, iodide, mesylate, or tosylate. Any suitable temperature can be 25 used with preferable temperatures between -78"C and OoC.

2 17 ~ 2~ 7 -~R + R9R7NH u~

R 4 (CR5R6)oor1 R3 (CR5R )oor CHO ~N--R7 The reductive amination process is preferably carried out by treating the aldehyde with an amine (usually as a salt) in the presence of a reducing agent such as sodium cyanoborohydride and sieves in a suitable solvent mixture of ether (e.g. diethyl ether, tetrahydrofuran, or dioxane) and protic solvent (e.g. methanol or ethanol) at ambient 1 0 temperature.

D.

R~ + F~8~ U/~
R3 Z~ R3 Z~
R4 N~ - R7 R4 N~ - R7 The process is preferably carried out by first adding an amine base (e.g. pyridine, collidine, or triethylamine) in an inert solvent such as chlorinated hydrocarbons (e.g. dichloromethane, 1,2-dichloroethane, or chloroform) or a strong base (n-butyl lithium, sodium hydride, potassium hydride, lithium diisopropyl amide, or potassium 20 bis(trimethylsilyl)amide) in an inert solvent such as ether (e.g. diethyl ether, tetrahydrofuran, or dioxane) or polar aprotic solvent (e.g. N,N-dimethylformamide or N,N-dimethylacetamide) to the tricyclic amine under an inert atmosphere (nitrogen or argon). Subsequently, the alkylating or acylating agent R8L is added wherein L represents a good 25 leaving group, e.g. L can be chloride, bromide, iodide, mesylate, or ~ 1 7 ~? .? 8 ~

tosylate. Any suitable temperature can be used between -78~C and 80~C.
E

~ redl~ction o~R10 ~ R10 The process is preferably carried out with any suitable reducing agent (e.g. Iithium aluminum hydride, alane, borane, or trichlorosilane) in an inert solvent such as ether (e.g. diethyl ether, 10 tetrahydrofuran, or dioxane) at temperatures between O"C and 60~C.

Y ~ U~ R1 R3 Z~ R3 Z

~~(O)oO,1R1~ H

The process is preferably carried out by treating the amide or carbamate compound under basic (e.g. sodium hydroxide, potassium hydroxide, or sodium peroxide in water with ethylene glycol, methanol, ethanol, tetrahydrofuran, dioxane, or diglyme) or acidic (e.g.
hydrochloric acid, sulfuric acid, or tosic acid in water with tetrahydrofuran, dioxane, or diglyme) conditions. Any suitable temperature can be used with preferable temperatures between 60~C
and 150~C.

217 3 2 ~ 7 -V - V~l R2 V-V\( R2 hydrolysis ~ ~
~T~J~R~ R1 R Z~ R ~Z~R7 O~,/~O ~ ~OH

The process is preferably carried out by treating the tricyclic 5 ester compound with a base (e.g. sodium hydroxide or potassium hydroxide) in water with tetrahydrofuran, dioxane, or diglyme. Any suitable temperature can be used with preferable temperatures between 25~C and lOO"C.

Preparation of a compound of formula I wherein Z~ -N represents a single bond and R3=alkoxy U~--(~R ~ ~>~3' R

R4 N--R R4 N\ - R7 The process is preferably carried out by first adding a strong base (e.g. potassium t-butoxide, sodium hydride, potassium hydride, n-20 butyl lithium, lithium diisopropylamide, or potassiumbis(trimethylsilyl)amide) to the tricyclic alcohol in an inert solvent (e.g.
ether such as tetrahydrofuran, dioxane, or diglyme or polar aprotic solvent such as N,N-dimethylformamide or N,N-dimethylacetamide) under an inert atmosphere (nitrogen or argon). Subsequently, the 25 alkylating agent R9L is added wherein L represents a good leaving 2I 7~ 2~ 7 group, e.g. L can be chloride, bromide, iodide, mesylate, or tosylate. Any suitable temperature can be used with preferable temperatures between 60~C and 150~C.

Preparation of a compound of formula I wherein Z-----N represents a single bond and R3=alkyl U/ ~ ~ hydrogenation U/~ ~/"~
~~ T/~ R1 ~~ T/~--R
alkenyl 'N--R7 alkyl R4 'N--R7 The process is prefer~bly carried out by treating the tricyclic alkene with a catalyst (e.g. p~lladiuln on carbon, platinum oxide, or raney nickel) under a hydrogen atmosphere in an inert solvent (e.g.
15 methanol, ethanol,or ethyl acetate) ~t ambient temperature.

SPECIFIC PREPARATIVE EXAMPLES
~' NMe2 IA

For Compound IA:
Added potassium metal (8.6 g, 0.26 mol) portionwise to 1.0 Iiter of liquid ammonia with a catalytic amount of iron (Ill) oxide. Allowed to stir at -33~C
until blue color disappeared to give a gray solution. Added 5-ethoxy-25 dibenzosuberone (47.66 g, 0.20 mol) dissolved in 200 mL of ether dropwise viaaddition funnel. Stirred at -33~C for 30 mins then added N,N-dimethyl-aminoethylchloride dissolved in 200 mL of ether dropwise via addition funnel.

- ' 2I 7~287 -Warmed gently on steam bath to reflux for 16 hours. Poured onto 1.0 Iiter of ice, and extracted with ether. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel elutingwith ethyl acetate. Combined appropriate fractions and evaporated to give 29.6 95 (48% yield) of 5-ethoxy-5-dimethylaminoethyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene. Dissolved free base in ethyl acetate, and added one equivalent of maleic acid dissolved in ethanol. Added ether to precipitate the maleate salt.
mp=124-125~C
mass spectrum: (Cl, CH4) m/e 310 (M+1 for free base) The following compounds were obtained according to a similar manner:

EtO EtO
NMe2 ~NMe2 ~ IYY
maleate mp=154-156~C bp=164-166~C at 0.7 mmHg ~ 217 12~
6~
RO
NR'R"

X R NR'R' salt mp C Et NEt2 maleate 120-121oC
C Et pyrrolidine maleate 142.5-143.5~C
C Et piperidine maleate 118-119~C
~/~GN' C Et HCI 191 -192~C

C Et 101-103~C
C iPr NMe2 maleate 154.5-155.5~C
C Bu NMe2 maleate 114-116~C
C CH2CHMe2 NMe2 fumarate 132-138~C
N Me NMe2 0.5 fumarate 178-180~C
N Et NMe2 fumarate 165-168~C
N Et NEt2 fumarate ~ 173-174~C
~/~GN' N Et fumarate 161 -163~C
N Bu NMe2 fumarate 122-124~C

To synthesize an intermediate (step 1 of Scheme 1):
Dissolved diisopropylamine (11.07 9, 0.109 mol) in 150 mL of dry THF and cooled to 0~C under a nitrogen atmosphere. Added 40.1 mL (0.100 mol) of 2.5 M n-butyl lithium in hexane dropwise via addition funnel. Stirred at25 0~C for 10 mins then cooled to -78~C. Added 10,11 -dihydro-5H-217~87 dibenzo[a,d]cyclohepten-5-nitrile (20.00 9, 0.0912 mol) dissolved in 100 mL of dry THF dropwise via addition funnel. Stirred at -78~C for 45 mins. Added allyl bromide (14.34 9, 0.119 mol) via syringe, and allowed reaction mixture to warm slowly to room temperature. Stirred at room temperature for 90 mins. Added 250 mL of 0.5 N HCI, and separated layers. Extracted aqueous solution with ethyl acetate. Washed combined organic extracts with saturated NaCI, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 5% ethyl acetate-hexane then 10%
ethyl acetate-hexane. Combined appropriate fractions and evaporated to give 23.65 9 (100% yield) of 10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-nitrile.
mp=51 -53~C
mass spectrum: (FAB) m/e 233 (M-CN) CHO

To synthesize an intermediate (step 2 of Scheme 1):
Dissolved 10,11 -dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-nitrile (24.94 g, 0.0962 mol) in 200 mL of dry dichloromethane, and cooled to -78~C under a nitrogen atmosphere. Added 1 M diisobutylaluminum hydride in dichloromethane (106 mL, 0.106 mol) dropwise via addition funnel. Stirred at -78~C for 60 mins. then at 0~C for 2.5 hours. Carefully added 200 mL of 1 N HCI
then 100 mL of 2 N HCI. Stirred at room temperature for 30 mins. Separated layers, and extracted aqueous solution with dichloromethane. Washed combined organic extracts with 1 N HCI, saturated NaCI, dried with MgSO4, filtered, and evaporated. Purified crude product by tlash chromatography on silica gel elutingwith 10% ethyl acetate-hexane. Combined appropriate fractions and evaporated to give 21.62 (86% yield) of 10,11 -dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-carboxaldehyde.
massspectrum: (El) m/e221 (M-allyl) 217~2~7 OTHP

To synthesize an intermediate (step 4 of Scheme 1):
Dissolved diisopropylamine (9.2 9, 0.0910 mol) in 200 mL of dry THF.
5 Cooled to 0~C under a nitrogen atmosphere. Added 2.5 M n-butyl lithium in hexane (35.2 mL, 0.0880 mol) via syringe. Stirred at 0~C for 10 mins then cooled to -78~C.
Added diethyl [(2-tetrahydropyranyloxy)methyl] phosphonate in 45 mL of dry THF
via addition funnel. Stirred at -78~C for 1 hour. Added 10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-carboxaldehyde in 100 mL of dry THF via 10 addition funnel. Warmed to room temperature then refluxed for 16 hours. Cooled to room temperature, and added 500 mL of saturated NH4CI. Separated layers, and extracted aqueous solution with ether. Washed combined organic extracts withsaturated NaHCO3, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 3% ether-hexane then 15 5% ether-hexane. Combined appropriate fractions and evaporated to give 12.7 9(46% yield) of 10,11 -dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl-(2-tetrahydropyranyloxy-ethene) .
mass spectrum: (Cl, CH4) m/e 361 (M+1) CHO

To synthesize an intermediate (step 5 of Scheme 1):
Dissolved 10,11 -dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl-(2-tetrahydropyranyloxy-ethene) (4.82 9, 13.37 mmol) in 50 mL of THF. Added25 50 mL of 0.2 N HCI, and refluxed for 18 hours. Cooled to room temperature, and added 150 mL of saturated NaHCO3. Extracted with ethyl acetate. Washed combined organic extracts with saturated NaCI, dried (MgSO4), filtered, and evaporated. Purified crude product by flash chromatography on silica gel elutingwith 10% ethyl acetate-hexane. Combined appropriate fractions and evaporated to - ?~17~87 give 3.32 9 (90% yield) of 2-[10,11-dihydro-5-(2-propenyl)-SH-dibenzo[a,d]cyclohepten~5-yl]-ethanal).
mass spectrum: (Cl, CH4) m/e 235 (M-allyl) NMe2 IE

For Compound IE:
Dissolved 2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-ethanal (1.79 g, 6.48 mmol) in 7 mL of dry THF and10 21 mL of dry MeOH. Added 3 A sieves, dimethylamine hydrochloride (2.64 9, 32.38 mmol), and sodium cyanoborohydride (0.407 g, 6.48 mmol). Stirred at room temperature for 72 hours. Added 50 mL of saturated NaHCO3 and 50 mL of dichloromethane. Filtered through celite, and separated layers. Extracted aqueous solution with dichloromethane. Dried combined organic extracts with MgSO4, 15 filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with a gradient of 3% MeOH-CH2CI2, 5% MeOH-CH2CI2, then 10%
MeOH-CH2CI2. Combined appropriate fractions and evaporated to give 1.41 9 (69% yield) of 10,11 -dihydro-N, N-dimethyl-5-(2-propenyl)-5H-dibenzo[a,d]cycloheptene-5-(2-ethanamine). Dissolved free base in ethyl acetate 20 and added one equivalent of maleic acid dissolved in ethanol. Evaporated. Added dichloromethane and evaporated. Added ether to precipitate maleate salt.
mp=122-124~C
mass spectrum: (Cl, CH4) m/e 306 (M+1 for free base) ~1 '.

NMe2 IC

For Compound IC:
Dissolved 10,11-dihydro-N,N-dimethyl-5-(2-propenyl)-5H-dibenzo~a,d]cycloheptene-5-(2-ethanamine) (1.06 9, 3.47 mmol) in 20 mL of ~ 7~;2~7 absolute ethanol. Added 10 wt% of palladium on carbon catalyst (0.10 g), and shook on Paar shaker at 55 psi of hydrogen pressure for 19 hours. Filtered, and washed catalyst with ethyl acetate. Evaporated filtrate to give 0.973 g (91% yield) of 10,1 1-dihydro-N,N-dimethyl-5-propyl-5H-dibenzo[a,d]cycloheptene-5-(2-5 ethanamine). Dissolved free base in ethyl acetate, and added one equivalent ofmaleic acid dissolved in ethanol. Evaporated. Added minimal dichloromethane then diethyl ether to precipitate maleate salt.
mp-70-75~C (soften and foam) mass spectrum: (Cl, CH4) m/e 308 (M+1 for free base) The following compounds were obtained according to a similar manner:

~Y
NR'R' X Y R NR'R" salt Mass Spectrum C H allyl pyrrolidine maleate (Cl, CH4) m/e332 (M+) C H allyl NHMe HCI (Cl, CH4) m/e 292 (M+1) C H allyl NH(CH2)3NMe2 maleate (Cl, CH4) m/e 363 (M+1) C H allyl N-Me-piperazine maleate (Cl, CH4) m/e361 (M+1) C H allyl t-Bu-glycine maleate (Cl, CH4) m/e 392 (M+1) C H allyl t-Bu-proline maleate (Cl, CH4) m/e 432 (M+1) C H propyl NHMe maleate (Cl, CH4) m/e 294 (M+1) C H propyl pyrrolidine (Cl, CH4) m/e334(M+) C H EtOCH2 NHMe maleate (FAB) m/e 310 (M+1) C H EtOCH2 NMe2 maleate (Cl, CH4) m/e 324 (M+1) C H methyl NMe2 HCI (Cl, CH4) m/e 280 (M+1) C H cyclopropyl NMe2 HCI (FAB) m/e 320 (M+1) methyl C H hexyl NMe2 HCI (Cl, CH4) m/e 350 (M+) C H hexyl NHMe maleate (Cl, CH4) m/e 336 (M+1) C H hexyl pyrrolidine maleate (Cl, CH4) m/e 376 (M+1) C H 1-butenyl NMe2 HCI (Cl, CH4) m/e 320 (M+1) C Cl allyl NMe2 maleate (Cl, CH4) m/e 340 (M+1) C Cl propyl NMe2 maleate (Cl, CH4) m/e 342 (M+1) O H allyl NHMe HCI (Cl, CH4) m/e 294 (M+1) O H allyl NMe2 maleate (Cl, CH4) m/e 308 (M+1) O H propyl NMe2 HCI (Cl, CH4) m/e 310 (M+1) 323~

,~ ~COOH

For Compound IVV:
Dissolved 1,1-dimethylethyl 1-[2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]ethyl]-2-pyrrolidinecarboxylate (2.40 9, 5.56 mmol) in 30 mL of dry THF. Added 25 mL of 4.0 M HCI in dioxane, and refluxed for 16 hourson steam bath. Cooled to room temperature, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 5% MeOH-CH2CI2.
Combined appropriate fractions and evaporated to give 0.80 g (40% yield) of 1-[2-[10,1 1-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]ethyl]-2-pyrrolidinecarboxylic acid. Dissolved free base in dichloromethane, and added 3.4 M HCI in ether to pH=2. Evaporated, and added ether to precipitate hydrochloridesalt.
mp=soften at 1 25~C
mass spectrum: (Cl, CH4) m/e 376 (M+1 for free base) The following compound was obtained according to a similar manner:

HN~,COOH
HCI
mp=1 44-1 47~C
MS (Cl, CH4) m/e 336 (M+1) 2 ~ 7 ~ ~ ~ 7 $~
N_COOEt lCC

For Compound ICC:
Dissolved 10,11 -dihydro-N-methyl-5-(2-propenyl)-5H-5 dibenzo[a,d]cycloheptene-5-ethanamine (0.50 9, 1.72 mmol) in 20 mL of dry THF.Added triethylamine (0.29 mL, 0.21 9, 2.06 mmol) and ethyl chloroformate (0.18 mL, 0.20 9,1.88 mmol). Stirred at room temperature for 5 hours. Added 50 mL of water, and extracted with dichloromethane. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica 10 gel eluting with dichloromethane. Combined appropriate fractions, and evaporated to give 0.50 g (81% yield) of ethyl N-[2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]ethyl-N-methylcarbamate .
mass spectrum: (FAB) m/e 364 (M+1) The following compound was obtained according to a similar manner:
$~
N_AC

mp=139-141 ~C
MS (FAB) m/e 334 (M+1) NOH
IUU

217~

For Compound IUU:
Dissolved 2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo~a,d]cyclohepten-5-yl]-ethanal (1.00 g, 3.62 mmol) in 10 mL of dry dichloromethane under a nitrogen atmosphere. Added 3A sieves, hydroxylamine 5 hydrochloride (0.38 9, 5.43 mmol), and pyridine (0.58 mL, 0.57 9, 7.24 mmol).
Stirred at room temperature for 16 hours. Filtered to remove sieve dust, and washed solid with water and dichloromethane. Separated layers of filtrate. Driedorganic solution with MgSO4, filtered, and evaporated. Purified crude product byflash chromatography on silica gel eluting with 20% EtOAc-CH2CI2. Combined 10 appropriate fractions and evaporated to give 0.65 9 (62% yield) of 2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yi]-ethanone oxime as a colorless oil.
mass spectrum: (Cl, CH4) m/e 291 ~M+1) The following compounds were obtained according to a similar 15 manner:

~NOH ~OH
IRR ITT

MS (Cl, CH4) m/e 306 (M+1) (Cl, CH4) m/e 308 (M+1) COOMe To synthesize an intermediate:
Washed sodium hydride (1.72 9 of 60 weight% in oil, 0.0429 mol) two times with hexane under a nitrogen atmosphere. Added 100 mL of dry THF, and cooled to 0~C. Added trimethyl phosphonoacetate (7.81 9, 6.9 mL, 0.0429 mol) dissolved in 15 mL of dry THF dropwise via addition funnel. Hydrogen evolution was observed. Added 50 mL of dry DMF, and stirred at room temperature for 30 - 2~ 7~?8~

mins. Added 10,11 -dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-carboxaldehyde (7.50 g, 0.0286 mol) dissolved in 25 mL of dry DMF dropwise via addition funnel. Stirred at room temperature for 45 mins then heated at 75~C for 16 hours. Cooled to room temperature, and added 0.5 N NaOH. Extracted with ethyl 5 acetate. Washed combined organic extracts with 0.5 N HCI and saturated NaCI, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 2% ethyl acetate-hexane, 5% ethyl acetate-hexane, then 10% ethyl acetate-hexane. Combined appropriate fractions, and evaporated to give 6.03 g (66% yield) of methyl 3-[10,11-dihydro-5-(2-10 propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-propenoate as a colorless oil.
mass spectrum: (FAB) m/e 319 (M+1) OH

To synthesize an intermediate:
Dissolved methyl 3-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-propenoate (6.00 g, 0.0188 mol) in 80 mL of dr~ THF.
Cooled to 0~C under a nitrogen atmosphere, and added lithium aluminum hydride (18.8 mL of 1.0 M in THF, 0.018 mol) via syringe. Warmed slowly to room 20 temperature and stirred for 20 hours. Recooled to 0~C, and carefully added 0.8 mL
water, 0.8 mL of 1 N NaOH, and then 2.5 mL of water in sequence. Stirred at roomtemperature for 1 hour, and filtered through celite. Washed filtrate with saturated NH4CI, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 1 :4 ethyl acetate:hexane then 1 :2 ethyl 25 acetate:hexane. Combined appropriate fractions, and evaporated to give 4.87 g(89% yield) of 3-~10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-prop-2-en-1-ol as a colorless oil.
mass spectrum: (Cl, CH4) mte 291 (M+1) - i 2~ 75~87 OH

To synthesize an intermediate:
Dissolved 3-[10,11-dihydro-5-(2-propenyl)-5H-5 dibenzo[a,d]cyclohepten-5-yl]-prop-2-en-1-ol (4.85 9, 16.70 mmol) in 75 mL of absolute ethanol. Added 10% palladium on carbon catalyst (1.20 g), and hydrogenated on Paar shaker at 58 psi of hydrogen pressure for 16 hours. Filtered to remove catalyst, and evaporated filtrate to give 4.43 9 (90% yield) of 3-[10,11-dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-propanol as a colorless oil.
mass spectrum: (Cl, isobutane) m/e 295 (M+1) ~1 CHO

To synthesize an intermediate:
Dissolved oxalyl chloride (1.6 mL, 2.38 9, 0.0187 mol) in 40 mL of dry dichloromethane, and cooled to -78~C under a nitrogen atmosphere. Added dimethylsulfoxide (2.7 mL, 2.93 g, 0.0374 mol) dissolved in 10 mL of dry dichloromethane dropwise via addition funnel. Stirred for 15 mins at -78~C, and then added 3-[10,11-dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-propanol 20 (4.41 9, 0.0150 mol) dissolved in 25 mL of dry dichloromethane dropwise via addition funnel. Stirred for 20 mins at -78~C, and then added triethylamine (6.3 mL, 4.55 9, 0.0449 mol). Warmed slowly to room temperature. Added water, and extracted with dichloromethane. Washed combined organic extracts with 0.5 N HCI
and saturated NaCI, dried with MgSO4, filtered, and evaporated. Purified crude 25 product by flash chromatography on silica gel eluting with 3% ethyl acetate-hexane, 6% ethyl acetate-hexane, and then 10% ethyl acetate-hexane. Combined appropriate fractions, and evaporated to give 3.85 9 (88% yield) of 3-[10,11 -dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-propanal as a colorless oil.

~ 75~87 mass spectrum: (Cl, CH4) m/e 293 (M+1) NMe2 IG

For Compound IG:
Dissolved 3-[10,11 -dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-propanal (0.75 9, 2.56 mmol) in 5 mL of dry THF and 10 mL of dry methanol.
Added 3A sieves, dimethylamine hydrochloride (1.05 9, 12.82 mmol), and sodium cyanoborohydride (0.161 9, 2.56 mmol). Stirred to room temperature for 24 hours.Added saturated NaHCO3, and filtered through celite. Extracted filtrate with dichloromethane. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel elutingwith 3% MeOH-CH2CI2 then 10% MeOH-CH2CI2. Combined appropriate fractions, and evaporated to give 0.53 9 (65% yield) of 10,11-dihydro-N,N-dimethyl-5-propyl-5H-dibenzo[a,d]cycloheptenepropanamine as an oil. Dissolved free base in dichloromethane, and added 28.8 weight% HCI-ethanol until acidic. Evaporated to give hydrochloride salt as a foam.
mass spectrum: (Cl, CH4) m/e 322 (M+1 for free base) IH

For Compound IH:
Dissolved 10,11 -dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-nitrile (4.68 g, 0.018 mol) is 150 mL of absolute ethanol, and added sodium 25 borohydride (1.70 9, 0.045 mol). Stirred at room temperature for 15 mins thencooled to 0~C. Added cobalt (Il) chloride (4.29 9, 0.018 mol) portionwise. Stirred at room temperature for 30 mins then added additional sodium borohydride (1.70 9, 0.045 mol). Stirred at room temperature for 16 hours. Evaporated, and added 0.5 N
HCI. Washed with ethyl acetate, and extracted organic solution with 1.0 N HCI.

_ - 2~ ~2~7 Combined acidic aqueous extracts, and made basic with 25 weight% NaOH.
Extracted basic solution with dichloromethane. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified by flash chromatography on silicagel eluting with ethyl acetate. Combined appropriate fractions, and evaporated to 5 give 1.4 9 (30% yield) of 10,11-dihydro-5-propyl-5H-dibenzo[a,d]cycloheptene-5-methanamine as an oil. Dissolved free base in ethyl acetate, and added one equivalent of maleic acid dissolved in ethanol. Added ether to precipitate maleate salt.
mp=174-175~C
mass spectrum: (Cl, CH4) m/e 266 (M+1 for free base) NMe2 ISS

For Compound ISS:
Dissolved 10,11 -dihydro-5-propyl-5H-dibenzo~a,d]cycloheptene-5-methanamine (1.0 g, 3.8 mmol) in 3.5 mL of 96% formic acid. Added 37% aqueous formaldehyde (1.4 mL, 0.57 9, 19.0 mmol). Heated at 100~C for 23 hours. Cooled to room temperature, and added 25 weight% NaOH. Extracted with dichloromethane. Dried combined organic extracts with MgSO4, filtered, and 20 evaporated. Purified crude product by flash chromatography on silica gel eluting with 5% MeOH-CH2CI2. Combined appropriate fractions, and evaporated to give 0.90 g (82% yield) of 10,11-dihydro-N,N-dimethyl-5-propyl-5H-dibenzo[a,d]cyclohepten-5-methanamine as an oil. Dissolved free base in ethanol,and added 28 weight% HCI-ethanol until acidic. Added hexane to precipitate~5 hydrochloride salt. Recrystallized salt from ethanol-ether.
mp=220-221 ~C
mass spectrum: (Cl, CH4) m/e 294 (M+1 for free base) 5~7 COOMe To synthesize an intermediate (step 7 of Scheme 2):
Washed sodium hydride (5.71 9 of 60 wt%, 0.143 mol) two times with 5 hexane under a nitrogen atmosphere. Added 170 mL of dry DMF, and cooled to 0~C. Added trimethyl phosphonoacetate (25.99 g, 0.143 mol) dropwise via additionfunnel. Hydrogen evolution was observed. Stirred at 0~C for 15 mins. then at room temperature for 15 mins. Added 6,11-dihydro-dibenz[b,e]oxepin-11-one (15.00 9, 0.0714 mol) dissolved in 70 mL ot dry DMF, and heated reaction mixture in a 80~C10 oil bath for 45 hours. Cooled to room temperature, and added 250 mL of half saturated NH4CI. Extracted with ethyl acetate. Washed combined organic extracts with saturated NaHCO3, saturated NaCI, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel elutingwith a gradient of 5% ethyl acetate-hexane, 7% ethyl acetate-hexane, then 20%
15 ethyl acetate-hexane. Combined appropriate fractions and evaporated to give 3.16 g (21% yield) of starting ketone and 13.16 g (69% yield) of methyl 6,11-dihydro-dibenz[b,e]oxepin-11 -ylidene acetate.
mass spectrum: (Cl, isobutane) m/e 267 (M+1) OH

To synthesize an intermediate (step 8 of Scheme 2):
Dissolved methyl 6,11-dihydro-dibenz[b,e]oxepin-11-ylidene acetate (12.68 g, 0.0476 mol) in 100 mL of dry dichloromethane, and cooled to -78~C under 25 a nitrogen atmosphere. Added 1 M diisobutylaluminum hydride in dichloromethane (104.8 mL, 0.105 mol) dropwise via addition funnel over 30 mins. Stirred at -78~C
for 45 mins. then at 0~C, and warmed slowly to room temperature. Recooled to 0~C, and carefully added 200 mL of 1 N HCI. Separated layers, and extracted aqueous solution with dichloromethane. Washed combined organic extracts with saturated ~7~2~7 NaCI, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 1:2 ethyl acetate:hexane. Combined appropriate fractions, and evaporated to give 11.17 9 (98% yield) of 2-[6,11-dihydro-dibenz[b,e]oxepin-11-ylidene]-ethanol as a yellow oil.
mass spectrum: (FAB) m/e 238 (M+) Br OH

To synthesize an intermediate (step 9 of Scheme 2):
Dissolved 2-[6,11-dihydro-dibenz[b,e]oxepin-11-ylidene]-ethanol (10.90 g, 0.0457 mol) in 175 mL of dichloromethane. Added ethanol (21.07 9, 26.8mL, 0.457 mol), and cooled to 0~C under a nitrogen atmosphere; Added N-bromosuccinimide (8.96 9, 0.0503 mol) portionwise. Warmed slowly to room temperature over 60 mins. Added 200 mL of saturated NaHCO3, and separated layers. Extracted aqueous solution with dichloromethane. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 1:4 ethyl acetate:hexane. Combined appropriate fractions, and evaporated to give 14.35 9 (86% yield) of 2-bromo-2-[6,11-dihydro-11-ethoxy-dibenz[b,e]oxepin-11-yl]-ethanol as a light yellow oil.
mass spectrum: (Cl, isobutane) m/e 363 (M+) 6~

OH

To synthesize an intermediate (step 10 of Scheme 2):
Dissolved 2-bromo-2-[6,11-dihydro-11-ethoxy-dibenz[b,e]oxepin-11-yl]-ethanol (14.34 9, 0.0395 mol) in 150 mL of dry toluene. Added tri-n-butyl tin hydride (17.24 9, 15.9 mL, 0.0592 mol) and AIBN (0.324 9, 0.00197 mol). Refluxedunder a nitrogen atmosphere for 18 hours. Cooled to room temperature, and evaporated. Dissolved residue in 300 mL of acetonitrile, and washed with hexane .

- 2173~7 to remove tin by-products. Dried acetonitrile solution with MgSO4, filtered, andevaporated. Purified crude product by flash chromatography on silica gel elutingwith 1 :4 ethyl acetate:hexane then 1 :3 ethyl acetate:hexane. Combined appropriate fractions, and evaporated to give 6.22 9 (55~/O yield) of 2-[6,11-dihydro-11-ethoxy-~ dibenz[b,e]oxepin-11-yl]-ethanol as a colorless oil.
mass spectrum: (FAB) m/e 284 (M+) EtO CHO

To synthesize an intermediate (step 11 of Scheme 2):
Dissolved oxalyl chloride (3.62 g, 2.5 mL, 0.0285 mol) in 30 mL of dry dichloromethane, and cooled to -78~C under a nitrogen atmosphere. Added dimethylsulfoxide (4.45 g, 4.0 mL, 0.0570 mol) in 10 mL of dry dichloromethane dropwise via addition funnel. Carbon monoxide and carbon dioxide evolution 15 observed. Stiired at -78~C for 15 mins. Added 2-[6,11-dihydro-11-ethoxy-dibenz[b,e]oxepin-11-yl]-ethanol (6.75 9, 0.0237 mol) dissolved in 30 mL of dry dichloromethane dropwise via addition funnel. Stirred at -78~C for 15 mins. thenadded triethylamine (7.21 9, 9.9 mL, 0.0712 mol). Warmed slowly to room temperature. Added 150 mL of water, and separated layers. Extracted aqueous 20 solution with dichloromethane. Washed combined organic extracts with 0.5 N HCI
and then saturated NaCI, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 5% ethyl acetate-hexane then 10% ethyl acetate-hexane. Combined appropriate fractions, and evaporated to give 3.47 g (52% yield) of 2-[6,11-dihydro-11-ethoxy-~5 dibenz[b,e]oxepin-11-yl]-ethanal as a colorless oil.
mass spectrum: (FAB) m/e 282 (M+) ~ 1 7 3 ~ ~ 7 EtO

IM

For Compound IM:
Dissolved 2-[6,11-dihydro-11-ethoxy-dibenz[b,e]oxepin-11-yl]-ethanal 5 (500 mg,1.77 mmol) in 2 mL of dry THF and 6 mL of dry methanol. Added 3 A
sieves, pyrrolidine hydrochloride (952 mg, 8.85 mmol), and then sodium cyanoborohydride (111 mg, 1.77 mmol). Stirred at room temperature under a drying tube for 24 hours. Added 30 mL of saturated K2CO3 and 15 mL of dichloromethane. Filtered through celite, and separated layers. Extracted aqueous 10 solution with dichloromethane. Dried combined organic extracts with MgSQ4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 3% MeOH-CH2Clz then 10% MeOH-CH2CI2. Combined appropriate fractions, and evaporated to give 0.21 9 (35% yield) of 1-[2-(11-ethoxy-6,11-dihydrodibenz[b,e]oxepin-11-yl)ethyl]pyrrolidine as a colorless oil. Dissolved 15 free base in ethyl acetate, and added one equivalent of maleic acid dissolved in ethanol. Evaporated, added ethyl acetate, and evaporated again. Added ether to precipitate maleate salt.
mp=108-110~C (foams) mass spectrum: (FAB) m/e 338 (M+1 for free base)~0 The following compounds were obtained according to a similar manner:

EtO EtO EtO Cl NMe2 NHMe NMe2 IB IU IS
maleate maleate maleate MS (FAB) m/e 312 (M+1) (SIMS) m/e 298 (M+1) (Cl, CH4) m/e 296 (M+1) -~ 217S~8 ~

Ph~

To synthesize an intermediate (step 13 of Scheme 3):
Dissolved 1-methylene-2,3,6,7-dibenzo-2,6-cyclopheptadiene (2.0 g, 9.7 mmol), N-benzylhydroxylamine hydrochloride (1.91 9, 12.0 mmol), triethylamine (1.21 g, 1.7 mL, 12.0 mmol), and paraformaldehyde (0.36 9, 12.0 mmol) in 40 mL of absolute ethanol. Refluxed reaction mixture for 75 hours, and cooled to room temperature. Evaporated, and added water. Extracted aqueous solution with dichloromethane. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel elutingwith 10% CH2CI2-hexane. Combined appropriate fractions, and evaporated to give 2.7 9 (82% yield) of 10,11-dihydro-2'-phenylmethylspiro[5H-dibenzo[a,d]cycloheptene-5,5'-isoxazolidine as a white solid.
mp=108-11 1~C
mass spectrum: (FAB) m/e 342 (M+1 ) To synthesize an intermediate (step 14 of Scheme 3):
Suspended 10,11-dihydro-2'-phenylmethylspiro[5H-dibenzo~a,d]cycloheptene-5,5'-isoxazolidine (4.1 9, 11.7 mmol) in 400 mL of methanol. Added 10% palladium on carbon (2.0 9) and ammonium formate (3.8 9, 60.3 mmol) dissolved in 100 mL of methanol. Heated reaction mixture at 70~C for 3 hours. Filtered reaction mixture while hot, and washed catalyst with methanol.
Evaporated filtrate, and added saturated NaHCO3. Extracted aqueous solution withdichloromethane. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with acetonitrile. Combined appropriate fractions, and evaporated to give 2.20 9(72% yield) of 10,11 -dihydro-5-(2-aminoethyl)-5H-dibenzo[a,d]cyclohepten-5-ol as a white solid.
mp=104-107~C
mass spectrum: (electrospray) m/e 254 (M+1) HO ~O
0~

To synthesize an intermediate (steD 15 of Scheme 3):
Dissolved 10,11-dihydro-5-(2-aminoethyl)-5H-dibenzo[a,d]cyclohepten-5-ol (3.58 9, 14.1 mmol) and phthalic anhydride (2.1 9, 14.1 mmol) in 30 mL of pyridine, and refluxed for 15 hours. Removed pyridine by evaporation, and added saturated NaHCO3. Extracted aqueous solution with dichloromethane. Washed the combined organic extracts with 1 N HCI and then water, dried with MgSO4, filtered, and evaporated. Crystallized product from ether to give 4.50 9 (83% yield) of 6-[2-(10,11-dihydro-5-hydroxy-5H-dibenz[a,d]cyclohepten-5-yl)ethyl]-5H-[pyrrolo[3,4-b]pyridine-5,7(6H)-dione as awhite solid.
mp=152-154~C
mass spectrum: (FAB) m/e 384 (M+1) EtO _~~
0~

- ~- 2~2~

To synthesize an intermediate (step 16 of Scheme 3):
Washed sodium hydride (0.36 g, 9 mmol, 60 weight % in oil) two times with hexane under a nitrogen atmosphere. Added 5 mL of dry dioxane and then 6-[2-(10,11 -dihydro-5-hydroxy-5H-dibenz[a,d]cyclohepten-5-yl)ethyl]-5H-[pyrrolo[3,4-5 b]pyridine-5,7(6H)-dione (1.15 9, 3 mmol) dissolved in 30 mL of dry dioxane dropwise. Refluxed the reaction mixture for 1 hour. Added ethyl iodide (1.4 9, 0.72 mL, 9 mmol) via syringe, and refluxed for 15 hours. Cooled to room temperature, and evaporated. Added water, and extracted with dichloromethane. Washed combined organic extracts with saturated NaCI, dried with MgSO4, filtered, and 10 evaporated. Purified crude product by chromatography on silica gel eluting with dichloromethane. Combined appropriate fractions, and evaporated to give 0.37 9 (30% yield) of 6-[2-(10,11-dihydro-5-ethoxy-5H-dibenz[a,d]cyclohepten-5-yl)ethyl]-5H-[pyrrolo[3,4-b]pyridine-5,7(6H)-dione.

EtO
~3 IL

For Compound IL:
Dissolved lithium aluminum hydride (0.15 g, 3.95 mmol) in 5 mL of dry tetrahydrofuran under a nitrogen atmosphere. Added 6-[2-(10,11 -dihydro-5-ethoxy-5H-dibenz[a,d]cyclohepten-5-yl)ethyl]-5H-[pyrrolo[3,4-b]pyridine-5,7(6H)-dione (0.35 9, 0.85 mmol) dissolved in 20 mL of dry tetrahydrofuran dropwise via addition funnel. Refluxed reaction mixture for 8 hours, and then cooled to 0~C. Carefullyadded 0.2 mL of water, 0.2 mL of 15 weight % NaOH, and then 0.6 mL of water to precipitate the aluminum salts. Filtered precipitate, and washed with tetrahydrofuran. Evaporated filtrate. Purified crude product by flash chromatography on silica gel eluting with CH2CI2 then 3% MeOH-CH2CI2.
Combined appropriate fractions and evaporated to give 0.19 9 (59% yield) of 2-[2-[5-ethoxy-10,11 -dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]ethyl]-1,3-dihydro-2H-isoindole as a pink solid.
mp=101 -104~C

- ~1752~ ~

mass spectrum: (Cl, CH4) mte 384 (M+1) The following compound was obtained according to a similar manner:

EtO
NHMe IK
maleate MS (FAB) m/e 296 (M+1 for free base) / ~SO2Me IN
For Compound IN:
Dissolved N-[2-(5-ethoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)ethyl]-N-methylamine (150 mg, 0.508 mmol) in 5 mL of dry dichloromethane.
Cooled to 0~C under a nitrogen atmosphere, and added triethylamine (0.14 mL, 0.10 g, 1.0 mmol) and then methanesulfonyl chloride (0.06 mL, 0.089 9, 0.76 mmol) dropwise via syringe. Stirred at 0~C for 90 mins. Added water, and extracted with dichloromethane. Washed the combined organic extracts with sodium phosphate monobasic, 1 N NaOH, and then saturated NaCI. Dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography eluting with 9:1 hexane:ethyl acetate. Combined appropriate fractions, and evaporated to solid.
Recrystallized from ethyl acetate-hexane to give 92 mg (48% yield) of N-[2-(5-ethoxy-10,11 -dihydro-5H-dibenzo[a,d]cycloheptenyl)ethyl]-N-methyl-methanesulfonamide as a white solid.
mp=72.5-73.5~C
mass spectrum: (FAB) m/e 396 (M+1+Na) 2~ ~32~7 The following compounds were obtained according to a similar manner:

EtO
~--R

R mp Mass Spectrum SO2Ph oil (FAB) m/e 436 (M+1) COMe 106- 109~C (FAB) m/e 338 (M+1) COOEt oil (FAB) m/e 368 (M+1) CH2COOEt oil (Cl, CH4) m/e 382 (M+1) CH2CH2OCH2CH2OH oil (Cl, NH3) m/e 384 (M+1) COPh(4-COOMe) oil (FAB) m/e 458 (M+1) CO(4-pyridine-N-oxide) oil (FAB) m/e 417 (M+1) EtO ~ ~O

CoOH IGG

For ComDound IGG:
Dissolved N-[2-[5-ethoxy-10,11 -dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]ethyl~-N-methyl-4-methoxycarbonylbenzamide (145 mg, 0.32 mmol) in 12 mL of 20 methanol. Added 12 mL of 2 N KOH, and stirred at room temperature for 60 mins.
Added sodium phosphate monobasic, and extracted with ethyl acetate. Washed combined organic extracts with saturated NaCI, dried with MgSO4, filtered, and evaporated to give 113 mg (80% yield) of 4-[[N-[2-[5-ethoxy-10,11 -dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]ethyl]-N-methyl]oxo]benzoic acid as a white solid.
mp=148-150~C

e~ e~ ~ 7 ~ . . ~

mass spectrum: (FAB) m/e 444 (M+1) The following compound was obtained according to a similar manner:
6~
EtO
I ~
COOH IKK
MS (FAB) m/e 354 (M+1 ) - 217528~

As mentioned above, the compounds of formula I exhibit good anti-TNF-a activity. The compounds of the invention are, therefore, useful when TNF-a activity is a factor in a given disease or disorder such as in the case of septic shock and various allergic diseases and 5 inflammatory conditions.

The anti-TNF-a properties of the compounds of the present invention may be demonstrated by use of a standard in vitro pharmacological testing procedure as described below. This test 10 procedure is a standard test used to determine anti-TNF-a activity and to evaluate the usefulness of said compounds for counteracting the biological effects of TNF-~.

1. In Vitr~ Study: Inhibition of LPS-Induced TNF-a Production From the Murine Cell Line WEHl-265 l ) Cells (obtained fi om cell cultures containing ~ l o6 cells/ml) are suspended at 0.2x106 cells/ml in complete medium (RPMIl640, with 10% FCS, 10-5 M 2-ME, 2 mM glutamine and lO mM HEPES
buffer) and plated in CoStar 24 well plates ( l .0 ml/well).
2 ) Compounds are dissolved in the appropriate vehicle at 400 times the concentration to be tested, and 5 ~l of compound is added to the wells.

3) LPS (from E. coli Olll:B4) is diluted to 6 llg/ml and l.0 ml is added to wells.

4 ) Plates are incubated 20-24 hours in 37~ C02 incubator.

5 ) Supernatant fluids are collected and analyzed for TNF content as described in J. Immunol., 142:3884.

The results of this procedure are shown in TABLE 1 below.

-2 ~ 2 ~ ~

TABT.F. 1 COMPOUND ~o INHIBITION AT 10~1M

IM

I:Z 3 7 217 ~2~7 -ILL S O

In addition to the in vitro test described above, the following in vivo test was also performed on several of the compounds of the present invention. Although the individual reported values may be subject to a 5 wide margin of error, collectively the In vivo data demonstrates that the compounds of the invention are inhibitors of TNF-a in a mammalian species.

g 7 2. In Vivo Study: Inhibition of ~ PS-Induced Serum TNF

l) Mice (C57BI/6J males, 6 - 8 weeks of age) are dosed with the indicated compound (dissolved in CMC suspension vehicle;
compounds are given orally or i.p. one hour before LPS challenge).
2) Mice are challenged with LPS (from E. coli Olll:B4; 50 llg i.p.).
3) Mice are bled 90 min after LPS challenge.
4) Sera are analyzed for TNF content by ELISA as described in J.
Immunol. l42:3884.
Results are shown in TABLE 2 below.

Compound ~o of inhibition at 25 mg/kg lZ O

IDD 3 l IGG O

- - -The effect of the compounds of the present invention against septic shock may be demonstrated by use of a standard pharmacological 5 testing procedure as described below. This test procedure is a standard test used to determine activity against septic shock.

3. In Vivo Study: Inhibition of LPS/Galactosamine-Induced T.ethality 1) Mice (C57BI/6J males, 6 - 8 weeks of age) are dosed with the indicated compound (dissolved in CMC suspension vehicle;
compounds are given orally or i.p. one hour before challenge with LPS and d-galactosamine).
15 2) Mice are challenged i.p. with a mixture of LPS (from E. coli 0111:B4; 100 ng) and d-galactosamine (8 mg).
3 ) Survival is determined 24 hours after challenge. See procedure published in J. Exp. Mecl. 165:657 (1987) ~0 Results are shown in TABLE 3 below.

Compound # dead/total at 25 m~/kg IC

~ 1 7 ~ 7 IX 9/1 o IAA S/l O

ILL 3/1 o 8 ~

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations 5 include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 70 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, - sugar, lactose. Tablets, powders, cachets and capsules can be used as 10 solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The 15 molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene 20 glycol solutions for parenteral injection.

Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a ' 217S2~7 transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0. l mg to l O00 mg, more preferably from about l mg. to 300 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller 20 dosages which are less than the optimum dose of the compound.
Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
The amount and frequency of administration of the compounds of the invention and the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient 30 as well as severity of the symptoms being treated. A typical recommended dosage regimen is oral administration of from lO mg to 2000 mg/day preferably l O to l O00 mg/day, in two to four divided doses to achieve relief of the symptoms.

2~ ~2~7 ._ DOSAGE FORMS
The following are examples of pharmaceutical dosage forms which contain a compound of the invention. As used therein, the term "active compound" is used to designate the compound H3CJ N(CH3)2 (lA).

The scope of the invention in its pharmaceutical composition aspect is not to be limited by the examples provided, since any other 10 compound of Formula I can be substituted into the pharmaceutical composition examples.

Pharmaceutical Dosage Form Examyles EXAMPT F. A
Tablets No. Ingredients mg/t mglt ablet ablet l . Active compound l 00 5 00 2. Lactose USP l22 1 l3 3. Corn Starch, Food Grade, 30 40 as a l0~o paste in Purified Water 4. Corn Starch, Food Grade 45 40 5. Magnesium Stearate 3 7 Total 300 700 ~ 7~2~7 Method of Manufacture Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes.
5 Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with Item No.
4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes.
Compress the mixture to appropriate size and weigh on a suitable tablet 1 0 machine.

.XAMPLE B
Capsules No. Ingredient m~/c~ sule m,~/cal sule 1. Active compound 100 500 2. Lactose USP 106 123 3. Corn Starch, Food Grade40 70 4. Magnesium Stearate NF 7 7 Total 253 700 Method of Manufacture Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating 20 machine.

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to 25 those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

1. A compound of the Formula I:

(I) or a pharmaceutically acceptable salt or solvate thereof, wherein:
one of T and U represents N and the other represents =CH; or each of T and U represents =CH-;
one of V and W represent.s oxygen and the other represents -CH2-;
or each of V and W represents -CH2-;
R1 and R2 are each independently selected from the group consisting of H and halogen;
R3 is alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, cycloalkyl, acyloxymethyl, alkoxy, alkoxymethyl, or alkyl substituted with cycloalkyl;
R4 is H, alkyl, alkenyl, alkoxy, or -OH;
represents an optional double bond; when is a double bond, Z represents -CH=, or -CH2C(R5)=, wherein R5 is H or lower alkyl; and R7 and R8 together represent OR9;

when represents a single bond, Z represents a direct bond, -CH2-, -CH=CH-, or -CH2C(R5)(R6)-, wherein R5 and R6 are independently H or lower alkyl (provided that, when R3 is -CH3, Z is not -(CH2)2-); and R7 and R8 are independently H, alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, cycloalkyl, -OR9; -C(O)OR10; -CH2C(O)OR9;
-C(O)R10; -SO2R10; -CO-4-pyridyl-N-oxide; -(CH2)n-N(CH3)2, where n is

2 to 4; -(CH2)nmO(CH2)jOH, where m and j are independently 2 or 3;

; or R7 and R8 together form either a five-membered or a six-membered ring optionally substituted with COOR9; a six-membered ring containing NR10; or a five-membered ring fused to a benzene ring;
R9 is H or lower alkyl; and R10 is alkyl or aryl.

2. A compound according to Claim 1, wherein R3 is alkoxy.

3. A compound according to Claim 2, wherein R3 is ethoxy.

4. A compound according to Claim 3, wherein R7 and R8 are independently H, alkyl, alkenyl, alkynyl, aryl, alkaryl, or aralkyl.

5. A compound according to Claim 4 having the following structure:

6. A compound according to Claim 4 having the following structure:

7. A compound according to Claim 1, wherein R3 is alkyl.

8. A compound according to Claim 7, wherein R3 is alkyl having from two to six carbon atoms.

9. A compound according to Claim 8, wherein R3 is propyl.

10. A compound according to Claim 9, wherein R7 and R8 are independently H, alkyl, alkenyl, alkynyl, aryl, alkaryl, or aralkyl.

11. A compound according to Claim 10 having the following structure:

12 . A compound according to Claim 10 having the following structure:

13. A compound according to Claim 1, wherein R3 is allyl.

14. A compound according to Claim 13, wherein R7 and R8 are independently H, alkyl, alkenyl, alkynyl, aryl, alkaryl, or aralkyl.

15. A compound according to Claim 14 having the following structure:

16. A compound according to Claim 1, wherein R3 is cyclopropylmethyl.

17. A compound according to Claim 16 having the following structure:

18. A compound according to Claim 1, wherein R3 is alkoxy, represents a single bond, and Z is -CH2-.

19. A compound according to Claim 1, wherein R3 is alkyl, represents a single bond, and Z is -CH2-.

20. A compound according to Claim 1, wherein R3 is allyl, represents a single bond, and Z is -CH2-.

21. A compound according to Claim 1, wherein each of T
and U represents =CH-.

22. A pharmaceutical composition comprising an effective amount of a compound of Claim 1 in combination with a pharmaceutically acceptable carrier.

23. A method of inhibiting tumor necrosis factor-.alpha.
comprising administering to a mammal in need of such inhibition an effective anti-tumor necrosis factor-.alpha. amount of a compound of Claim 1.

24. A method of treating inflammation comprising administering to a mammal in need of such treatment an effective anti-inflammatory amount of a compound of Claim 1.

25. A method of treating septic shock comprising administering to a mammal in need of such treatment an effective anti-septic shock amount of a compound of Claim 1.

26. A method of treating allergy comprising administering to a mammal in need of such treatment an effective anti-allergic amount of a compound of Claim 1.

27. A pharmaceutical composition comprising an effective amount of a compound of the following structure IA in combination with a pharmaceutically acceptable carrier:

(IA).

28. A method of inhibiting tumor necrosis factor .alpha.
comprising administering to a mammal in need of such inhibition an effective anti-tumor necrosis factor-.alpha. amount of a compound having the structure IA in claim 27.

29. A method of treating inflammation comprising administering to a mammal in need of such treatment an effective anti-inflammatory amount of a compound of structure IA in Claim 27.

30. A method of treating septic shock comprising administering to a mammal in need of such treatment an effective anti-septic shock amount of a compound of structure IA in Claim 27.

31. A method of treating allergy comprising administering to a mammal in need of such treatment an effective anti-allergic amount of a compound of structure IA in Claim 27.

32. A compound according to Claim 1 having a structure selected from the group of structures consisting of:

; ;
(IA) (IB) ; ;
(IC) (ID) ; ;
(IE) (IF) ; ;
(IG) (IH) (IJ); (IK);

(IL) ; (IM);

(IN) ; (IO) ;

(IP) ; (IQ) ;

(IR) ; (IS) ;

(IT) ; (IU) ;

(IV) ; (IW) ;

(IX) ; (IY) ;

(IZ) ; (IAA) ;

(IBB) ; (ICC) ;

(IDD) ; (IEE) ;

(IFF) ; (IGG) ;

(IHH) ; (IJJ) ;

(IKK) ; (ILL);

(IMM) ; (INN) ;

(IOO) ; (IP.P) ;

(IQQ) ; (IRR) ;

(ISS) ; (ITT) ;

(IUU) ; (IVV) ;

(IWW) ; IXX;

and (IYY) .