HK1018939A - Methods of treatment with compounds having rara receptor specific or selective activity - Google Patents

Description

With RARαMethods of treatment with receptor-specific or selectively active compounds

no marking

Background

1. Field of the invention

The invention relates to utilization of RAR_αRetinoid receptors having specificityOr selective agonist-like active compounds for the treatment of diseases suitable for treatment with retinoids. More particularly, the present disclosure relates to utilizing RAR_αThe receptor-specific or selective drugs are used for treating tumors.

2. Background of the invention

Compounds having retinoid-like activity are well known to those skilled in the art and are described in numerous U.S. and other patents and scientific publications. It is generally recognized and accepted in the art that retinoid-like activity can be used to treat mammals, including humans, to cure or alleviate the symptoms and conditions of many diseases. In other words, it is generally accepted in the art that pharmaceutical compositions having one or more retinoid-like compounds as active ingredients are useful as modulators of cell proliferation and differentiation, particularly as agents for treating skin-related diseases including actinic keratosis, arsenical keratosis, inflammatory and non-inflammatory acne, psoriasis, ichthyosis and other keratinizing and skin hyperproliferative disorders, eczema, atopic dermatitis, Darriers' disease, lichen planus, prevention and reversal of glucocorticoid (steroid atrophy) damage, as a topical antimicrobial and skin anti-pigmentation agent and for treating and reversing the effects of age and light damage on the skin. Retinoids are also useful in the prevention and treatment of cancerous and precancerous conditions, including premalignant and malignant hyperproliferative diseases such as breast cancer, skin cancer, prostate cancer, cervical cancer, uterine cancer, colon cancer, bladder cancer, esophageal cancer, stomach cancer, lung cancer, laryngeal cancer, oral cancer, cancers of the blood and lymphatic system, tissue deformation of the mucosa, dysplasia, neoplasia, leukoplakia and papilloma and can be used in the treatment of kaposi's sarcoma. In addition, retinoids are also useful as pharmaceuticals in the treatment of ocular diseases including, but not limited to, Proliferative Vitreoretinopathy (PVR), retinal detachment, dry eye and other corneal diseases (comenopathies) and in the treatment and prevention of various cardiovascular diseases including, but not limited to, diseases associated with lipid metabolism such as dyslipidemias(dyslipdemiias) to prevent restenosis following angioplasty and as a medicament to increase the level of circulating Tissue Plasminogen Activator (TPA). Other uses of retinoids include the prevention and treatment of various diseases associated with Human Papillomavirus (HPV) including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as alzheimer's disease, parkinson's disease and stroke, pituitary dysfunction including growth hormone hyposecretion; modulation of apoptosis (apoptosis), including induction of apoptosis and inhibition of T cell activated apoptosis (apoptosis); restoring hair growth comprises administering the compound and other agents such as Minoxidil^RPerforming combination therapy; preventing and treating diseases related to immune system, including using the compound as immunosuppressant and immunostimulant, regulating rejection of organ transplantation and promoting wound healing, including improving xerochezia labialis.

U.S. Pat. Nos. 4,740,519 (shooter et al), 4,826,969(Maiqnan et al), 4,326,055(Loeliqer et al), 5,130,335 (chandaratna et al), 5,037,825(Klaus et al), 5,231,113 (chandaratna et al), 5,324,840 (chandarratna), 5,344,959 (chandaratna), 5,130,335 (chandaratna et al),

published European patent application Nos. 0170105(shudo),0176034A (Wuest et al.),0350846A (Klaus et al.),0176032A (Frickel et al.),0176033A (Frickel et al.),0253302A (Klaus et al.),0303915A (Bryce et al.), British patent application GB2190378A (Klaus et al.), German patent application Nos.

DE 3715955 Al (Klaus et Al.), DE 3602473 Al (Wuest et Al, and the articules J. Amer. Acad. Derm.15:756-764(1986) (Sporn et Al.), chem. Pharm. Bull.33: 404-407(1985) (Shudo et Al.), J. Med. chem.198831, 2182-2192 (Kaqechika et Al.), Chemistry and Biology of Synthetic derivatives CRCPres Inc.1990 p 334-335, 354 (Dawson et Al.), describe or relate to compounds containing a tetrahydronaphthyl component and having retinoid-like or related biological activity.

U.S. patent nos. 4,980,369, 5,006,550, 5,015,658, 5,045,551, 5,089,509, 5,134,159, 5,162,546, 5,234,926, 5,248,777, 5,264,578, 5,272,156, 5,278,318, 5,324,744, 5,346,895, 5,346,915, 5,348,972, 5,348,975, 5,380,877, 5,399,561, 5,407,937 (assigned to the same assignee as the present application) and the patents and publications cited therein describe or relate to chromans, thiochromanes, and 1,2,3, 4-tetrahydroquinoline derivatives having the biological activity of retinal derivatives.

U.S. Pat. No. 4723028(Shudo), published European patent application No. 0170105(Shudo), German patent application No. DE 3524199A 1(Shudo), PCTWO91/16051(Spada et al), PCT WO85/04652(Polus) and J.Med.Chem.,1988,31,2182-substituted 2192(Kagechika et al), describe or relate to aryl and heteroaryl or diaryl substituted olephines or amides having retinoid derivatives or related biological activity.

U.S. patent nos. 4992468,5013744,5068252,5175185,5202471,5264456,5324840,5326898,5349105,4391753,5414007 and 5434173 (assigned to the same assignee as the present application), and the patents and publications cited therein, describe or relate to compounds having retinoid-like biological activity and structures thereof wherein the phenyl and heteroaryl groups or the phenyl and another phenyl group are linked by an olephinic or acetylenic linkage. Further, several co-pending applications and recently published patents designated as the assignee of the present application relate to other compounds having retinoid-like activity.

It is well known in the art that there are 2 major types of retinoid receptors in mammals (and other organisms). These 2 major types or families of receptors are designated as RARs and RXRs, respectively. There are also subtypes within each type; the subtype in the RAR family is named RAR_α、RAR_β、RAR_γIn the RXR family, subtypes are: RXR_α、RXR_βAnd RXR_γ. It is also known in the art that the 2 major retinoid receptor types and several subtypes are not uniformly distributed in different tissues and organs of mammals.

It is also known in the art that the use of retinoid-like compounds for the treatment of various diseases and conditions is not without problems or side effects. Side effects at therapeutic dose levels include headache, teratogenicity, mucosal and cutaneous toxicity, musculoskeletal toxicity, lipaemic separation (discodemias), skin irritation, headache, hepatotoxicity, and the like. These side effects limit the acceptance and use of retinoids for the treatment of disease. Research is still ongoing in the art to determine which subtype or subtypes of the RAR or RXR family, and of each family, are responsible for mediating certain therapeutic effects, and which type or subtypes are responsible for mediating one or more undesirable side effects. Thus, specificity or selectivity for a major receptor type or family, or even for one or more subtypes of a family of receptors, in compounds capable of binding to a retinoid receptor is considered a desirable pharmacological property. Such selectivity or specificity can be used as a research tool for finding the role of several receptor types and subtypes in mediating various effects of retinoids on biological systems, and can thereby be used to design retinoid drugs having specific therapeutic effects and/or reduced side effects and toxicity. In view of these considerations, U.S. patent No. 5324840 describes a class of compounds having retinoid-like activity with concomitant reduction in skin toxicity and reduction in teratogenicity. U.S. patent No. 5399586 describes the effect of compounds having RXR retinoid receptor agonist activity in treating mammals suffering from tumors. U.S. patent No. 5455265 describes a method of treating mammals with compounds having agonist-like activity for the RXR receptor. Published PCT application number WO93/11755 also relates to the use of agonists of RXR receptors that are selective.

The invention provides a utilization pair RAR_αA method for treating tumor by the compound with specificity or selectivity of receptor.

Summary of the invention

According to the present invention, we have found that the compounds act on RAR_βAnd RAR_γCompared to receptor subtypes, retinoids tend to act selectively or even preferably specifically on RAR_αReceptor subtypes, such retinoid-like compounds having the desired pharmaceutical properties associated with retinoids, are particularly useful for treating tumors, such as acute monocytic leukemia, cervical cancer, bone marrow cancer, ovarian cancer, head and neck cancer, without one or more of the undesirable side effects of retinoids, such as inducing weight loss, mucosal and skin toxicity, skin irritation, and teratogenicity (teratogenicity).

Accordingly, the present invention relates to the utilization of RAR_αTreatment of diseases for which a retinoid is indicated, specifically or selectively, and especially treatment with RAR_αThe specific or selective retinoid compounds have therapeutic effects on tumors, mainly acute monocytic leukemia, cervical cancer, bone marrow cancer, ovarian cancer and head and neck cancer. According to the invention RAR_αThe selective compounds are also particularly useful in the treatment of Proliferative Vitreoretinopathy (PVR) and age-related macular degeneration (AMD).

For the purposes of this description, a compound is transfer-activated RAR if it is used in a transfer activation (transduction) assay (described below)_αThe concentration of receptor is significantly lower than that of transfer-activated RAR_βAnd RAR_γThe receptor considers the compound as RAR_αSpecific or selective. Instead of measuring metastasis activation, it is also possible to measure the binding of one compound to 3 RAR receptor subtypes, respectively. Binding data in kd values obtained in a binding assay (described below) also indicate that a compound acts specifically or selectively on RAR_αReceptor hyperactivity on RAR_βAnd RAR_γThe ability of the receptor. If a compound is combined with RAR_αKd value of receptor binding to RAR_βAnd RAR_γThe kd value for receptor affinity is about 500-fold less, and the compound is considered to be RAR_αSpecific or selective.

Brief description of the drawings

FIG. 1 shows all-trans retinoic acid (ATRA) and 2 RARs according to the invention_αResults of selective compound treated RPMI8226 cell culture assays.

FIG. 2 is another diagram showing 2 RARs according to the present invention_αSelective Compound and 2 non-RAR_αResults of selective compound-treated AML193 cell culture analysis.

FIG. 3 shows 3 RARs according to the invention_αResults of selective compounds and all-trans retinoic acid (ATRA) treated AML193 cell culture assays.

FIG. 4 shows the proliferation of ovarian tumor cells in a cell culture assay (EDR assay) when the concentration of Compound 2 according to the invention is varied.

FIG. 5 shows the proliferation of RPE cells in the presence of all-trans retinoic acid or compound 42 in the culture medium.

Figure 6 shows the administration of different doses of an RAR according to the invention for 3 consecutive days_αBody weight of rat experimental group after selective compound.

Fig. 7 is a histogram showing body weights at the end of the 4-day experimental period in groups of experimental mice after administration of different doses of compound 18 according to the invention for 3 consecutive days.

Figure 8 shows guinea pigs treated for 15 days of body weight with different doses of compound 42.

Detailed description of the invention general embodiments definitions relating to chemical compounds are used in the present invention

The term alkyl refers to and includes any of the well-known n-alkyl, branched-chain alkyl and cyclic alkyl groups. The term alkenyl refers to and includes normal alkenyl, branched alkenyl, and cycloalkenyl groups having one or more sites of unsaturation. Similarly, the term alkynyl refers to and includes n-alkynyl, as well as branched alkynyl groups having one or more triple bonds.

Lower alkyl means n-lower alkyl having 1 to 6 carbons in the broad alkyl group defined above, and the usual lower branched and cyclic alkyl groups having 3 to 6 carbons. Lower alkenyl is similarly defined as n-lower alkenyl groups having 2 to 6 carbons, and branched and cyclic lower alkenyl groups having 3 to 6 carbons. Lower alkynyl is also similarly defined as n-lower alkynyl groups having 2 to 6 carbons, and branched lower alkynyl groups having 4 to 6 carbons.

The term "ester" as used herein relates to and includes any compound which is within the definition of a term as commonly used in organic chemistry. It includes organic and inorganic esters. Where B is-COOH in the formula of the preferred compounds for use in the present invention, the term includes products derived from the treatment of the functional group with an alcohol or thiol, preferably an aliphatic alcohol having from 1 to 6 carbons. When the ester is derived from a compound wherein B is-CH₂OH, the term includes compounds derived from organic acids capable of forming esters, including phosphorus-based acids and sulfur-based acids, or the formula-CH₂OCOR₁₁Wherein R is₁₁Is any substituted or unsubstituted aliphatic, aromatic, heteroaromatic or aliphatic aromatic group, preferably having from 1 to 6 carbons in the aliphatic moiety.

Unless otherwise stated herein, preferred esters are derived from saturated fatty alcohols or acids containing 10 or less than 10 carbon atoms or cyclic or saturated fatty alcohols or acids containing 5 to 10 carbon atoms or cyclic or saturated aliphatic cyclic alcohols or acids containing 5 to 10 carbon atoms. Aliphatic esters derived from lower alkyl acids and alcohols are particularly preferred. Phenyl esters or lower alkyl phenyl esters are also preferred.

Amides have the meaning typically accorded to the definition of amides in organic chemistry. It includes both unsubstituted amides and all aliphatic and aromatic mono-and disubstituted amides herein. Unless otherwise specified in this application, preferred amides are mono-and disubstituted amides derived from saturated aliphatic groups containing 10 or less than 10 carbon atoms or cyclic or saturated aliphatic cyclic groups containing from 5 to 10 carbon atoms. Especially preferred are amides derived from substituted and unsubstituted lower alkyl amines. Also preferred are mono-and di-substituted amides derived from substituted and unsubstituted anilines or lower alkyl anilines. Unsubstituted amides are also preferred.

Acetals and ketals include groups of formula CK, where K is (OR)_z. Where R is lower alkyl. K may also be-OR₇O-wherein R₇Is a straight or branched chain lower alkyl group of 2 to 5 carbon atoms.

Pharmaceutically acceptable salts may be prepared from any compound used in the present invention having a functionality, such as an acid, capable of forming such a salt. A pharmaceutically acceptable salt is any salt which retains the activity of the parent compound and which does not have any deleterious or deleterious effect on the recipient of the drug and the process by which the drug is administered. Pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a monovalent or multivalent ion. Of particular importance are the inorganic ions, sodium, potassium, calcium and magnesium ions. The organic salts may be derived from amines, especially ammonium salts such as mono-, di-and trialkylamines or ethanolamines. Salts can also be formed from caffeine, tromethamine and similar molecules. When there is a nitrogen sufficiently basic to form an acid addition salt, then the salt can be generated from any inorganic or organic acid or alkylating agent such as methyl iodide. Preference is given to salts formed from inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Any simple organic acid such as a monobasic, dibasic to tribasic acid may also be utilized.

Certain compounds useful in the present invention may have both trans and cis (E and Z) isomers. In addition, the compounds used in the present invention may contain one or more chiral centers and may therefore exist in enantiomeric and diastereomeric forms. The scope of the invention is intended to include the use of all such isomers per se, as well as mixtures of cis and trans isomers, diastereomeric mixtures and racemic mixtures of enantiomers (optical isomers). Description of the Compounds preferred for use in the Process of the invention

Retinoid-like compounds for RAR used in the therapeutic methods of the invention_αThe receptor is specific or selective. A compound pair RAR_αWhether a receptor is specific or selective can be determined by a conversion activation assay (described below) in which RAR is present_αSpecific or selective compound conversion-activated RAR_αThe receptor was used at concentrations significantly higher than those used for conversion-activated RAR_βOr RAR_γLow for the receptor. In binding assays that measure the ability of compounds to bind to these receptor subtypes, RAR is considered to be a candidate for the present invention_αSpecific or selective compounds with RAR_αBinding stress ratio of receptor to RAR_βOr RAR_γReceptor binding is at least 500-fold stronger. It can also be said that if a compound is paired with RAR in a binding assay_αThe kd value of the acceptor is about 10^-1-5×10²Nanomolar range for RAR_βOr RAR_γA receptor having a kd greater than 1000 nanomolar, this compound is considered to be RAR_αSpecific or selective. The latter is indicated at 0.00 in the table provided below, which lists binding data (kd values) for certain exemplary compounds of the invention.

Formula 1 and formula 2 list the RARs which are preferably used according to the invention_αExamples of selective compounds:

wherein X₁Is O or X₁Is [ C (R) ]₁)₂]_nWherein n is an integer between 0 and 2;

R₁independently H or alkyl of 1 to 6 carbon atoms;

R₂independently hydrogen, or lower alkyl of 1 to 6 carbon atoms;

R₃is hydrogen, lower alkyl of 1 to 6 carbon atoms or F;

m is an integer of 0 to 5;

o is an integer of 0 to 4;

p is an integer of 0 to 2;

r is an integer of 0 to 2;

X₂is N or CH;

y is a phenyl or naphthyl group, or a heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl (pyrrazolyl), said phenyl, naphthyl and heteroaryl groups optionally being substituted by one or 2R₂Substituted by groups;

W₁is independently selected from C substituted by F, Br, Cl, I, fluorine_1-6Alkyl radical, NO₂And OH, provided that:

(ii) the compound corresponds to formula 1 and Z is O, then the sum of p and r is at least 1 and W₁Is not a fluoro group at the 3-position of the tetralin ring;

(ii) the compound corresponds to formula 1, r is 0, p is 1 and W₁Is OH, then the OH group is in the alpha position to the L group;

W₂is independently selected from C substituted by F, Br, Cl, I, fluorine_1-6Alkyl radical, NO₂And OH;

W₃is independently selected from F, Br, Cl, I, C_1-6Alkyl, fluoro substituted C_1-6Alkyl radical, NO₂And OH, provided that: the compound is in accordance with formula 2, X₂Is CH, and r is 0, then p is not 0 and at least one W₃The group is not alkyl;

l is- (C = Z) -NH-or-NH- (C = Z) -;

z is O or S, and

b is COOH or a pharmaceutically acceptable salt thereof, COOR₈、CONR₉R₁₀、-CH₂OH、CH₂OR₁₁、CH₂OCOR₁₁、CHO、CH(OR₁₂)₂、CHOR₁₃O、-COR₇、CR₇(OR₁₂)₂、CR₇OR₁₃O, wherein R₇Is alkyl, cycloalkyl or alkenyl having 1 to 5 carbon atoms, R₈Is an alkyl group having 1 to 10 carbon atoms or a trimethylsilylalkyl group having 1 to 10 carbon atoms in the alkyl group, or a cycloalkyl group having 5 to 10 carbon atoms, or R₈Is phenyl or lower alkylphenyl, R₉And R₁₀Independently of one another hydrogen, an alkyl radical having from 1 to 10 carbon atoms, or a cycloalkyl radical having from 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R₁₁Is lower alkyl, phenyl or lower alkylphenyl, R₁₂Is lower alkyl, and R₁₃Is a divalent alkyl group containing 2 to 5 carbon atoms.

With respect to symbol X in formula 1₁Among the preferred compounds for the process of the invention, X is₁Is [ C (R) ]₁)₂]_nAnd n is 1 (tetrahydronaphthalene derivative) and X₁And may also be O (chroman derivatives). With respect to symbol X in formula 2₂,X₂Compounds which are CH or N are equally preferred. When X is present₂In the case of CH, the phenyl ring is preferably substituted in the 1,3,5 positions, the L group occupying positions 1 and W₃And/or R₂The groups occupy the 3 and 5 positions. When symbol X₂When N is used, the pyridine ring is preferably substituted in the 2,4,6 positions, the L group occupies the 4 position and W₃And/or R₂The groups occupy the 2 and 6 positions.

R in formula 1₁The radical is preferably H or CH₃. R in formula 1₃The radical is preferably H. Preferred compounds of the invention are those in which the group B is COOH or a pharmaceutically acceptable salt thereof, COOR₈Or CONR₉R₁₀Wherein R is₈、R₉And R₁₀As defined above.

Now with respect to W in formula 1₁And W₂The radicals, in general, being electron-withdrawing groups, are present in the compounds of the inventionOr as a substituent for an aryl or heteroaryl group Y, or in the presence of an aromatic moiety of the condensed ring system. Preferably W₂The radicals being present in the radical Y, and W₁Groups are also present in the aromatic portion of the condensed ring system. W when the Z group is S (thioamide)₁Or W₂The group need not be present in the compounds according to formula 1, although preferably at least one W₁Or W₂The groups are still present. The aryl or heteroaryl Y moiety in the compounds of formula 1 and 2 is preferably W₂The group is located adjacent to the B group; the B group is preferably para in the phenyl ring relative to the "amide" moiety, so W is preferred₂The group is in the meta position relative to the amide moiety. When there is one W₁When a group is present in the aromatic part of the condensed ring system in the compound of formula 1, it preferably occupies the 8-position of the chroman nucleus, while the Z = C-NH-group occupies the 6-position. In the tetrahydronaphthalene compounds of the formula 1, preferably the Z = C-NH-group is in position 2 and preferably W₁The group is located at the 4-position. However, when in the compound of formula 1W₁When the group is OH, then preferably OH is located at the 3-position of the tetralin ring.

Preferred W₁And W₂The radical being F, NO₂、Br、I、CF₃、CLN₃And OH. Particularly preferred is the group Y (W)₂) One or 2 fluorine substituents are present. When the Y group is phenyl, the fluorine substituents are preferably in the ortho and (ortho)' positions relative to the B group, where preferably the B group is COOH or COOR₈。

Now with respect to W in equation 2₃The radical, in general, is also an electron-withdrawing group or an alkyl radical, particularly preferably W₃Group F, NO₂、Br、I、CF₃、N₃And OH. In addition, in the phenyl or pyridine ring (substituent shown in formula 2) ("W)₃)_p") W₃Is alkyl, preferably branched alkyl, such as t-butyl, and preferably P is 2.

As regards the symbols Y in formula 1 and in formula 2, the compounds preferably used in the process of the invention are those in which Y is phenyl, pyridyl, 2-thiazolyl, thiazolyl,Thienyl or furyl, and phenyl is more preferred. As regards the substitution in the Y (phenyl) and Y (pyridyl) groups concerned, preference is given to compounds in which the phenyl group is substituted in the 1,4 (para) position by L and B groups and the pyridine ring is substituted in the 2,5 positions by L and B groups. (the substitution in the 2,5 position in the "pyridine" nomenclature corresponds to the substitution in the 6 position in the "nicotinic" nomenclature.) in preferred compounds of the invention there is no alternative R in the Y group₁Substituents (other than H).

The L group in formula 1 and formula 2 is preferably- (C = Z) -NH-, and Z is preferably O. In other words, those carbamoyl or amide compounds are preferred according to the invention when the-NH-moiety is attached to the Y group.

The presently most preferred compounds for use in the methods of treatment of the present invention are shown below, in table 1 in relation to formulas 3 and 4 and in table 2 in relation to formula 5.

Formula 5

Compound numbers of table 1 formula R₁ ^* W₄ W₅ Z W₆ W₇ R8^*1 3 -- H H O F H Et2 3 -- H H O F H H3 3 -- H Br O F H Et4 3 -- H Br O F H H5 3 -- OH H O F H Et6 3 -- OH H O F H H7 4 H H Br O F H Et8 4 H H Br O F H H9 4 CH₃ H Br O F H Et10 4 CH₃ H Br O F H H11 4 CH₃ H CF₃ O F H Et12 4 CH₃ H CF₃ O F H H13 4 CH₃ H N₃ O F H Et14 4 CH₃ H N₃ O F H H15 4 CH₃ H CF₃ O F F CH₃16 4 CH₃ H CF₃ O F F H17 4 CH₃ H I O F H Et18 4 CH₃ H I O F H H19 4 CH₃ H CH₃ O F H Et20 4 CH₃ H CH₃ O F H H21 3 -- H H S H H Et22 3 -- H H S H H H23 3 -- H H S F H Et 24 3 -- H H S F H H25 3 -- H Br O NO₂ H CH₃26 3 -- H Br O NO₂ H H27 4 CH₃ H H O F H Et28 4 CH₃ H H O F H H29 3 -- OH Br O F H Et30 3 -- OH Br O F H H31 3 -- OH Br O F F Me32 3 -- OH Br O F F H33 3 -- H H O F F Me34 3 -- H H O F F H

TABLE 2 Compound # X₂ W₈ W₉ W₁₀ R^* ₈；41 N H F H Et42 N H F H H43 N H H H Et44 N H H H H45 CH H F H Et46 CH H F H H47 CH OH F H Et48 CH OH F H H49 N H F F Me50 N H F F H51 CH H F F Me52 CH H F F H53 N H NO₂ H Me54 N H NO₂H H administration form

RAR for use in the method of the invention_αSpecific or selective compounds may be administered systemically or locally depending on such conditions as the disease to be treated, the particular site of treatment, the amount administered, and many other conditions.

In the treatment of skin disorders, topical administration is generally preferred, although oral administration may be employed in some cases, such as the treatment of severe cystic acne or psoriasis. Any of the usual topical dosage forms such as solutions, suspensions, gels, ointments or salves may be used. The preparation of these topical dosage forms is described in detail in the pharmaceutical arts by way of example, for example, Remington's pharmaceutical Science,17 th edition, Mack Publishing Company, Easton, Pennsylvania. For topical application, these compounds can be administered in powder or spray form, especially in the form of an aerosol. If administered systemically, the drug may be in the form of a powder, pill, tablet, etc., or in the form of a syrup or elixir for oral administration. For intravenous or intraperitoneal administration, the compounds will be prepared as solutions or suspensions to enable administration by injection. In some cases, it may be useful to formulate the compounds into injections. In some cases, it will be useful to formulate these compounds in the form of suppositories or subcutaneously embedded sustained release formulations or intramuscular injections.

Other drugs may be added to these topical formulations to achieve secondary objectives such as treating dry skin and sun protection; other medicines for treating dermatoses can also be added; adding medicine for preventing infection, reducing irritation and inflammation.

A skin disorder or any other condition known or discovered to be susceptible to treatment with a retinoic acid-like compound can be therapeutically effective by administering a therapeutically effective amount of one or more compounds of the present invention. Therapeutic concentrations refer to concentrations that alleviate or prevent the development of a particular disease. In certain instances, the compounds can be used effectively in a prophylactic form to prevent the occurrence of a particular disease.

The effective therapeutic or prophylactic concentration may vary from disease to disease and may in some instances vary with the severity of the disease to be treated and the patient's sensitivity to the treatment. Thus, there is no single concentration that is effective in each case, but rather is tailored to the particular disease being treated. Such concentrations can be obtained by routine experimentation. However, it is expected that in the treatment of skin conditions such as acne or the like, a formulation content of between 0.01mg/ml and 1.0mg/ml will constitute a therapeutically effective concentration for all indications. If administered systemically, it is expected that amounts of between 0.01mg and 5mg per kilogram of body weight per day will produce therapeutic effects in a number of conditions for which these compounds are suitable.

In the treatment of tumors, pre-treatmentThe effective dose is about 0.5-5mg per kg body weight per day. In addition, as is often used in the treatment of malignant tumors, patients are given an initial dose of 1mg/kg per day, after which the dose is raised until the maximum tolerated dose is reached. RAR_αAssays for receptor-selective biological activity and assays for their importance in reducing side effects and toxicity.

As mentioned in the introductory part of this patent application, there are 2 major types of retinoic acid receptors (RAR and RXR) in mammals (as well as other organisms). Within each type there is a subtype (RAR)_α、RAR_β、RAR_γ、RXR_α、RXR_βAnd RXR_γ). It is distributed differently in different tissues and organs of mammals. Due to the different distribution of the subtypes in different tissues or organs of a mammal, selective binding to one or both retinoid receptor subtypes within a family of retinoid receptors can provide beneficial pharmacological properties. Binding to all or any retinoid receptor, as well as specific or selective activity for a family of receptor types or specific or selective activity for any receptor subtype, for the reasons summarized above, is considered a desirable pharmacological property.

Test compounds have been established for RAR according to the aforementioned prior art_α、RAR_β、RAR_γ、RXR_α、RXR_βAnd RXR_γAssay procedure for agonist-like activity of body subtypes. For example, test pairs RAR_α、RAR_β、RAR_γAnd RXR_αAgonist-like activity of receptor subtypes and chimeric (chimeric) receptor conversion activation assays based on articles published on Feigner p.l. and Holm m. (1989) Focus, 112 are described in detail in U.S. patent No. 5455265. The specification of U.S. patent No. 5455265 is incorporated herein by reference.

A whole receptor conversion activation assay and a ligand binding assay for testing the ability of a compound to bind to several retinoid receptor subtypes, respectively, is described in PCT application No. WO93/11755 (especially pages 30-33 and 37-41) published 24/6.1993, the disclosure of which is also incorporated herein by reference. The following also provides an illustration of the ligand binding assay. Binding assays

All binding assays were performed in a similar format. All 6 receptor subtypes are derived from the expressed receptor type (RAR) expressed in baculovirus_α、RAR_β、RAR_γ、RXR_α、RXR_βAnd RXR_γ). All compound stocks were made up as 10mM ethanol solutions and serial dilutions to 1: 1 DMSO: ethanol. Assay test buffers for all 6 receptor assays consisted of: 8% Glycerol, 120mM KCl, 8mM Tris, 5mM HAPS, 4mM DTT and 0.24mM PMSF, pH-7.4@ RT.

All receptor binding assays were performed in the same format. The final test volume was 250. mu.l, and contained 10 to 40. mu.g of the extracted protein and accompanied by 5nM, depending on the receptor to be tested³H]All-trans retinoic acid or 10nM³H]9-cis retinoic acid and concentrations ranging from 0-10^-5Different concentrations of competing ligands for M. The assay test is formatted to fit a 96-well micro cuvette system. The culture was carried out at 4 ℃ until equilibrium was reached. Non-specific binding is defined as the binding still present in the 1000nM of the modest unlabeled retinoic acid isomer. At the end of the incubation period, 50 μ l of 6.25% hydroxyapatite (hydroxyapatite) was added to the appropriate wash buffer. The wash buffer was composed of 100mM KCl,10mM Tris and/or 5mM HAPS (RXR)_α、RXR_βAnd RXR_γ) Or 0.5% Triton X-100 (RAR)_α、RAR_β、RAR_γ) And (4) forming. The mixture was stirred and incubated at 4 ℃ for 10 minutes, centrifuged and the supernatant discarded. The added hydroxyapatite was washed 3 more times with the appropriate wash buffer. The receptor-ligand complex is adsorbed onto hydroxyapatite. The number of receptor-ligand complexes can be determined by liquid scintillation counting of hydroxyapatite particles.

After correction for non-specific binding, IC can be determined₅₀The value is obtained. IC (integrated circuit)₅₀Values are defined as those of competing ligands required to reduce specific binding by 50%And (4) concentration. IC (integrated circuit)₅₀Values can be determined graphically by a logarithmic plot of the data. The kd value may be determined by IC₅₀Values, labeled ligand concentrations, and kd of labeled ligand were determined using the Cheng-Prussof equation.

The results of the ligand binding assay are expressed in kd values. (see Cheng et al, Biochemical Pharmacology 22 Vol. 3099 and page 3108, the description of which is incorporated herein by reference).

Table 3 shows the results of the ligand binding assay test for certain exemplary compounds of the invention.

TABLE 3

Ligand binding assay test

Compound # K_d(nanomole)

RARα RARβ RARГ RXRα RXRβRXRГ

2 1.90 480.0 0.00 0.00 0.00 0.00

4 1.3 0.00 0.00 0.00 0.00 0.00

6 3.00 0.00 0.00 0.00 0.00 0.00

10 24.0 0.00 0.00 0.00 0.00 0.00

12 14.0 0.00 0.00 0.00 0.00 0.00

14 52.0 0.00 0.00 0.00 0.00 0.00

16 51.0 0.00 0.00 0.00 0.00 0.00

18 16.0 0.00 0.00 0.00 0.00 0.00

20 57.0 0.00 0.00 0.00 0.00 0.00

22 15 0.00 0.00 0.00 0.00 0.00

24 7.5 0.00 0.00 0.00 0.00 0.00

26 245.0 0.00 0.00 0.00 0.00 0.00

28 162.0 0.00 0.00 0.00 0.00 0.00

30 ＜3.00 0.00 0.00 0.00 0.00 0.00

32 2.30 0.00 0.00 0.00 0.00 0.00

34 9.00 0.00 0.00 0.00 0.00 0.00

42 14.00 0.00 0.00 0.00 0.00 0.00

44 19.00 0.00 0.00 0.00 0.00 0.00

46 26.0 0.00 0.00 0.00 0.00 0.00

48 77.0 0.00 0.00 0.00 0.00 0.00

50 62.0 0.00 0.00 0.00 0.00 0.00

52 87.0 0.00 0.00 0.00 0.00 0.00

54 94.0 0.00 0.00 0.00 0.00 0.00

TTNPB¹725360.00 denotes values greater than 1000nM (nanomolar)¹TTNPB is retinaldehyde (4- (E) -2- (5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethylnaphthalen-2-yl) propen-1-yl) benzoic acid, well known in the art, as a non-RAR_αAnd (4) selectivity is achieved.

From the foregoing data, it can be seen that the compounds used according to the invention specifically or selectively bind to RAR_αRetinoid receptor binding. It has been found in accordance with the present invention that this unique selective form allows the compounds to achieve beneficial retinoid like properties while reducing certain side effects and toxicity. In particular, certain in vitro cell culture assays, as described below, demonstrate RAR_αSpecific or selective compounds have the ability to significantly inhibit the growth of cancer cells. Cancer cell line assay test materials and methods hormones

All-trans retinoic acid (t-RA) (Sigma Chemicals co.st. louis, MO) was stored at-70 ℃. Compounds were dissolved in 1mM 100% ethanol prior to each experiment and diluted in culture media immediately prior to use. All experiments were performed under soft light. The control was tested with the same concentration of ethanol as in the experimental plate and the concentration of this diluent had no effect on both assays. Cells and cell culture

Cell lines RPMI8226, ME-180 and AML-193 were from the American type Culture Collection (ATCC, Rockville, Md.). RPMI8226 is an artificial blood cell line obtained from peripheral blood of patients with multiple myeloma. The cell is similar to lymphoblasts in other human lymphocyte cell lines and secretes alpha-type light chain immunoglobulins. RPMI-8226 cells were grown in RPMI medium (Gibco) supplemented with 10% fetal bovine serum, glutamine, and antibiotics. The cells were contained in suspension culture at 37 ℃ in 5% CO₂To maintain growth in a humid atmosphere. Cells were diluted to 1X 102 times per week⁵Concentration per ml.

ME-180 is a cancer cell line from human epidermoid tumors of the cervix. The tumor has irregular cell clusters andhighly invasive squamous cell carcinoma without significant keratinization. ME-180 cells were grown and maintained in McCoy' S5 a medium (Gibco) supplemented with 10% fetal bovine serum, glutamine and antibiotics. The cells were cultured as a monolayer in 5% CO at 37 deg.C₂To maintain growth in a humid atmosphere. Cells were diluted to 1X 102 times per week⁵Concentration per ml.

AML-193 was derived from immature cells classified as M5 acute monocytic leukemia. Growth factors are required to establish this cell line: granulocyte colony stimulating factor (GM-CSF); growth factors are essential in order for the cell line to continue to proliferate in chemically defined media. AML-193 cells were grown and maintained in Dulbecco's modified Iscove's medium supplemented with 10% fetal bovine serum, glutamine and antibiotics, and 5. mu.g/ml insulin (Sigma Chemical Co.) and 2ng/ml rhGM-CSF (R and D systems). Cells were diluted to 3X10 2 times per week⁵Concentration per ml.³Binding of H-thymidine

The method employed for determining the binding of radiolabeled thymidine is modified from the procedure described by Shrivastav et al. RPMI-8226 cells were seeded at a density of 1000 cells per well in 96-well round-bottomed microtiter plates (Costar). The retinoid test compound was added to the appropriate wells at a final concentration indicated by a final volume of 150 μ l/well. The plates were incubated at 37 ℃ with 5% CO₂Was cultured in a humid atmosphere for 96 hours. Then, 1. mu. Ci [ 5' -³H]Thymidine (Amersham, U.K.43Ci/mmol specific activity) was added to each well and the cells were cultured for an additional 6 hours. The culture was further processed according to the procedure described below.

ME-180 cells trypsinized were seeded in a 96-well flat-bottomed microtiter plate (Costar) at a density of 2000 cells/well. The culture was treated by the method described above for RPMT8226 but with the following exceptions. After incubation with thymidine addition, the supernatant was carefully discarded and the cells were washed with 0.5mM thymidine solution dissolved in phosphate buffered saline. ME 180 cells were simply treated with 50. mu.l of 2.5% trypsin to remove the cells from the plate.

AML-193 cells were seeded at a density of 1000 cells/well in 96-well round-bottom microtiter plates (Costar). The retinoid test compound was added to the appropriate wells at a final concentration indicated by a final volume of 150 μ l/well. The plates were incubated at 37 ℃ in a solution containing 5% CO₂Was cultured in a humid atmosphere for 96 hours. Then, one μ Ci [ 5' -³H]Thymidine (Amersham, U.K.43Ci/mmol specific activity) was added to each well and the cells were cultured for an additional 6 hours.

The cell lines were then subjected to the following procedures: cellular DNA was precipitated onto glass fiber filter pads using a SKATRON multi-well cell harvester (Skatron Instruments, Sterling VA) with 10% trichloroacetic acid. Radioactivity incorporated into the DNA, as a direct measure of cell growth, can be determined by liquid scintillation counting. These numbers represent the mean division per minute of bound thymidine in the ± SEM from triplicate wells.

FIG. 1 of the drawings shows the inhibition of growth of these malignant cells by compounds 4 and 12 (2 exemplary compounds according to the invention applied) in the above-described RPMI8226 cell (malignant myeloma) culture assay, as well as the profile of the control compound, all-trans retinoic acid (ATRA). The graph in FIG. 1 also demonstrates that at low concentration ranges (10)^-12To about 10^-9) The all-trans retinoic acid (ATRA) actually promoted the growth of these cells, and the RAR of the present invention_αSelective compounds 4 and 12 do not stimulate but inhibit the growth of these malignant cells at this low concentration.

Figure 2 shows that compounds 22 and 42 according to the invention inhibit the growth of these malignant cells in the AML193 (acute monocytic leukemia) cell culture assay described above. The other two compounds whose data are also shown in this figure are designated AGN193090 and AGN 193459. (AGN number is an optional design code used by the cooperative designer of the present inventionNo.) compounds AGN193090 and AGN 193459 are non-RARs_αAnd (4) selectivity is achieved. These compounds are respectively 4- [ (8-cyano-5, 6-dihydro-5, 5-dimethylnaphthalen-2-yl) ethynyl]Benzoic acid and 4- [ (5, 6-dihydro-5, 5-dimethylnaphthalen-7 (6H) -8- (1-2, 2-dimethylpropylidene) naphthalen-2-yl) ethynyl]Benzoic acids, their para-RAR_α、RAR_βAnd RAR_γThe kd values for the acceptors were 109,34,77 and 6,2,7, respectively. The graph in figure 2 demonstrates RAR_αSelective or specific compounds inhibit the growth of malignant cells at low concentrations while the full (pan) agonist AGN193090 and AGN 193459 compounds do not inhibit, but even stimulate, the growth of such cells at these low concentrations.

FIG. 3 is another graph showing the results of an AML-193 cell culture assay in which compounds 4,12 and 18 and all-trans retinoic acid (ATRA) in accordance with the present invention were tested. Data display RAR_αSelective compounds reduce cell proliferation at low concentrations while ATRA actually promotes cell proliferation at the same low concentrations.

In another aspect of the assay, the inhibitory effect of retinoids on cells obtained from a solid tumor in a patient is tested. This EDR analysis test is as follows:

freshly resected solid tumor biopsies were obtained at 24 hours of surgery. After a portion of the tumor was retained by paraffin embedding and histopathological examination of specimen viability and tissue diagnosis, the samples were processed for analytical testing. The residual sample was broken into small pieces with sterile scissors. Then in a CO₂These small tissue fragments were mixed with collagenase and dnase for 2 hours in an incubator to free the tumor cells from the associated tissue matrix. The resulting cell suspension was washed and cell number was determined by cell rotation preparation. Tumor cells were resuspended in 0.3% agarose in RMPI 1640 supplemented with 15% FCS, glutamine and antibiotics at a concentration of 40000 cells per ml, and 0.5ml of the suspension was seeded on 0.5ml of 0.5% agarose layer in 24-well culture plates. These culture conditions prevent cell adhesion and therefore allow only transformed cells to proliferate. In addition, it is thinThe cells grow into three-dimensional spheres and their in vivo morphology is recapitulated.

Retinals were added 24 hours after inoculation to ensure that the sample re-equilibrated with the growth environment after stringent (rigours) transport and reaction had taken place. Cells were grown in the presence of drug for 4 days and added 48 hours prior to collection³H-thymidine (5. mu. Ci/ml) to ensure that sufficient proliferating cells are labeled. After liquefaction of the agarose-cell suspension at 90 ℃, cells were collected by glass fiber filtration and counted in 5ml scintillation fluid using a Beckman 6500 liquid scintillation counter.

Untreated control cells proliferated as part of the reported results. Treatment groups were run in duplicate or triplicate, while controls were run in quadruplicate.

The graph in figure 4 shows the effect of compound 2 on ovarian tumors from 4 patients and demonstrates that the compound inhibits the proliferation of such tumor cells in a concentration-dependent manner.

One skilled in the art will appreciate RARs_αThe ability of the selective compounds to significantly inhibit the growth of malignant cells in the above assay tests may be administered to produce beneficial effects in the treatment of tumors in mammals, including humans, suffering from such tumors, particularly in acute monocytic leukemia, cervical cancer, myeloma, ovarian cancer and head and neck cancer.

RAR has also been found according to the present invention_αSelective compounds inhibit proliferation of retinal pigment epithelial cells.

Background data show that retinal pigment epithelial tissue (RPE) regresses, proliferates, and migrates into the subretinal space following retinal detachment (Campachiaro et al, invest. Opthal & Vis. Sci.32:65-72 (1991)). Such a process may have an impact on the success of the retinal reattachment process. RAR agonists like all-trans retinoic acid (ARTA) exhibit antiproliferative effects on the growth of human primary RPE cultures (Campachiaro et al, invest. Opthal & Vis. Sci.32:65-72(1991)) and have been shown in human studies to reduce the incidence of retinal detachment following retinal reattachment surgery (Fekrat et al, Opthamology102: 412-.

The graph in fig. 5 shows the concentration-dependent inhibitory effect of all-trans retinoic acid (ATRA) and compound 42 on RPE proliferation during the course of the assay test described below.

Analysis of original RPE cultures

A primary culture of human retinal pigment epithelial tissue (RPE) was obtained from the eye as described previously, (Camphor et al invest&Vis.Sci.32:65-72 (1991)). Will be 5X 10⁴The cells were seeded in 16mm wells of a 24-well multi-well culture plate in Dulbecco's modified Eagle's medium (DMEM Gibco) containing 10% Fetal Bovine Serum (FBS). Ethanol alone (control), ATRA in ethanol (10)^-10To 10^-6M) and Compound 42 (10) in ethanol^-10To 10^-6M) to process. The culture was carried out every 2 days in fresh medium containing appropriate concentrations of these compounds for 6 days. Cells were removed from the plate by treatment with trypsin and counted in an electronic cell counter. As can be seen from fig. 5, treatment of naive RPE cells with ATRA and compound 42 resulted in a dose-dependent reduction of RPE cell proliferation.

In use of the RAR of the present invention_αTopical administration of RAR according to the invention to laboratory nude mice in a topical skin irritation assay test with Selective Compound 18_αThe effect of selective retinoid production was evaluated. In particular, skin irritation was semi-quantitatively determined by subjective evaluation of daily skin scaling and lesions. A single value for the local irritation score, a separate data, summarizes the skin irritation induced in one animal during the course of the experiment. The local stimulation score was calculated as follows. The local stimulus score is the algebraic sum of the combined scaling score and the combined damage score. The combined score ranges were: scaling ranged from 0 to 9, and damage ranged from 0 to 8, with the primary consideration being maximum severity, duration of onset, and average severity of scale and damage observed.

Severity of scaling was scored on a 5-point scale and severity of injury was scored on a 4-point scale, with higher scores indicating greater severity. The most severe component of the combined values in the observation process is the highest daily severity value of the animals involved.

For the time of onset component in the combination values, values ranging from 0 to 4 were set as follows:

the occurrence severity is 2

Or greater scale formation or

Time of injury

Time to onset (day) score

8 0

6-7 1

5 2

3-4 3

1-2 4

The combined score mean severity component was the sum of the daily scale or damage scores divided by the number of days observed. The first day of treatment is not counted as the pharmaceutical compound has not had an opportunity to act at the time of the first treatment.

The combined scaling and damage score was calculated by summing the average severity score and the time to onset score and dividing by 2. This result is added to the maximum severity score. The total local stimulation value can then be given by summing the combined scaling and injury scores. Each animal had a local stimulation score, which was expressed as the mean ± SD of the individual values of a group of animals. Rounding the value to the nearest integer.

Female nude mice [ Crl: SKHI-hrBR ] (8-12 weeks of age, n =4) were topically treated with compound 18 for 5 consecutive days at nanomolar/25 g (listed in Table 4). The dorsal skin was treated with a total volume of 4ml/kg (-0.1 ml). Mice were observed daily and scaled and lesions scored until day 3 (including day 3) after the last treatment, i.e., day 8.

TABLE 4

Dose mortality rate in nude mice 8 days local assay test dose mortality Rate Scale-on-body lesions mix (from 4)% obtained (or lost) value 10008 + -7011 + -1100004 + -1112 + -0 of TTNPB 0.905 + -2538 + -22.70 (4 + -3) 639 + -290 (11 + -3) 7511 + -2

These data indicate RAR in the experimental model_αThe selective compounds do not actually cause skin irritation and weight loss at doses up to 1000nmol/25 g. For comparison it should be noted that the non-RAR of the prior art known in the above mentioned experiments_αThe selective retinoid compound 4- (E) -2- (5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethylnaphthalen-2-yl) propen-1-yl) benzoic acid (TTNPB) causes very severe skin irritation (as shown in the table above).

Administering RAR to a mammal_αAnother important benefit of selective retinoids is that RAR is significantly reduced as compared to many other retinoids_αTeratogenicity of the selective compound, as determined by the biological identification of chondrogenesis inhibition. The determination method comprises the following steps:

as a biological assay, high density "spot" cultures of limb bud stromal cells were used to compare the ability of various concentrations of experimental drugs to inhibit differentiation of cartilage genes. Mouse embryonic forelimb buds on day 12 of gestation (54. + -. 2 somites) were isolated in trypsin-EDTA solution and the resulting monocyte suspension was seeded in plastic culture plates in 20. mu.l spots (200000 cells/spot). 24 hours after the start of the inoculation, retinoids were added to the medium at concentrations ranging from 0.3ng/ml to 3. mu.g/ml (1nM to 10. mu.M) (Eagle's MEM + 10% fetal bovine serum, GIBCO). Control cultures received vehicle only (ethanol, concentration by volume ≦ 1%); retinoic acid was used as a positive control in another culture line.

The culture was terminated after 96 hours of inoculation, at which time the medium was removed and the cells were fixed in 10% formalin containing 0.5% cetylpyridinium chloride for 1 hour. Cultures were washed in acetic acid and stained in 0.5% Alcian blue solution at pH 1.0 for 1 hour, identified in 3% acetic acid, then dehydrated in ethanol and scored for cartilage formation under a microscope. Reduction in the number of cartilage nodules in the stained culture compared to the control culture or not used as an assay to inhibit cartilage formation. The number of pigmented cartilage nodules in the whole culture spot, the average number of nodules and the standard deviation of quadruplicate replicates per treatment were calculated. Median concentration (IC) that caused 50% inhibition of chondrogenesis compared to control₅₀) Calculations can be performed by a logarithmic curve fit to the dose response data. IC (integrated circuit)₅₀Values are expressed in units of nanograms per milliliter (ng/ml). Greater concentration of IC in this assay₅₀Values indicate less teratogenic effect. Table 5 shows the results obtained in this identification experiment for compounds 10,18 and 42 according to the invention, and also the results compared with all-trans retinoic acid (ATRA) and 4- (E) -2- (5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethylnaphthalen-2-yl) propen-1-yl) benzoic acid (TTNPB).

TABLE 5

Compound IC₅₀(ng/ml)

10 250

18 220

42 65

ATRA 55

TTNPB 0.01

As can be seen, the compounds according to the invention used form less malformations than all-trans retinoic acid and are more pronounced than the TTNPB compounds of the prior art (10)⁴Order of magnitude) less malformations.

The decrease or increase in body weight of the test animals following administration of the retinoid is another drug toxicity test, and significant weight loss if the retinoid is administered at relatively low doses is indicative of an important toxic side effect. In one experiment, several groups of 5 rats per group were treated with experimental retinoids at different doses (drug administered in corn oil) for 3 days. Rats were sacrificed 24 hours after the last dose (euthanize). The graph in figure 6 shows the average body weight of rats in each group treated with compound 42 at daily doses of 10,30 and 90 μmol/kg/day, and the average body weight of rats in the control group to which no retinoid was administered. As can be seen, except for RAR at very high dose (90. mu. mol/kg/day) compared to control_αSelective compound 42 caused virtually no weight loss. The graph in figure 7 shows the body weight of rats at day 4 (24 hours after the last retinoid administration) in a similar experiment with different doses of compound 18, with 0 dose representing the control. As can be seen, the RAR_αThe selective retinoid causes virtually no weight loss even at high doses of 90. mu. mol/kg/day. It is noteworthy that TTNPB (see table 3), which binds to all three RAR receptor subtypes in similar experiments, caused a very significant weight loss. In experiments involving treatment of rats with compound 42, no significant mucocutaneous toxicity was observed.

In another experiment, 3 week old male Hartley guinea pigs were intraperitoneally implanted with osmotic pumps containing 20% DMSO/80 polyethylene glycol (vehicle) or compound 42 at a concentration of 4.4,13.3, or 40mg/ml in the vehicle. Estimating from the initial body weight and the known pump speedThe doses of compound 42 were approximately 0,2,6 and 18 mg/kg/day. Body weight was recorded at least every 2 days after implantation and clinical observations were taken for 14 days. After 14 days the guinea pigs were sacrificed and the pumps were checked for possible failure. The graph in figure 8 shows the body weight of the animals used in this over 15 day experiment. As can be seen from the figure, RAR was present at a lower or moderate dose compared to control animals_αThe selective retinoid compound (compound 42) caused no, or only a statistically insignificant, inhibition of weight gain. Significant inhibition of body weight gain was observed only at the high dose (18 mg/kg/day) of compound 42. Importantly, no mucocutaneous toxicity was observed at any dose of compound 42 in this experiment. When the RAR according to the present invention is used as described above_αThe observation of significantly reduced mucocutaneous toxicity when animals are treated with selective compounds is an important advantage, since mucocutaneous toxicity is a major and annoying retinoid side effect or toxicity in patients. Preparation of RAR of the preferred embodiment of the invention_αProcess for the synthesis of selective compounds

The general structures of the compounds preferably used in the methods of treatment of the present invention are shown in formulas 1 and 2 above. These compounds can be prepared by the chemical synthetic routes described herein. Synthetic chemists will, without doubt, agree that the conditions set forth herein are to achieve a particular embodiment of the preparation and can be generalized to any and all compounds represented in the formulas.

In general, the process for the preparation of compounds according to formula 1 which is preferably employed in the process of the present invention comprises reacting a compound of formula 6 with a compound of formula 7 or reacting a compound of formula 6a with a compound of formula 7a to form an amide. Similarly, the process for preparing the compound corresponding to formula 2 comprises reacting the compound of formula 8 with the compound of formula 7, or reacting the compound of formula 8a with the compound of formula 7a to form an amide.

The compound of formula 6 is substituted with an aromatic moiety in tetralin, (X)₁=[C(R₁)₂]_nAnd n is 1), indane (b)[C(R₁)₂]_nWherein n is 0) or chroman (X)₁Is O) an "activated form" of a core-bound acid or carboxylic acid. The carboxylic acid or "activated form" thereof is linked to the 2 or 3 position of tetralin and to the 6 or 7 position of the chroman moiety. In the compounds preferably used according to the invention, the linkage takes place in the 2-position of tetralin and in the 6-position of chroman.

The term "activated form" of a carboxylic acid is to be understood as a derivative of a carboxylic acid capable of forming an amide when reacted with a primary amine of formula 7. The activated form of the carboxylic acid in the case of the "inverted amide" is a derivative (formula 7a) capable of forming an amide when reacted with a primary amine in formula 6 a. Generally, this means that such carboxylic acid derivatives are generally known in the art and are used to form amide bonds with amines. Examples of suitable forms or derivatives for this purpose are acid chlorides, acid bromides and esters of carboxylic acids, especially active esters, wherein the alcohol part of the ester forms a good leaving group. A preferred reagent according to formula 6 (or formula 7a) is an acid chloride (X)₃As Cl). The acid chloride in formula 6 (or formula 7a) can be prepared from the corresponding ester (e.g., X) by conventional methods₃Ethyl) by hydrolysis and treatment with thionyl chloride. The acid chlorides of formula 6 (or formula 7a) can also be prepared by treating the carboxylic acid directly with thionyl chloride, wherein the carboxylic acid (rather than the ester thereof) is commercially available or is prepared by known synthetic methods. The acid chloride of formula 6 (or formula 7a) can typically be reacted with the amine of formula 7 (or formula 6 a) in the presence of an acid acceptor such as pyridine in an inert solvent such as dichloromethane.

The carboxylic acid according to formula 6 (or formula 7a) is also suitable for amide formation when reacted with an amine, catalyst (4-dimethylaminopyridine) in the presence of a dehydrating agent such as Dicyclohexylcarbodiimide (DCC) or more preferably 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC).

In general, the carboxylic acids or corresponding esters in formula 6 can be prepared using methods described in the chemical sciences and patent literature and, if desired, the literature methods of preparation can be modified by chemical reactions or methods known per se in the art. For example, in general, 2,2,4,4 and/or 2,2,4, 4-substituted chroman 6-carboxylic acids and chroman 7-carboxylic acids are obtained according to the procedures set forth in U.S. Pat. Nos. 5006550,5314159,5324744 and 5348975, the disclosures of which are expressly incorporated herein by reference. In general, 5,6,7, 8-tetrahydronaphthalene-2-carboxylic acid is obtained according to the method of U.S. Pat. No. 5130335, the disclosure of which is expressly incorporated herein by reference.

The foregoing general description of the reaction leading to the amide of formula 1 applies, in general, to the amide of formula 2. Reagents used according to the general rule for forming amide compounds of formula 2 mentioned above are: activated forms of the carboxylic acids shown in formula 8 and formula 7a, and amines in formula 7 and formula 8 a.

In general, the carboxylic acids or corresponding esters in formula 8 can be prepared as described in the literature of chemical science and the patent literature and the literature methods of preparation can be modified, if desired, by chemical reactions or methods known per se in the art.

Reaction scheme 1

Reaction scheme 2

Reaction scheme 2 (continue)

Reaction schemes 1 and 2 provide examples of the synthesis of derivatives of 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethylnaphthalene-2-carboxylic acid, which are within the range of formula 6 and which can be reacted with amines in formula 7 to yield (5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethylnaphthalen-2-yl) carbamoyl derivatives within the range of formula 1. Thus, as in the reverseAs shown in scheme 1, nitration of ethyl 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethylnaphthalene-2-carboxylate (Compound A) produces the corresponding 3-nitro compound (Compound B). The nitro group of compound B is reduced to form the corresponding 3-amino compound (compound C) described by Lehmann et al Cancer Research,1991,51, 4804. Bromination of ethyl 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-3-aminonaphthalene-2-carboxylate (Compound C) yields the corresponding 4-bromo derivative (Compound D), which is treated with isoamyl nitrite and H₃PO₂The reduction can convert into ethyl 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-4-bromonaphthalene-2-carboxylate (compound E). Saponification of compound E can yield 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-4-bromonaphthalene-2-carboxylic acid (compound F), which is used as a reagent according to formula 6. Diazotization of ethyl 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-3-aminonaphthalene-2-carboxylate (compound C) and reaction with HBF4 also yields ethyl 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-3-fluoronaphthalene-2-carboxylate (compound G), which can be used as reagent according to formula 6, either by itself or after saponification.

5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2-hydroxynaphthalene (compound H, obtainable according to the method of Krause in published Synthesis 1972,140) is the starting material for the example shown in scheme 2. Bromination of compound H yields the corresponding 3-bromo compound (compound I), which is then protected at the hydroxy function via treatment with methoxymethyl chloride (MOMCl) to yield 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-3-methoxymethoxy-2-bromonaphthalene (compound J). Reaction of compound J with t-butyllithium and carbon dioxide produces the corresponding carboxylic acid (compound K), and removal of the methoxymethyl protecting group from compound K by the acid affords 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-2-hydroxynaphthalene-3-carboxylic acid (compound L). Bromination of compound L yields 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-1-bromo-2-hydroxynaphthalene-3-carboxylic acid (compound M). Compound L and compound M were used as reagents according to formula 6. For further conversion, the hydroxyl group of compound M is protected with methoxymethyl chloride (MOMCl) in the presence of a base to give 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-1-bromo-2-methoxymethylnaph-alene-3-carboxylic acid (compound N).

Reaction scheme 3

Reaction scheme 4

Reaction scheme 5

Reaction schemes 3,4 and 5 provide examples of the synthesis of 2,2,4,4 and 4, 4-substituted chroman-6-carboxylic acid derivatives that can be used as reagents for the synthesis of carbamoyl (amide) compounds within the scope of the present invention according to formula 6. Thus, referring now to reaction scheme 3,2, 4, 4-tetramethylchroman-6-carboxylic acid (compound O, see U.S. Pat. No. 5006550) is brominated with bromine in acetic acid to yield the corresponding 8-bromo derivative (compound P). Compound P is converted to an acid chloride by treatment with thionyl chloride and the acid chloride produced is suitably reacted with an amine of formula 3 to produce the carbamoyl (amide) compound of the present invention. The acid chloride can also be reacted with an alcohol (methanol) in the presence of a base to give the corresponding ester, methyl 2,2,4, 4-tetramethyl-8-bromochroman-6-carboxylate (compound R). The bromine functionality of compound R can be converted to a trifluoromethyl functionality by treatment with sodium trifluoroacetate in the presence of an iodinated ketone catalyst and 1-methyl-2-pyrrolidone (NMP), and the carboxylate group can be saponified to give 2,2,4, 4-tetramethyl-8-trifluoromethylchroman-6-carboxylic acid (compound S). Compound S is within the scope of formula 6 and is suitable for reaction with the amine of formula 7, either as an acid chloride or in other activated form, to yield the carbamoyl (amide) compounds of the present invention. It is also possible to convert 2,2,4, 4-tetramethylaminotetralin-6-carboxylic acid (compound O) to the methyl ester (compound T) and then nitrate the resulting compound T to give 2,2,4, 4-tetramethyl-8-nitrobenzchroman-6-carboxylic acid (compound V), still another reagent within the scope of formula 6. In addition, in the example further shown in reaction scheme 3,2, 4, 4-tetramethylchroman-6-carboxylic acid (compound O) is converted to ethyl ester and then nitrated to yield ethyl 2,2,4, 4-tetramethyl-8-nitrobenzdihydropyran-6-carboxylate (compound W). Further, compound O was reacted with ICl to give 2,2,4, 4-tetramethyl-8-iodochroman-6-carboxylic acid (compound X).

According to the example shown in reaction scheme 4, 2-methylphenol is subjected to a series of reactions to produce 2,2,4,4, 8-pentamethylbenzodihydropyran (compound Y) according to the method of U.S. patent No. 5045551, incorporated herein by reference. Bromination of compound Y with bromine in acetic acid yields 2,2,4,4, 8-pentamethyl-6-bromochroman (compound Z), reaction of compound Z with tert-butyllithium followed by reaction with carbon dioxide yields 2,2,4,4, 8-pentamethylbenzodihydropyran-6-carboxylic acid (compound A)₁)。

Reaction scheme 5 illustrates the synthesis of 4, 4-dimethyl-8-bromochroman-6-carboxylic acid (compound B) by bromination of 4, 4-dimethyl-chroman-6-carboxylic acid obtained according to the procedure in U.S. Pat. No. 5059621₁) The description of this patent is incorporated herein by reference. According to formula 62, 2,4,4, 8-pentamethylbenzodihydropyran-6-carboxylic acid (Compound A)₁) And 4, 4-dimethyl-8-bromochroman-6-carboxylic acid (Compound B)₁) Either as such or as the corresponding acid chloride (or other "activated form") may be used as a reagent for the synthesis of the carbamoyl (amide) compounds of this invention.

Returning now to the reaction between the reagent of formula 6 and the amine compound of formula 7, it has generally been noted that the amine compound can be obtained according to methods described in today's technology, such as scientific literature and patent literature. In particular, the amine compounds of formula 7 can be prepared using methods described in the scientific literature or in the patent literature, or from compounds discussed in the known literature via chemical reactions or transformations within the skill of experimental organic chemists. Reaction scheme 6 illustrates an example of the preparation of an amine compound of formula 7 (where Y is phenyl) from commercially available starting materials (Aldrich Chemical Company, or Research Plus, Inc.). Can be converted by the above formula 7Compounds several compounds are synthesized which are preferably used in the process of the present invention.Thus, according to reaction scheme 6, 3-nitro-6-methyl-fluorobenzene (Aldrich) is subjected to oxidation to convert the carboxylic acid produced to an acid chloride and then to ethyl ester, followed by reduction of the nitro group to produce ethyl 2-fluoro-4-amino-benzoate (Compound C)₁). 3-Nitro-6-methyl-bromobenzene (Aldrich) and 3-nitro-6-methyl-chlorobenzene were subjected to a series of reactions essentially the same as above to give ethyl 2-bromo-4-amino-benzoate (Compound D), respectively₁) And ethyl 2-chloro-4-amino-benzoate (Compound E)₁). Conversion of 2-nitro-4-aminobenzoic acid (Research Plus) into its methyl ester by means of the corresponding acid chloride (compound F)₁). In the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 4-dimethylaminopyridine in CH₂Treatment with ethanol in the presence of Cl esterifies 2,3,5, 6-tetrafluoro-4-amino-benzoic acid (Aldrich) to give ethyl 2,3,5, 6-tetrafluoro-4-amino-benzoate (Compound G)₁). Conversion of 2,4, 6-trifluorobenzoic acid (Aldrich) to the methyl ester by acid chloride, displacement of the 4-fluorine atom by reaction with sodium azide, followed by hydrogenation, yields methyl 2, 6-difluoro-4-aminobenzoate (Compound H)₁). A compound C according to formula 7₁、D₁、E₁、F₁、G₁And H₁Can be used as amine reagent. Further examples of reagents according to formula 7 are nitro, fluoro, chloro, bromo and trifluoromethyl derivatives of amino-substituted heteroarylcarboxylic acids, or their lower alkyl esters, such as ethyl 2-amino-4-chloropyridine-2-carboxylate, ethyl 5-amino-3-chloropyridine-5-carboxylate, and 3, 4-dibromo-5-aminothiophene-2-carboxylic acid. The latter exemplary reagents may be prepared by chlorination or bromination of 2-aminopyridine-5-carboxylic acid or its ester, 3-aminopyridine-6-carboxylic acid or its ester (described in WO 93/06086) and 2-aminothiophene-5-carboxylic acid (described in PCT/US 92/06485), respectively.

The reaction between the compound of formula 6 and the compound of formula 7 or between the compound of formula 6a and the compound of formula 7a as described aboveThe reaction of (a) actually involves the synthesis of the carbamoyl (amide) compound of the present invention. Numerous examples of this reaction will be described in detail in the experimental section below. Referring to formula 1 wherein Z is S, the carbamoyl (amide) compound of the present invention can be converted into a thiocarbamoyl (thioamide) compound of the present invention by reacting the carbamoyl (amide) compound with 2, 4-bis (4-methoxyphenyl) -1, 3-dithia-2, 4-diphosphane (diphosphetane) -2, 4-disulfide (Lawesson' S reagent). This reaction is illustrated in scheme 7 with 2 specific examples of compounds employed in the process of the invention.

Reaction scheme 7

The starting material, 4- [5 ', 6', 7 ', 8' -tetrahydro-5 ', 5', 8', 8' -tetramethylnaphthalen-2-yl) carbamoyl in reaction scheme 7]Benzoic acid ethyl ester (Compound I)₁) Obtainable according to the technique of Kagechika et al J.MedChem.198831, 2182-2192. Starting material, 2-fluoro-4- [5 ', 6', 7 ', 8' -tetrahydro-5 ', 5', 8', 8' -tetramethylnaphthalen-2-yl) carbamoyl]Ethyl benzoate (Compound 1) is obtainable according to the invention.

Reaction scheme 8

Reaction scheme 9

Reaction scheme 10

Reaction schemes 8,9 and 10 disclose preparation examples of carbamoyl (amide) compounds of the present invention, in which a compound of formula 6 and a compound of formula 7 are first subjected to a coupling reaction, and then the carbamoyl (amide) compound directly obtained initially in the coupling reaction is subjected to a subsequent coupling reactionOr multiple reactions. Thus, as shown in reaction scheme 8,5, 6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-3-methoxymethylnaph-thalene-2-carboxylic acid (compound K) and ethyl 4-amino-2-fluorobenzoate (compound C) are reacted in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and Dimethylaminopyridine (DMAP)₁) In CH₂Cl₂Intermediate coupling to give 2-fluoro-4 [5 ', 6', 7 ', 8' -tetrahydro-5 ', 5', 8', 8' -tetramethyl-2 '-methoxymethoxy-naphthalen-3' -yl) carbamoyl]Benzoic acid ethyl ester (Compound K)₁). Treatment with thiophenol and boron trifluoride etherate to remove the methoxymethyl protecting group from Compound K₁Removal of the resulting 2-fluoro-4 [5 ', 6', 7 ', 8' -tetrahydro-5 ', 5', 8', 8' -tetramethyl-2 '-hydroxy-naphthalen-3' -yl) carbamoyl]Ethyl benzoate (Compound 5). The hydroxyl functionality of compound 5 is converted to n-hexyl ether by treatment with hexyl iodide in the presence of a mild base.

According to reaction scheme 9 in the presence of ethylcarbodiimide hydrochloride (EDC) and DMAP in CH₂Cl₂5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-1-bromo-2-methoxymethyloxynaphthalene-3-carboxylic acid (compound N) and methyl 4-amino-2, 6-difluorobenzoate (compound H) are added to a solvent₁) Coupling gives 2, 6-difluoro-4- [ (5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethyl-1 ' -bromo-2 ' -methoxymethoxy-naphthalen-3 ' -yl) carbamoyl]Benzoic acid methyl ester (Compound M)₁) Esterified methyl groups and methoxymethyl protecting groups are separately removed from compound M via base and acid treatments₁Removal to give 2, 6-difluoro-4- [ (5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethyl-1 ' -bromo-2 ' -hydroxy-naphthalen-3 ' -yl) carbamoyl]Benzoic acid (compound 32).

Reaction scheme 10 discloses the conversion of 2,2,4, 4-tetramethyl-8-nitrobenzchroman-6-carboxylic acid (compound V) to the corresponding acid chloride via thionyl chloride treatment followed by ethyl 4-amino-2-difluorobenzoate (compound C)₁) Coupled and hydrogenated to give 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-amino-6' -chromanyl) carbamoyl]Benzoic acid ethyl ester (Compound N)₁) Examples of (3). Compound N₁By treatment of isoamyl nitrate and NaN₃After treatment, 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-azido-6' -chromanyl) carbamoyl group is converted to the corresponding 8-azido compound]Ethyl benzoate (Compound 13).

Reaction scheme 11

Reaction scheme 11 illustrates the reaction from acid chlorides (X)₃= Cl) or other forms of the active acid in formula 6, wherein the primary amine in formula 6a is not obtainable according to publicly published literature methods. Thus, the acid chloride of formula 6 is reacted with sodium azide in acetone to produce the azide compound of formula 9, generally according to the step of the Curtius rearrangement. Heating the azide of formula 9 in a high boiling polar solvent such as t-butanol produces the isocyanate intermediate of formula 10 which is then hydrolyzed to produce the compound of formula 6 a.

Reaction scheme 12

Reaction scheme 12 illustrates examples of the preparation of compounds of formula 7a, which are not commercially available or obtainable by published literature methods. Thus, according to the method of the example, 2, 5-difluoro-4-bromobenzoic acid (obtainable according to the method of Sugawara et al, Kogyo Kaguku Zasshi 1970,73, 972-979) is first esterified by treatment with ethanol and acid to give the corresponding ester, which is then reacted with butyllithium and subsequently with carbon dioxide to give the monoester of 2, 5-difluoroterephthalic acid (compound T₁). A series of similar reactions carried out with respect to 2,3,5, 6-difluoro-4-bromobenzoic acid (obtainable according to Reuman et al J.Med.chem.1995,38, 2531-2540) yielded the monoester of 2,3,5, 6-tetrafluoroterephthalic acid (compound V)₁). In general, all of the compounds of formula 7a can be synthesized using the series of reactions just described with modifications well known to those skilled in the artIt will be readily understood by the skilled person that these compounds are not obtainable according to known literature methods.

Reaction scheme 13 provides for the preparation of 2, 6-di-tert-butyl-isonicotinic acid (Compound C)₃) According to formula 8, compound C₃Reagents for the preparation of several preferred compounds of the invention. Thus, 2, 6-di-tert-butyl-4-methylpyridine (commercially available from Aldrich Chemical Co.) was reacted with N-bromosuccinimide and benzoyl peroxide to give 4-bromomethyl-2, 6-di-tert-butylpyridine (Compound A)₃). Mixing the compound A₃Reaction with base (sodium hydroxide) to give the corresponding hydroxymethyl compound (Compound B)₃) Then oxidized by Jones oxidation to form 2, 6-di-tert-butyl isonicotinic acid (compound C)₃)。

Reaction scheme 13

Scheme 13 further gives examples of compounds that can be used as reagents for preparing the carbamoyl (or amide) compounds of the present invention. Bromination of 2, 4-di-tert-butylphenol (Aldrich) in glacial acetic acid gave 2-bromo-4, 6-di-tert-butylphenol (Compound D)₃) Then the compound D is added₃Reaction with methoxymethyl chloride (MOMCl) to give O-methoxymethyl-2-bromo-4, 6-di-tert-butylphenol (Compound E)₃). Compound E₃Treatment with t-butyllithium followed by carbon dioxide yielded O-methoxymethyl-3, 5-di-t-butylsalicylic acid (Compound F)₃). Due to the compound F₃The hydroxy function in (A) is protected by a methoxymethyl (MDM) group, and thus it is a different reagent from the compounds generally included in formula 8. However, the methoxymethyl protecting group is removed after formation of the carbamoyl (amide) bond, as exemplified in reaction scheme 14. Aromatic bromo compounds (e.g., compound D), as described herein₃) The reaction with t-butyllithium followed by carbon dioxide is the preferred method for preparing several aromatic carboxylic acids according to formula 8 and formula 7 a.

Substantially following the Curtius rearrangement step, from acid chlorides (X)₃= Cl) or other forms of the active acid in formula 8 preparation of primary amine compounds in formula 8a that are not commercially available or can not be prepared by published literature methods, this step is similar to the reaction step described above according to reaction scheme 11.

Reaction scheme 14

Reaction scheme 14 (continue)

Reaction scheme 14 depicts an example of the formation of a carbamoyl (amide) compound according to formula 2 via reaction of a reagent in formula 8 with a reagent in formula 7. Thus, 2, 6-di-tert-butyl-isonicotinic acid (compound C)₃) With thionyl chloride (SOCl)₂) Reacting to produce an intermediate acid chloride, and reacting the intermediate acid chloride with ethyl 2-fluoro-4-amino-benzoate (Compound C)₁) Reaction in the presence of an acid acceptor (pyridine) to give 2-fluoro-4- [ (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl]Ethyl benzoate (Compound 41). As a further example, 3, 5-di-tert-butylbenzoic acid (obtainable by the method of Kagechika et al, J.Med.chem.1988,31,2182, incorporated herein by reference) is reacted with thionyl chloride and then with ethyl 2-fluoro-4-aminobenzoate (compound C)₁) Reaction to give 2-fluoro-4- (3 ', 5' -di-tert-butylphenyl) carbamoyl]Ethyl benzoate (Compound 45). As another example, O-methoxymethyl-3, 5-ditert-butyl salicylic acid (Compound F)₃) With ethyl 2-fluoro-4-aminobenzoate (Compound C)₁) Reaction in the presence of 4-Dimethylaminopyridine (DMAP) catalyst and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) to give 2-fluoro-4- [ (2 ' -methoxymethyl-3 ', 5 ' -di-tert-butylphenyl) carbamoyl]Benzoic acid ethyl ester (Compound G)₃). Treatment of methoxymethyl protecting group with boron trifluoride etherate and thiophenol from Compound G₃In the presence of a catalyst to produce 2-fluoro-4- [ (2 ' -hydroxy-3 ', 5 ' -di-tert-butylbenzene) carbamoyl]Ethyl benzoate (Compound 47).

In yet another example shown in reaction scheme 14, 2, 6-di-tert-butyl-isonicotinic acid (Compound C)₃) With thionyl chloride (SOCl)₂) Reaction of the resulting intermediate acid chloride with methyl 2, 6-difluoro-4-aminobenzoate (Compound H)₁) After the reaction, the ester group is saponified to give 2, 6-difluoro-4- [ (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl]Benzoic acid (compound 50). Subjecting 3, 5-di-tert-butylbenzoic acid to the same series of reactions can give 2, 6-difluoro-4- [ (3 ', 5' -di-tert-butylphenyl) carbamoyl]Benzoic acid (compound 52).

An example is also shown in scheme 14, which is to say 2, 6-di-tert-butyl-isonicotinic acid (compound C)₃) With thionyl chloride (SOCl)₂) Reaction, followed by reaction with methyl 2-nitro-4-aminobenzoate (Compound F)₁) Reacting and saponifying the ester function to give 2-nitro-4- [ (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl]Benzoic acid (compound 54).

Numerous other reactions suitable for preparing the compounds of the present invention, for converting compounds of formula 1 and/or formula 2 into compounds for further use in the therapeutic methods of the present invention, and also suitable for preparing reagents of formula 6, formula 7, formula 8, formula 6a, formula 7a, and formula 8a will be readily understood by those skilled in the art in light of this disclosure. The compounds of formula 1 and/or 2 may be converted to other homologues and/or derivatives according to the general synthetic methods described below, whilst reagents useful in the preparation of formula 6, formula 7 and formula 8 (and 6a,7a and 8a) are also noted.

Typical carboxylic acid esterification can be carried out by refluxing the acid in an appropriate alcohol solution in the presence of an acid catalyst such as hydrochloric acid or thionyl chloride. Alternatively, the carboxylic acid may be condensed with an appropriate alcohol in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine. The ester can be recovered and purified by conventional methods. Acetals and ketals are readily prepared by the method described in March, "advanced organic chemistry", 2 nd edition, McGraw-Hill Book Cimpany, page 810. Alcohols, aldehydes and ketones can be protected by known methods such as those described in Mc Omie, Plenum publishing Press,1973 and Protecting Groups, Ed.Greene, John, Wiley & Sons,1981 to form ethers and esters, acetals or ketals, respectively.

The acids and salts derived from the compounds of formula 1 and 2 are readily obtained from the corresponding esters. Alkali saponification with an alkali metal base will generate an acid. For example, the ester is preferably dissolved in a polar solvent such as an alkanol together with an about 3 molar excess of a base such as potassium hydroxide or lithium hydroxide at room temperature under an inert environment. The solution is stirred for a prolonged period of time, e.g. 15 to 20 hours, cooled, acidified and the hydrolysate recovered by conventional methods.

Amide formation from the corresponding ester or carboxylic acid (B is CONR in formulas 1 and 2) using any suitable amidation method known in the art₉R₁₀). One method of preparing such compounds is to convert the acid to an acid chloride and then treat the compound with ammonium hydroxide or a suitable amine.

Preparation of the alcohols the corresponding acids can be converted to acid chlorides by thionyl chloride or other methods (J. March, "advanced organic chemistry", second edition, Mc Graw-Hill Book Company) which then reduce the acid chlorides with sodium borohydride (March, Ibid, page 1124) which produces the corresponding alcohols. In addition, the esters can also be reduced with lithium aluminum hydride at reduced temperatures. Alkylation of these alcohols with the appropriate alkyl halides under Williamson reaction conditions (March, Ibid, p. 357) produces the corresponding ethers. These alcohols can be converted to esters by reaction with a suitable acid in the presence of an acid catalyst or dicyclohexylcarbodiimide and dimethylaminopyridine.

Aldehydes are prepared from the corresponding primary alcohols using mild oxidizing agents such as pyridinium dichromate in dichloromethane (Corey, e.j., Schmidt, g., tet.lett.,399,1979) or dimethyl sulfoxide/oxalyl chloride (Omura, k., Swern, d., Tetrahedron,1978,34,1651) in dichloromethane.

Ketones can be prepared from the appropriate aldehyde by treating the aldehyde with an alkyl Grignard reagent or similar reagent and oxidizing.

Acetals or ketals can be prepared from the corresponding aldehydes or ketones using the method described in March, Ibid 810.

Specific example 4-amino-2-fluorobenzoic acid ethyl ester (Compound C)₁)

6.83ml of H₂SO₄2-fluoro-4-nitrotoluene (1.0g,6.4mmol, Aldrich) and Na were slowly added₂Cr₂O₇(2.74g,8.4mmol) in 13.7ml of a mixture of HOAc. Heating the mixture slowly to 90 ℃ for 1 hour produced a pale green heterogeneous solution. The mixture was cooled to room temperature and diluted with ethyl acetate. The pH of the solution was adjusted to 4 with NaOH (aq.). The mixture was extracted with ethyl acetate. The organic layer was first treated with NaHCO₃(sat.), then washed with brine and passed over Na₂SO₄And (5) drying. After filtration, the solution was concentrated to dryness and then redissolved in 6ml of SOCl₂Heating at 80 deg.C for 1 hr. Excess SOCl was added under reduced pressure₂The residue was removed and dissolved in 5ml CH₂Cl₂2ml EtOH and 2ml pyridine. The mixture was stirred at room temperature for 2 hours and concentrated to dryness. The residue was subjected to column chromatography and eluted with ethyl acetate/hexane (1/9) to give ethyl 2-fluoro-4-nitrobenzoate as a white solid. The solid was then dissolved in 10ml of ethyl acetate and Pd/C (50mg) was added. Hydrogenation was carried out using a hydrogen flask to convert ethyl 2-fluoro-4-nitrobenzoate to the desired compound.¹H NMRδ7.77(t,J=8.4Hz,1H),6.41(dd,J₁=8.6,J₂=2.2Hz,1H),6.33(dd,J₁=13.0,J₂=2.2Hz,1H),4.33(q, J =7.1Hz,2H),4.3(b,2H),1.37(t, J =7.1Hz,3H), 4-amino-2, 6-difluorobenzoic acid methyl ester (compound H, 1H)₁)

Trifluorobenzoic acid (150mg,0.85mmol, Aldrich) was added to 0.5ml of SOCl₂The solution in (1) was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and the excess SOCl was removed under reduced pressure₂Removing. The residue was dissolved in 1ml pyridine and 0.2ml methanol. After stirring at room temperature for 30 minutes, the solvent was purified by column chromatography (ethyl acetate/hexane 1/10) to give methyl trifluorobenzoate as a colorless oil. This oil was then dissolved in 1ml of CH₃Adding NaN into CN₃(100mg,1.54mmol) in 0.5ml of water. The reaction mixture was refluxed for 2 days. The salt was filtered and the residual solution was concentrated to an oil. The oil was then dissolved in 1ml of methanol and a catalytic amount of Pd/C (10%, w/w) was added. The reaction mixture was hydrogenated under a hydrogen cylinder for 12 hours. The catalyst was removed and the solution was concentrated to an oil. After column chromatography (ethyl acetate/hexane 1/3), the title compound was obtained as colorless crystals.¹H NMR δ 6.17(d, J =10.44 Hz,2H),4.2(b,2H),3.87(s,3H), 8-bromo-2, 2,4, 4-tetramethyl-6-chromanic acid (compound P)

Adding Br₂(0.07ml,1.28mmol) was added to a solution of 2,2,4, 4-tetramethyl-6-chromanic acid (200mg,0.85mmol) in 0.5ml AcOH. The resulting dark orange solution was allowed to stand overnight at room temperature. Excess bromine was removed under reduced pressure. The solution was then poured into 5ml of water and extracted with ethyl acetate (3X 3 ml). With NaHCO₃(sat.), the combined ethyl acetate layers were further washed with brine and passed over MgSO₄It is dried. After concentration, the residue was purified by column chromatography (silica gel, ethyl acetate/hexane 1/3) to give the desired product (170mg) as a white solid.¹H NMR δ 8.11(d, J =2.2Hz,1H),8.00(d, J =2.2Hz,1H),1.90(s,2H),1.43(s,6H),1.39(s,6H), 8-iodo-2, 2,4, 4-tetramethyl-6-chromanic acid (compound X)

ICl (0.07ml,1.4mmol) was added to a solution of 2,2,4, 4-tetramethyl-6-chromanic acid (66mg,0.28mmol) in 0.8ml AcOH. The resulting colored solution was stirred at room temperature overnight. The same procedure as used for the synthesis of 8-bromo-2, 2,4, 4-tetramethyl-6-chromanic acid (compound P) was followed, and the reaction yielded the target compound (107mg) as a white solid.¹H NMR δ 8.35(d, J =2.2Hz,1H),8.03(d, J =2.2Hz,1H),1.87(S,2H),1.43(S,6H),1.38(S,6H), 2,4, 4-tetramethyl-8-trifluoromethylchroman-6-ic acid (compound S)

8-bromo-2, 2,4, 4-tetramethyl-6-chromanic acid (compound R,150mg,0.48mmol) is added to 1ml SOCl₂The solution in (1) was refluxed for 2 hours. After cooling to room temperature, excess SOCl was removed under reduced pressure₂And the residue was dissolved in 1ml of pyridine and 0.2ml of methanol. The mixture was stirred at room temperature for 30 minutes. The solvent was removed and the residue was passed through a column (silica gel, ethyl acetate/hexane 1/10) to give methyl 8-bromo-2, 2,4, 4-tetramethylchromanate (158mg) as a colorless oil. Adding NaCO₂CF₃(502mg,3.7mmol) and CuI (350mg,1.84mmol) were added to a solution of the methyl ester in 3ml of N-methylpyrrolidone (NMP). The resulting mixture was heated to 175 ℃ (bath temperature) for 2 hours. The resulting mixture was cooled to room temperature and poured into ice water. The product was extracted with ethyl acetate (3X 3 ml). The combined organic layers were dried and concentrated to dryness. Purification of the crude product by column chromatography (ethyl acetate/chloroform 1/10) gave the title compound (120mg) as a colorless oil. The compound is hydrolyzed under standard conditions to yield the target compound.¹H NMR δ 8.21(d, J =2.1Hz,1H),8.17(d, J =2.1Hz,1H),1.92(s,2H),1.41(s,12H), 8-nitro-2, 2,4, 4-tetramethyl-6-chromanoic acid ethyl ester (compound W)

Ethyl 2,2,4, 4-tetramethyl-6-chromanate (150mg,0.57mmol) is slowly added to 0.3ml of concentrated H at 0 deg.C₂SO₄In (1). 0.03ml of HNO₃Very slowly added to the mixture. The reaction mixture was stirred at 0 ℃ for 30 minutes and poured into ice water. The product is extracted with 5ml of ethyl acetate and NaHCO₃(sat.) brine wash and passage over MgSO₄And (5) drying. After concentration, the product was purified by column chromatography (ethyl acetate/hexane 1/10) to yield 74mg of a pale yellow oil.¹H NMR δ 8.24(d, J =2.1Hz,1H),8.17(d, J =2.1Hz,1H),4.38(q, J =7.1Hz,2H),1.95(s,2H),1.43(s,6H),1.42(s,6H),1.40(t, J =7.1Hz,3H), 2-oxo-4, 4, 8-trimethylchroman (compound P1)

In a 500ml round bottom flask, NaH (1.66g, 60% suspension in oil, 0.046mol) was washed with anhydrous hexane. Then dry THF (22ml) was added followed by a further 10ml dryO-cresol (O-cresol) (5g,0.046mmol) in dry THF. The reaction mixture was stirred at 0 ℃ for 30 minutes and then 3, 3-dimethylacryloyl chloride in 10ml THF was added. The resulting white slurry was stirred at room temperature for 12 hours and then quenched with water slowly. The mixture was then extracted with ethyl acetate. The organic layer was washed with brine, water and MgSO₄And (5) drying. After filtration and removal of the solvent, a yellow oil (10.44g) was obtained. The oil was then dissolved in 50ml of anhydrous CH₂Cl₂Then, it is inserted into AlCl with a sleeve₃(10.8g,0.069mmol) in 10ml CH₂Cl₂In the solution of (1). The reaction mixture was stirred at room temperature for 12 hours. Ice water was then added carefully and the organic layer was separated with NaHCO₃(sat), brine, water wash, and finally MgSO₄And (5) drying. After removal of the drying agent and solvent, the residue was purified by column chromatography (silica gel, ethyl acetate/hexane 1/9) to give the title compound (4.408g) as an oil.¹H NMR Delta 7.1(m,3H),2.62(s,2H),2.33(s,3H),1.36(s,6H), 2, 4-dimethyl-4- (2 '-hydroxy-3' -methylphenyl) pentan-2-ol (Compound R)₁)

Methylmagnesium bromide (12.67ml,38mmol, 3M solution in THF) was added to 2-oxo-4, 4, 8-trimethylchroman (compound P)₁2.20g,11.5mmol) in 40ml of anhydrous ether. The reaction mixture was stirred at room temperature for 12 hours and then with NH₄Cl (sat.) allowed to quench until all precipitate dissolved. The mixture was extracted with ether and the combined organic layers were separated and washed with brine, water, over MgSO₄And (5) drying. After filtration and removal of the solvent, the title compound (2.215g) was obtained as a brown solid.¹H NMR δ7.16(d,J=7.88Hz,1H),7.00(d,J=6.72Hz,1H),6.81(t,J=7.6Hz,1H),5.89(b,1H),2.21(s,3H),2.17(s,2H),1.48(s,6H),1.10(s,6H).

2,2,4,4, 8-pentamethyl-6-bromochroman (compound Z)

2, 4-dimethyl-4- (2 '-hydroxy-3' -methylphenyl) pentan-2-ol (compound R)₁2,215g,9.98mmol) in 30ml of 15% H₂SO₄The solution in (a) is heated toAt 110 ℃. After cooling to room temperature, the reaction mixture was extracted with diethyl ether. With NaHCO₃(sat.), brine and water. After filtration and removal of the solvent, the residue was passed through a column (silica gel, pure hexane) to give the title compound (1.636g) as a clear oil. This oil was then dissolved in 1.5ml of HOAc, and Br was added₂(0.4113ml,7.98 mmol). The reaction mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure and ethyl acetate was added to the residue, followed by NaHCO₃(sat.), brine, water wash the resulting mixture and over MgSO₄And (5) drying. After filtration and removal of the solvent, the residue was passed through a column (silica gel, pure hexane) to give the target compound (2.227g) as a white solid.¹H NMR Delta 7.21(s,1H),7.06(s,1H),2.14(s,3H),1.79(s,2H),1.32(s,6H),1.31(s,6H), 2,4,4, 8-pentamethyl-6-chromanic acid (Compound A)₁)

5.48ml of tert-BuLi (1.7M in hexane, 9.33mmol) were slowly added to a solution of 2,2,4,4, 8-pentamethyl-6-bromochroman (Compound Z) (1.2g,4.24mmol) in 18ml of dry THF at-78 ℃ under a stream of argon. The reaction mixture was stirred at-78 ℃ for 1 hour. Then bubbling CO₂A gas stream was passed through the solution for 1 hour. CO removal₂After the gas flow, the reaction mixture was stirred at-78 ℃ for another hour. Then 10% HCl was added. After the reaction mixture was warmed to room temperature, it was extracted with ethyl acetate. The organic layer was further washed with brine and passed over Na₂SO₄And (5) drying. After concentration, the residue was purified by column chromatography (ethyl acetate/hexane 5/95) to give the title compound (774mg) as a white solid.¹H NMR Delta 7.96(s,1H),7.75(s,1H),2.23(s,3H),1.88(s,2H),1.39(s,6H), 8-bromo-4, 4-dimethyl-6-chromanic acid (Compound B)₁)

The title compound was obtained as a white solid in the same manner as in the synthesis of 8-bromo-2, 2,4, 4-tetramethylchromanic acid (compound P) but using 4, 4-dimethylchromanic acid (100mg,0.49 ml).¹H NMR δ 8.10(d, J =2.1Hz,1H),7.98(d, J =2.1Hz,1H),4.39(t, J =5.44Hz,2H),1.89(t, J =5.4Hz,1H),1.38(s,6H), 2-amino-1-bromo-5, 5,8, 8-tetrahydro-5, 5, 8-c-l-b-oro-1-ol-ethyl 5,5,8, 8-tetramethylnaphthalene-3-carboxylate (Compound D)

Adding Br₂(0.02ml,0.42mmol) was added to a solution of ethyl 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-3-aminonaphthalene-2-carboxylate (compound C,58mg,0.21mmol) in 2ml HOAc. The clear solution was stirred at room temperature for 2 days. Removing excess Br under reduced pressure₂And HOAc and passing the residue through a column (silica gel, ethyl acetate/hexanes 1/10) gave the title compound as a light orange oil (59mg, 79.5%).¹H NMR δ 7.90(s,1H),6.41(b,2H),4.36(q, J =7.2Hz,2H),1.70(m,4H),1.58(s,6H),1.40(t, J =7.2Hz,3H),1.28(s,6H), 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-4-bromonaphthalene-2-carboxylic acid ethyl ester (compound E)

Ethyl 2-amino-1-bromo-5, 5,8, 8-tetrahydro-5, 5,8, 8-tetramethylnaphthalene-3-carboxylate (compound D,59mg,0.17mmol) was dissolved in 2ml EtOH at 0 ℃. To this solution, 1ml of trifluoroacetic acid and 1ml of isoamyl nitrite were added. The reaction mixture was stirred at 0 ℃ for 30 minutes and then H was added₃PO₂(0.325ml,3.14 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. Adding NaHCO₃(sat.) and extracting the reaction mixture with ethyl acetate over MgSO₄Drying, filtration and concentration gave an oil. The product was purified by column chromatography (silica gel, ethyl acetate/hexane 1/10) to give the title compound as a colorless oil.¹H NMRδ8.02(d,J=2.0Hz,1H),7.95(d,J=2.0Hz,1H),4.35(q,J=7.1Hz,2H),1.71(m,4H),1.56(s,6H),1.38(t,J=7.1Hz,3H),1.31(s,6H).

5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-3-fluoronaphthalen-2-yl-carboxylic acid ethyl ester (Compound G)

In an ice bath, 0.24ml HBF₄(48% solution in water) to 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-3-aminonaphthalen-2-yl-carboxylic acid ethyl ester (Compound C,150mg,0.55mmol), and NaNO added₂(81mg,1.16mmol) in 1ml of water. The slurry was left in the refrigerator for 3 days. The reaction mixture was washed successively with ethyl acetate until TLC showed no UV visible spots on the baseline. The ethyl acetate layer is over MgSO₄Dried and the solution was concentrated to an oil. The oily substance is added intoThe reaction mixture was dissolved in 1ml of toluene and the mixture was heated under reflux for 2 hours. After the reaction was cooled to room temperature, the solvent was evaporated and the residue was passed through a column (silica gel, ethyl acetate/hexane 1/10) to give the target compound as an oil.¹H NMR δ 7.85(d, J =7.8Hz,1H),7.04(d, J =12.3Hz,1H),4.38(q, J =7.1Hz,2H),1.69(s,4H),1.38(t, J =7.1Hz,3H),1.30(s,6H),1.28(s,6H), 2-bromo-3-hydroxy-5, 5,8, 8-tetrahydro-5, 5,8, 8-tetramethylnaphthalene (compound I)

The same procedure as for the synthesis of 8-bromo-2, 2,4, 4-tetramethyl-6-chromanic acid (compound P) was used but 2-hydroxy-5, 5,8, 8-tetrahydro-5, 5,8, 8-tetramethyl (700mg,3.43mmol) and Br in 1.5ml HOAc were used₂(0.177ml,3.43mmol), the objective compound (747mg) was obtained as a white solid.¹H NMR Delta 7.36(s,1H),6.96(s,2H),5.32(b,1H),1.66(s,4H),1.25(s,12H), 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-3-methoxymethyloxy-2-bromonaphthalene (Compound J)

Diisopropylethylamine (1.138ml,12.75mmol) was added to 2-bromo-3-hydroxy-5, 5,8, 8-tetrahydro-5, 5,8, 8-tetramethylnaphthalene (compound I,600mg,2.12mmol) and a catalytic amount of Bu at 0 deg.C₄NBr in 20ml anhydrous CH₂Cl₂To the solution in (1), methoxymethyl chloride (0.484ml,6.39mmol) was further added. The reaction mixture was heated at 45 ℃ for 12 hours. With 10% citric acid and then with NaHCO₃(sat.), the reaction mixture was washed with brine and passed over MgSO₄And (5) drying. After filtration and removal of the solvent, the residue was purified by column chromatography (ethyl acetate/hexane 1/9) to give the title compound (722mg) as a white solid.¹H NMR Delta 7.43(s,1H),7.06(s,1H),5.21(s,2H),3.54(s,3H),1.66(s,4H),1.26(s,6H),1.25(s,6H), 3-methoxymethyloxy-5, 5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalen-2-ylcarboxylic acid (Compound K)

Synthesis of 2,2,4,4, 8-pentamethyl-6-chromanic acid (Compound A)₁) In the same manner, but using 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-3-methoxymethyloxy-2-bromonaphthalene (compound J,722mg,2.21mmol) and 2.86ml of tert-BuLi (4.87mmol, 1.7M solution in hexane), the objective compound (143mg) was obtained as a white solid.¹H NMR Delta 8.12(s,1H),7.19(s,1H),5.40(s,2H),3.58(s,3H),1.70(s,4H),1.30(s,12H), 2-fluoro-4- [ (5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) carbamoyl]Ethyl benzoate (Compound 1)

1ml of thionyl chloride was added to 5,5,8, 8-tetramethyl-5, 6,7, 8-tetrahydro-2-naphthoic acid (46mg,0.2 mmol). The mixture was refluxed for 2 hours. Excess thionyl chloride was removed under reduced pressure and the residue was dissolved in 2ml CH₂Cl₂In (1). 4-amino-2-fluorobenzoic acid ethyl ester (compound C)₁37mg,0.2mmol) was added to the solution, and 0.5ml of pyridine was added. The reaction mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. Purification of the residue by column chromatography (ethyl acetate/hexane 1/10) gave the title compound as a white solid.¹H NMRδ8.06(b,1H),7.93(t,J=8.4Hz,1H),7.85(d,J=2.0Hz,1H),7.78(dd,J₁=2.0Hz,J₂=12.9Hz,1H),7.55(dd,J₁=2.0Hz,J₂=8.2Hz,1H),7.40(d,J=8.3Hz,1H),7.32(dd,J₁=2.02Hz,J₂=8.8Hz,1H),4.38(q, J =7.2Hz,2H),1.71(s,4H),1.40(t, J =7.2Hz),1.32(s,6H),1.30(s,6H), 2-fluoro-4- [ (5 ', 6', 7 ', 8' -tetrahydro-4 '-bromo-5', 5 ', 8', 8 '-tetramethylnaphthalen-2' -yl) carbamoyl]Ethyl benzoate (Compound 3)

Synthesis of 2-fluoro-4- [ (5 ', 6', 7 ', 8' -tetrahydro-4 '-bromo-5', 5 ', 8', 8 '-tetramethylnaphthalen-2' -yl) carbamoyl]The same procedure as for ethyl benzoate (compound 1) was followed, but using 5,6,7, 8-tetrahydro-5, 5,8, 8-tetramethyl-4-bromonaphthalene-2-carboxylic acid (compound F), the title compound was obtained as a white solid.¹H NMRδ8.30(b,1H),7.92(t,J=8.4Hz,1H),7.84(d,J=2.1Hz,1H),7.81(d,J=2.1Hz,1H),7.74(dd,J₁=2.1Hz,J₂=12.8Hz,1H),7.35(dd,J₁=2.0Hz,J₂=8.4Hz,1H),4.36(q, J =7.2Hz,2H),1.67(m,4H),1.55(s,6H),1.39(t, J =7.2Hz,3H),1.31(s,6H), 2-fluoro-4- [ (3 '-methoxymethoxy-5', 6 ', 7', 8 '-tetrahydro-5', 5 ', 8', '8-tetramethylnaphthalen-2' -yl) carbamoyl]Benzoic acid ethyl ester (Compound K)₁)

Synthesis of 2-fluoro-4- [ (3' -methyl-)Oxymethoxy-4 '-bromo-5', 6 ', 7', 8 '-tetrahydro-5', 5 ', 8', '8-tetramethylnaphthalen-2' -yl) carbamoyl]Benzoic acid ethyl ester (Compound S)₁) The same procedure was followed but using 3-methoxymethyloxy-5, 5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalen-2-ylcarboxylic acid (compound K,143mg,0.49mmol) and 4-amino-2-fluorobenzoate (compound C)₁98.5mg,0.54mmol), the title compound can be obtained as a white solid.¹H NMR δ 10.1(b,1H),8.20(s,1H),7.93(t, J =8.8Hz,1H),7.83(d, J =13.4Hz,1H),7.29(d, J =8.0Hz,1H),5.41(s,2H),4.39(q, J =7.1Hz,2H),3.59(s,3H),1.70(s,4H),1.31(s,12H),1.26(t, J =7.1Hz,3H), 2-fluoro-4- [ (3 ' -hydroxy-5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethyl-2-naphthyl) carbamoyl]Ethyl benzoate (Compound 5)

Thiophenol (0.061ml,0.55mmol) was added to 2-fluoro-4- [ (3 '-methoxymethyloxy-5', 6 ', 7', 8 '-tetrahydro-5', 5 ', 8', 8 '-tetramethylnaphthalen-2' -yl) carbamoyl]Benzoic acid ethyl ester (Compound K)₁50.7ml,0.11mmol) in 2ml CH₂Cl₂In the solution of (1). The reaction mixture was stirred at 0 ℃ for 5 minutes, followed by addition of BF₃·Et₂O (0.027ml,0.22 mmol). The reaction mixture was stirred at 0 ℃ for 2 hours, then NaHCO was added₃(sat.). The organic layer was separated, washed with brine, water and MgSO₄And (5) drying. After filtration and removal of the solvent, the residue was passed through a column (silica gel, ethyl acetate/hexane 1/3) to give the title compound (44.2mg) as a white solid.¹H NMR δ 8.61(b,1H),7.94(t, J =8.42Hz,1H),7.71(dd, J =10.8,2.0Hz,1H),7.53(s,1H),7.35(dd, J =6.4,2.0Hz,1H),6.96(s,1H),4.39(q, J =7.1Hz,2H),1.69(s,4H),1.40(t, J =7.1Hz,3H),1.29(s,6H),1.27(s,6H), 2-fluoro-4- [ (4 ', 4' -dimethyl-8 '-bromochroman-6' -yl) carbamoyl group]Ethyl benzoate (Compound 7)

In a 10ml round bottom flask, SOCl was added₂(1ml, Large excess) to 4, 4-dimethyl-8-bromo-6-chromanic acid (Compound B)₁139mg,0.485 mmol). The resulting solution was heated at 90 ℃ for 2 hours and allowed to cool to room temperature. Excess SOCl₂Evaporated under reduced pressure. Removing residuesThe residue is dissolved in CH₂Cl₂(3 ml). 4-amino-2-fluorobenzoic acid ethyl ester (Compound C) was added₁90mg,0.49mmol), and pyridine (0.5ml, large excess) was added. The reaction mixture was stirred overnight and then concentrated to dryness. Column chromatography of the residue with ethyl acetate/hexane (1/5) gave the title compound (190mg) as a white solid.¹H NMR δ 7.95(t, J =8.31Hz,1H),7.88(b,1H),7.83(d, J =2.2Hz,1H),7.80(d, J =2.2Hz,1H),7.75(dd, J =12.89,2.0Hz,1H),7.30(dd, J =8.55,2.0Hz,1H),4.37(m,5H),1.89(t, J =5.49Hz,2H),1.40(t, J =7.1Hz,3H),1.39(s,6H), 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-bromochroman-6' -yl) carbamoyl group]Ethyl benzoate (Compound 9)

Synthesis of 2-fluoro-4- [ (4 ', 4' -dimethyl-8 '-bromochroman-6' -yl) carbamoyl]The same procedure was followed for ethyl benzoate (Compound 7) except that 2,2,4, 4-tetramethyl-8-bromo-6-chromanic acid (Compound P,70mg,0.22mmol) and ethyl 4-amino-2-fluorobenzoate (Compound C) were used₁38mg,0.22mmol), the objective compound (80mg, 76%) was obtained as a white solid.¹H NMRδ8.25(b,1H),7.92(t,J=8.4Hz,1H),7.83)s,2H),7.74(dd,J₁=2.0,J₂=13.0Hz,1H),7.34(dd,J₁=2.0,J₂=8.7Hz,1H),4.37(q, J =7.1Hz,2H),1.88(s,2H),1.41(s,6H),1.39(t, J =7.1Hz,3H),1.37(s,6H), 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-trifluoromethylchroman-6' -yl) carbamoyl]Ethyl benzoate (Compound 11)

Synthesis of 2-fluoro-4- [ (4 ', 4' -dimethyl-8 '-bromochroman-6' -yl) carbamoyl]The same procedure was followed for ethyl benzoate (Compound 7), except that 2,2,4, 4-tetramethyl-8-trifluoromethyl-6-chromanic acid (Compound S,57mg,0.19mmol) and ethyl 4-amino-2-fluorobenzoate (Compound C) were used₁35mg,0.19mmol) to obtain the objective compound as a white solid¹H NMR δ 8.06(d, J =2.2Hz,1H),7.99(b,1H),7.95(t, J =8.55Hz,1H),7.81(d, J =2.2Hz,1H),7.76(dd, J =12.8,2.1Hz,1H),7.33(dd, J =8.55,1.9Hz,1H),4.37(q, J =7.1Hz,2H),1.93(s,2H),1.41(s,12H),1.40(t, J =7.2Hz,3H), 2-fluoro-4- [ (2 ', 2', 4'-tetramethyl-8 '-amino-chroman-6' -yl) carbamoyl]Benzoic acid ethyl ester (Compound N)₁)

Synthesis of 2-fluoro-4- [ 4', 4' -dimethyl-8 '-bromochroman-6' -yl) carbamoyl from 8-nitro-2, 2,4, 4-tetramethylchroman-6-carboxylic acid (Compound V)]Ethyl benzoate (Compound 7) in the same manner as above, 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-nitrobenzchroman-6' -yl) was obtained as a white solid]Carbamoylbenzoic acid ethyl ester. This compound (50mg,0.12mmol) was dissolved in 2ml of methanol. Adding a catalytic amount of Pd/C to the solution and dissolving the solution in H₂(hydrogen cylinder) overnight. Removal of the catalyst by filtration and evaporation of the solvent gave the title compound as a white solid.¹H NMR δ 7.93(t, J =8.43Hz,1H),7.90(b,1H),7.73(dd, J =12.9,2.0Hz,1H),7.29(dd, J =8.43,1.96 Hz,1H),7.23(d, J =2.14Hz,1H),7.01(d, J =2.2Hz,1H),4.35(q, J =7.1Hz,2H),1.88(s,2H),1.39(s,6H),1.38(t, J =7.1Hz,3H),1.37(s,6H), 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-azidochroman-6' -yl) carbamoylyl]Ethyl benzoate (Compound 13)

0.5ml of trifluoroacetic acid (TFA) and 0.5ml of nitrosoisoamyl ester were added to 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-aminochroman-6' -yl) carbamoyl at 0 deg.C]Benzoic acid ethyl ester (Compound N)₁32mg,0.077mmol) in 3ml EtOH. When NaN is added₃(5mg) solution in 0.2ml of water, the reaction mixture was stirred for 2 hours. The reaction mixture was allowed to warm to room temperature and stirred overnight. Removal of the solvent and purification of the residue by column chromatography (silica gel, ethyl acetate/hexane 1/10) gave the title compound as a colorless oil.¹H NMR δ 8.0(b,1H),7.94(t, J =7.8Hz,1H),7.73(d, J =12.1Hz,1H),7.64(s,1H),7.31(dd, J =8.5,2.0Hz,1H),7.21(d, J =2.0Hz,1H),4.37(q, J =7.1Hz,2H),1.90(s,2H),1.39(t, J =7.1Hz,3H),1.45(s,6H),1.40(s,6H), 2, 6-difluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-trifluoromethylchroman-6' -yl) carbamoyl group]Benzoic acid ethyl ester (Compound 15)

Use andsynthesis of 2-fluoro-4- [ (4 ', 4' -dimethyl-8 '-bromochroman-6' -yl) carbamoyl]The same procedure was followed for ethyl benzoate (Compound 7), except that 2,2,4, 4-tetramethyl-8-trifluoromethylchromanic acid (Compound S,11.2mg,0.037mmol) and methyl 4-amino-2, 6-difluorobenzoate (Compound H)₁6.6mg,0.035mmol) white crystalline title compound can be obtained.¹H NMR δ 8.21(b,1H),8.05(s,1H),7.82(s,1H),7.36(d, J =10.20Hz,1H),3.93(s,3H),1.92(s,2H),1.40(s,12H), 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-iodochroman-6' -yl) carbamoyl]Ethyl benzoate (Compound 17)

Synthesis of 2-fluoro-4- [ (4 ', 4' -dimethyl-8 '-bromochroman-6' -yl) carbamoyl]The same procedure was followed for ethyl benzoate (Compound 7), but using 2,2,4, 4-tetramethyl-8-iodochromanic acid (Compound X,81mg,0.25mmol) and ethyl 4-amino-2-fluorocarboxylate (Compound C)₁55mg,0.30mmol) to obtain the target compound as a white solid.¹H NMR δ 8.05(b,1H),8.01(d, J =2.2Hz,1H),7.94(t, J =8.4Hz,1H),7.86(d, J =2.2Hz,1H),7.75(dd, J =12.88,2.1Hz,1H),7.33(dd, J =8.8,2.1Hz,1H),4.37(q, J =7.1Hz,2H),1.89(s,2H),1.42(s,6H),1.38(s, 6H). 2-fluoro-4- [ (2 ', 2', 4', 4', 8 '-pentamethylbenzodihydropyran-6' -yl) carbamoyl]Ethyl benzoate (Compound 19)

Synthesis of 2-fluoro-4- [ (4 ', 4' -dimethyl-8 '-bromochroman-6' -yl) carbamoyl]The same procedure was followed for ethyl benzoate (Compound 9), but using 2,2,4,4, 8-pentamethyl-6-chromanic acid (Compound A)₁92mg,0.37mmol) and ethyl 4-amino-2-fluorocarboxylate (Compound C)₁75mg,0.41mmol), the objective compound (100mg) was obtained as a white solid.¹H NMR δ 8.31(b,1H),7.90(t, J =8.24Hz,1H),7.76(dd, J =14.29,1.7Hz,1H),7.74(s,1H),7.43(s,1H),7.35(dd, J =8.67,1.7Hz,1H),4.32(q, J =7.1Hz,2H),2.18(s,3H),1.84(s,2H),1.38(t, J =7.1Hz,3H),1.35(s,6H),1.34(s,6H), 4- [ (5 ', 6', 7 ', 8' -tetrahydro-5 ', 5', 8', 8' -tetramethyl-2-naphthyl) thiocarbamoyl]Ethyl benzoate (Compound 21)

Lawesson's reagent (45mg,0.112mmol) was added to 4- [ (5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2-yl) carbamoyl]Benzoic acid ethyl ester (Compound I)₁61mg,0.16mmol) in 2ml dry benzene. The resulting yellow solution was taken up in N₂Reflux was carried out under a stream of air for 2 hours. Removal of the solvent and purification of the residue by column chromatography (silica gel, ethyl acetate/hexane 1/5) gave the title compound (55mg, 87%) as a yellow solid.¹H NMR δ 9.04(b,1H),8.11(d, J =8.70Hz,2H),7.85(b,2H),7.75(b,1H),7.55(dd, J =8.2,1.9Hz,1H),7.36(d, J =8.3Hz,1H),4.38(q, J =7.1Hz,2H),1.71(s,4H),1.40(t, J =7.1Hz,3H),1.30(s,12H), 2-fluoro-4- [ (5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) thiocarbamoyl group]Ethyl benzoate (Compound 23)

Synthesis of 4- [ (5 ', 6', 7 ', 8' -tetrahydro-5 ', 5', 8', 8' -tetramethyl-2-naphthyl) thiocarbamoyl]The same procedure as for ethyl benzoate (Compound 21) was followed, except that 2-fluoro-4- [ (5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) carbamoyl was used]Ethyl benzoate (compound 1,167mg,0.42mmol) was neutralized with Lawensson's reagent (220mg,0.544mmol) in 8ml of benzene to give the title compound (127.5mg) as a bright yellow solid.¹H NMR δ 9.30(b,1H),8.05(b,1H),7.95(t, J =8.37Hz,1H),7.77(d, J =1.89Hz,1H),7.53(dd, J =8.24,2.1Hz,1H),7.49(b,1H),7.35(d, J =8.24Hz,1H),4.33(q, J =7.1Hz,1H),1.71.(s,4H),1.32(s,6H),1.30(s,6H), 3-hydroxy-5, 5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalen-2-yl carboxylic acid (compound L)

2.86ml of tert-BuLi (1.7M in hexane, 4.8mmol) were slowly added to a solution of 2-bromo-3-methoxymethyloxy-5, 5,8, 8-tetrahydro-5, 5,8, 8-tetramethylnaphthalene (Compound J,722mg,2.2mmol) in 10ml of dry THF at-78 ℃ under argon flow. The reaction mixture was stirred at-78 ℃ for 1 hour. Then bubbling CO into the solution₂The gas flow was for 1 hour. CO removal₂After the gas flow, the reaction mixture was stirred at-78 ℃ for a further 1 hour. After adding 10% HCl and heating to room temperature, the reaction mixture was allowed to stand overnight and then extracted with ethyl acetate. The organic layer was washed with brine andthrough Na₂SO₄And (5) drying. After concentration, the residue is purified by column chromatography (ethyl acetate/hexane 1/3) to yield the title compound as a white solid¹H NMR d 7.85(s,1H),6.93(s,1H),1.68(s,4H),1.28(s,12H), 4-bromo-3-hydroxy-5, 5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalen-2-ylcarboxylic acid (Compound M)

3-hydroxy-5, 5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalen-2-oic acid (compound L,155mg,0.62mmol) was dissolved in 1ml of HOAc. Adding Br₂(0.033ml,0.62mmol) was added to the solution. The reaction mixture was allowed to stand overnight at room temperature. Removing unreacted Br by passing a stream of air through the reaction mixture₂. The residual solid was dissolved in a small amount of THF and purified by column chromatography (ethyl acetate/hexanes 1/1) to yield the desired product as a cream-colored solid.¹H NMR d 7.91(s,1H),1.75(m,2H),1.64(m,2H),1,62(s,6H),1.30(s,6H), 4-bromo-3-methoxymethyloxy-5, 5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalen-2-yl-carboxylic acid (Compound N)

Chloromethyl methyl ether (0.162ml,2.1mmol), diisopropylethylamine (0.764ml,4.2mmol) and a catalytic amount of tetrabutylammonium bromide were added to 4-bromo-3-hydroxy-5, 5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalen-2-oic acid (compound M,233mg,0.71mmol) in 6ml CH₂Cl₂In the solution of (1). The reaction mixture was heated to 45 ℃ for 2 hours. The reaction mixture was concentrated and the residue was purified by column chromatography (ethyl acetate/hexane 1/9) to give methoxymethyl ester of the objective compound (200mg) as a white solid. The white solid was further dissolved in 20ml EtOH. An aqueous solution of NaOH (0.5ml,1M) was added. The reaction mixture was stirred at room temperature overnight. The EtOH was removed and 2ml of ethyl acetate and 3ml of water were added to the residue. The mixture was acidified very slowly with 10% HCl to pH =7. The ethyl acetate layer was separated and washed with brine, over Na₂SO₄And (5) drying. After filtration of the drying agent and removal of the solvent, the reaction yielded the target compound (155mg) as a white solid.

¹H NMR d 7.99(s,1H),5.20(s,2H),3.66(s,3H),1.74(m,2H),1.67(m,2H),1.60(s,6H),1.32(s,6H), 2-fluoro-4- [ (3 '-methoxymethoxy-4' -bromo-)5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) carbamoyl]Benzoic acid ethyl ester (Compound S)₁)

DMAP (60mg,0.26mmol), ethyl 2-fluoro-4-aminobenzoate (Compound C)₁43mg,0.24mmol) and EDC (50mg,0.26mmol) were added to 4-bromo-3-methoxymethyloxy-5, 5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalen-2-oic acid (compound N,80mg,0.22mmol) in 4ml CH₂Cl₂In the solution of (1). The reaction mixture was stirred at room temperature overnight and then concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/hexane 1/3) to give the title compound (45mg) as a clear oil.¹H NMR d 9.92(b,1H),8.10(s,1H),7.94(t, J =8.4Hz,1H),7.81(dd, J = 12.9; 1.9Hz,1H),7.35(dd, J = 8.5; 1.8Hz,1H),5.20(s,2H),4.39(q, J =7.1Hz,2H),3.61(s,3H),1.74(m,2H),1.64(m,2H),1.60(s,6H),1.40(t, J =7.1Hz,3H),1.34(s,6H), 2, 6-difluoro-4- [ (3 ' -methoxymethoxy-4 ' -bromo-5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) carbamoyl]Benzoic acid methyl ester (Compound M)₁)

Using and synthesizing the compound 2-fluoro-4- [ (3 ' -methoxymethoxy-4 ' -bromo-5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) carbamoyl]Benzoic acid ethyl ester (Compound S)₁) In the same manner, but using 4-bromo-3-methoxymethyloxy-5, 5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalen-2-oic acid (compound N,80mg,0.22mmol), DMAP (60mg,0.26mmol), methyl 2, 6-difluoro-4-aminobenzoate (compound H,52mg,0.24mmol) and EDC (50mg,0.26mmol), the title compound was obtained as a clear oil.¹H NMR d 10.01(b,1H),8.11(s,1H),7.42(d, J =10.0Hz,2H),5.2(s,2H),3.95(s,3H),3.63(s,3H),1.75(m,2H),1.65(m,2H),1.61(s,6H),1.35(s,6H), 4-bromomethyl-2, 6-di-tert-butylpyridine (compound a)₃)

Benzoyl peroxide (24mg,0.097mmol) and NBS (1.9g,10.7mmol) were added to 2, 6-di-tert-butyl-4-methylpyridine (Aldrich,2.0g,9.73mmol) in 25mL anhydrous CCl₄In the mixture of (1). The reaction mixture was refluxed for 16 hours. After cooling to room temperature, the solvent is removed in vacuo and the residue is subjected to column chromatography (Silica gel, hexanes) gave an oil (1.957g) containing 82% of the desired product and 18% of the starting material.

¹H NMR. delta.7.09 (s,2H),4.39(s,2H),1.35(s,18H), 4-hydroxymethyl-2, 6-di-tert-butylpyridine (Compound B3)

4-bromomethyl-2, 6-di-tert-butylpyridine (compound A)₃1.743g, 82% purity) was refluxed for 12 hours in a heterogeneous solution of 12% NaOH in 20ml water and 10ml 1, 4-dioxane. The solution automatically separated into 2 layers when cooled to room temperature. The upper layer was separated and ethyl acetate was added. The organic layer was then washed with brine, water and MgSO₄And (5) drying. The desired product was purified by column chromatography (ethyl acetate/hexane 1/9) to yield a white solid.¹H NMR delta 7.09(s,2H), 4.67(d, J =4.4Hz,2H),2.3(b,1H),1.36(s,18H), 2, 6-di-tert-butylisonicotinic acid (Compound C)₃)

Jone's reagent was added dropwise to 4-hydroxymethyl-2, 6-di-tert-butylpyridine (Compound B)₃302mg,1.37mmol) in 5ml of acetone until the solution changes color from light yellow to orange (55 drops of Jone's reagent were consumed). After 5 minutes 2ml of isopropanol were added to the reaction mixture to form Cr³⁺Green precipitation of the salt. The precipitate was removed by filtration and the solution diluted with ethyl acetate then washed with brine, water and over MgSO₄And (5) drying. After filtration, removal of the solvent gave the desired product as a white solid (227 mg).¹H NMR Delta 7.71(s,2H),1.34(s,18H), 2-bromo-4, 6-di-tert-butylphenol (Compound D)₃)

Br2(0.5ml,9.7mmol) was added to a solution of 2, 4-di-tert-butylphenol (Aldrich,2.0g,9.7mmol) in 2ml HOAc. The reaction mixture was stirred at room temperature for 12 hours. Removal of the solvent under reduced pressure and purification of the residue by column chromatography (ethyl acetate/hexanes 1/20) gave the desired product as a white solid (2.54 g).

¹H NMRδ7.33(d,J=2.3Hz,1H),7.24(d,J=2.3Hz,1H),1.41(s,9H),1.29(s,9H).

O-methoxymethyl-2-bromo-4, 6-di-tert-butylPhenol (Compound E)₃)

Diisopropylethylamine (9.51ml,53mmol) was added to 2-bromo-4, 6-di-tert-butylphenol (compound D) at 0 deg.C₃2.54g,8.88mmol) and catalytic amount of Bu₄NI in 20ml anhydrous CH₂Cl₂To the solution in (1), methoxymethyl chloride (2.02ml,26.6mmol) was then added. The reaction mixture was heated at 45 ℃ for 12 hours. Then using 10% citric acid and then NaHCO₃(sat.), the reaction mixture was washed with brine and passed through MgSO₄And (5) drying. After filtration and removal of the solvent under reduced pressure, the residue was purified by column chromatography (pure hexane) to give the objective compound (2.79g) as a colorless oil.¹H NMRδ7.40(d,J=2.44Hz,1H),7.30(d,J=2.4Hz,1H),5.22(s,2H),3.70(s,3H),1.43(s,9H),1.29(s,9H).

O-methoxymethyl-3 ', 5' -di-tert-butylsalicylic acid (Compound F)₃)

11ml of tert-BuLi (1.7M in hexane, 18.7mmol) were added to o-methoxymethyl-2-bromo-4, 6-di-tert-butylphenol (compound E) at-78 ℃ under argon₃2.79g,8.5mmol) in 30ml of dry THF. The mixture was stirred at-78 ℃ for 1 hour. Then bubbling CO into the solution at-78 deg.C₂(g) The gas flow was for 1 hour. CO removal₂After the gas flow, the reaction mixture was stirred at-78 ℃ for a further 1 hour. Then 10% HCl was added and the mixture was allowed to warm to room temperature and extracted with ethyl acetate. The organic layer was washed with brine and over Na₂SO₄And (5) drying. After concentration, the residue was purified by column chromatography (ethyl acetate/hexane 1/1) to give the title compound (492mg) as a white solid.¹H NMR δ 7.75(d, J =2.81Hz,1H),7.60(d, J =2.8Hz,1H),5.07(s,2H),3.62(s,3H),1.33(s,9H),1.26(s,9H), 2-fluoro-4- [ (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl group]Benzoic acid ethyl ester (Compound 41)

2, 6-di-tert-butyl isonicotinic acid (compound C)₃47.3mg,0.20mmol) in 2ml of SOCl₂The solution in (a) was heated under reflux for 2 hours. Removal of excess SOCl in vacuo₂And the residue was dissolved in 2ml of anhydrous CH₂Cl₂In, addAddition of ethyl 2-fluoro-4-aminobenzoate (Compound C)₁40.2mg,0.22mmol) and pyridine (0.0835ml,0.69 mmol). The reaction mixture was stirred at room temperature for 12 hours. Removal of the solvent and purification of the residue by column chromatography (ethyl acetate/hexane 1/9) gave the title compound (71.2mg) as white crystals.¹H NMR δ 8.56(b,1H),7.91(t, J =8.36Hz,1H),7.53(dd, J =12.82,2.0Hz,1H),7.39(dd, J =8.7,2.0Hz,1H),4.33(q, J =7.1Hz,2H),1.37(t, J =7.1Hz,3H),1.35(s,18H), 4- [ (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl group]Ethyl benzoate (Compound 43)

Synthesis of 2-fluoro-4 (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl]The same procedure as for ethyl benzoate (Compound 41), but using 2, 6-di-tert-butylisonicotinic acid (Compound C)₃101mg,0.43mmol) and ethyl 4-aminobenzoate (78mg,0.47mmol), the objective compound (135mg) was obtained as a white solid.¹H NMRδ8.43(b,1H),,8.02(d,J=8.7 Hz,2H),7.75(d,J=8.7Hz,2H),7.48(s,2H),4.33(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H),1.35(s,18H).

Ethyl 2-fluoro-4- [ (3 ', 5' -di-tert-butylphenyl) carbamoyl ] benzoate (Compound 45)

Synthesis of 2-fluoro-4 (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl]The same procedure is followed for ethyl benzoate (Compound 41), but using 3, 5-di-tert-butylbenzoic acid (60mg,0.26mmol, available from literature methods, see Kagechika et al, J.Med chem.1988,31, 2182-one 2192) and ethyl 2-fluoro-4-aminobenzoate (Compound C)₁51.5mg,0.28mmol), the objective compound (66mg) was obtained as a white solid.

¹H NMRδ8.21(b,1H),7.93(t,J=8.3Hz,1H),7.79(dd,J=12.8,2.0Hz,1H),7.67(d,J=1.8Hz,2H),7.65(t,J=1.7Hz,1H),7.35(dd,J=8.7,2.1Hz,1H),4.36(q,J=7.2Hz,2H),1.39(t,J=7.2Hz,3H),1.36(s,18H).

2-fluoro-4- [ (2 ' -methoxymethyl-3 ', 5 ' -di-tert-butylphenyl) carbamoyl]Benzoic acid ethyl ester (Compound G)₃)

1- (3-dimethyl ammonia)Aminopropyl) -3-ethylcarbodiimide hydrochloride (117mg,0.61mmol) was added to o-methoxymethyl-3 ', 5' -di-tert-butylsalicylic acid (Compound F)₃150mg,0.51mmol), 4-dimethylaminopyridine (142mg,0.61mmol) and ethyl 2-fluoro-4-aminobenzoate (Compound C)₁102mg,0.56mmol) in 5ml of anhydrous CH₂Cl₂In the mixture of (1). The reaction mixture was stirred at room temperature for 12 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate, washed with brine, water and over MgSO₄And (5) drying. After filtration, the solvent was removed and the residue was purified by column chromatography (ethyl acetate/hexane 1/3) to give the title compound (58 mg).¹H NMR δ 8.97(b,1H),7.94(t, J =8.37Hz,1H),7.78(d, J =2.7Hz,1H),7.61(d, J =13.0Hz,1H),7.56(d, J =2.6Hz,1H),7.35(d, J =8.7Hz,1H),5.00(s,2H),3.53(s,3H),4.38(q, J =7.1Hz,2H),1.47(s,9H),1.39(t, J =7.2Hz,3H),1.33(s,9H), 2-fluoro-4- [ (2 ' -hydroxy-3 ', 5 ' -di-tert-butylphenyl) carbamoyl]Ethyl benzoate (Compound 47)

Adding 10 drops of HOAc to 2-fluoro-4- [ (2 ' -methoxymethyl-3 ', 5 ' -di-tert-butylphenyl) carbamoyl]Benzoic acid ethyl ester (Compound G)₃34mg,0.07mmol) in 1ml of THF. The reaction mixture was heated to reflux for 12 hours. The solvent was removed and ethyl acetate was added. The solution was treated with NaCHO₃(sat.), brine, water wash and over MgSO₄And (5) drying. The solvent was removed in vacuo to give an oil. The oil was exposed to air for 12 hours during which time crystals formed. The crystals were collected and washed several times with hexane to give the title compound (13.5mg) as a white solid.¹H NMR δ 10.73(s,1H),7.98(d, J =2.56Hz,1H),7.88(b,1H),7.75(t, J =8.26Hz,1H),7.60(d, J =2.44Hz,1H),7.32(dd, J =12.3,2.0Hz,1H),7.02(dd, J =8.6,2.0Hz,1H),4.35(q, J =7.2Hz,2H),1.39(s,9H),1.37(t, J =7.2Hz,3H),1.5(s,9H), 2, 6-difluoro-4- [ (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl]Benzoic acid (Compound 50)

1ml of SOCl₂To 2, 6-di-tert-butyl-isonicotinic acid (Compound C)₃20mg,0.085 ml). The mixture was heated to reflux for 2 hours. Cooling to room temperature, and removing the excessSOCl of₂Remove and dissolve the residue in 2ml CH₂Cl₂In (1). Methyl 2, 6-difluoro-4-aminobenzoate (compound H)₁16mg,0.085mmol) and triethylamine (0.015ml,0.1mmol) were added to the solution. The reaction mixture was kept at room temperature for 2 hours and then concentrated to dryness. The residue was purified by column chromatography eluting with ethyl acetate/hexane (1/10) to give the methyl ester of the title compound. Saponification of the compound according to the general method (see below) gives the desired compound as a colorless solid.

¹H NMR δ 7.44(s,2H),7.40(d, J =11.8Hz,2H)1.37(s, 18H).2, 6-difluoro-4- [ (3 ', 5' -di-tert-butylphenyl) carbamoyl]Benzoic acid (Compound 52)

Synthesis of 2, 6-difluoro-4- [ (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl]The same procedure was followed for benzoic acid (Compound 50) but using 3, 5-di-tert-butylbenzoic acid (37mg,0.16mmol) and methyl 2, 6-difluoro-4-aminobenzoate (Compound H)₁29mg,0.16mmol) to obtain the objective compound as colorless crystals.¹H NMR δ 7.92(b,1H)7.60(m,3H),7.42(d, J =10.0Hz,2H),1.38(s,18H), 2-nitro-4- [ (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl]Benzoic acid (Compound 54)

Synthesis of 2, 6-difluoro-4- [ (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl]Benzoic acid (Compound 50) was prepared in the same manner, but using 2, 6-di-tert-butylisonicotinic acid (40mg,0.17mmol) and methyl 2-nitro-4-aminobenzoate (Compound F)₁33mg,0.17mmol), the title compound was obtained as a pale yellow oil.¹H NMR delta (acetone-d)⁶)10.25(b,1H),8.32(s,1H),7.97(d, J =8.1Hz,1H),7.93(b,1H),7.70(s,2H),1.36(s,18H), 2-nitro-4- [ (4 '-bromo-5', 6 ', 7', 8 '-tetrahydro-5', 5 ', 8', 8 '-tetramethylnaphthalen-2' -yl) carbamoyl]Benzoic acid methyl ester (Compound 25)

The same procedure as for the synthesis of Compound 1 was used, but Compound F and Compound F were used₁The desired product is obtained as a white solid.¹H NMRδ9.24(b,1H),9.23(d,J=1.8Hz,1H),7.92(dd,J=8.4,2.4,Hz,1H),7.87(d,J=2.1Hz,1H),7.84(d,3=2.1Hz,1H),7.80(d,J=8.7Hz,1H),3.91(s,3H),1.75(m,2H),1.65(m,2H),1.58(s,3H),1.33(s,3H).

General procedure for the synthesis of benzoic acid derivatives by hydrolysis of the corresponding methyl or ethyl esters.

5ml of 1N NaOH in water were added to a solution of the ester (3.0mmol) in 20ml of EtOH. The reaction mixture was stirred overnight at room temperature and neutralized with 10% HCl to pH =5. The alcohol was removed by evaporation and the aqueous layer was extracted with ethyl acetate (3 × 10 ml). With NaHCO₃(sat.), the combined ethyl acetate layers were washed with brine and passed over MgSO₄And (5) drying. After concentration, the desired acid can be obtained which can be recrystallized in ethyl acetate or acetonitrile. 2-fluoro-4- [ (5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) carbamoyl]Benzoic acid (Compound 2)¹H NMR Delta (acetone-D)₆)9.86(b,1H),7.95(m,3H),7.75(dd, J =7.9,2.2Hz,1H),7.62(dd, J =8.5,1.6Hz,1H),7.50(d, J =8.3Hz,1H),1.73(s,4H),1.32(s,6H),1.30(s,6H), 2-fluoro-4- [ (4 '-bromo-5', 6 ', 7', 8 '-tetrahydro-5', 5 ', 8', 8 '-tetramethylnaphthalen-2' -yl) carbamoyl]Benzoic acid (Compound 4)¹H NMR Delta (acetone-D)₆)9.97(b,1H),8.04(d, J =1.89Hz,1H),8.01(d, J =1.90Hz,1H),7.95(t, J =8.55Hz,1H),7.90(dd, J =12.28,2.0Hz,1H),7.59(dd, J =8.67,1.50Hz,1H),1.76(m,4H),1.58(s,6H),1.35(s,6H), 2-fluoro-4- [ (3 '-hydroxy-5', 6 ', 7', 8 '-tetrahydro-5', 5 ', 8', 8 '-tetramethylnaphthalen-2' -yl) carbamoyl]Benzoic acid (Compound 6)¹H NMR (acetone-D)₆) δ 11.3(b,1H),10.2(b,1H),7.94(m,2H),7.85(dd, J =11.4,1.95Hz,1H),7.53(dd, J =6.59,2.08Hz,1H),6.94(s,1H),2.85(b,1H),1.70(s,4H),1.29(s,6H),1.28(s,12H), 2-fluoro-4- [ (8 '-bromo-4', 4 '-dimethylchroman-6' -yl) carbamoyl group]Benzoic acid (Compound 8)¹H NMR (acetone-d)₆) δ 9.87(b,1H),8.04(d, J =2.1Hz,1H),8.03(d, J =2.1Hz,1H),7.94(t, J =8.66Hz,1H),7.91(dd, J =13.8,2.0Hz,1H),7.57(dd, J =8.6,2.0Hz,1H),4.37(t, J =5.44Hz,2H),1.92(t, J =5.44Hz,2H),1.40(s,6H), 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-bromochroman-6' -yl)) Carbamoyl radical]Benzoic acid (Compound 10)¹H NMR delta (acetone-d)₆)9.87(b,1H),8.06(d, J =2.2Hz,1H),8.04(d, J =2.1Hz,1H),7.94(t, J =8.54Hz,1H),7.91(dd, J =14.0,2.0Hz,1H),7.59(dd, J =8.5,2.3Hz,1H),1.96(s,2H),1.42(s,6H),1.41(s,6H), 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-trifluoromethylchroman-6' -yl) carbamoyl]Benzoic acid (Compound 12)¹H NMR (acetone-d)₆) δ 10.02(b,1H),8.31(s,1H),8.09(s,1H),7.92(m,2H),7.56(d, J =7.69Hz,1H),2.00(s,2H),1.44(s,6H),1.41(s,6H), 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-azidochroman-6' -yl) carbamoyl]Benzoic acid (Compound 14)¹H NMR δ 8.03(t, J =8.4Hz,1H),7.87(b,1H),7.79(dd, J =13,2.0Hz,1H),7.64(d, J =2.2Hz,1H),7.32(dd, J =8.66,1.9Hz,1H),7.22(d, J =2.1Hz,1H),1.91(s,2H),1.45(s,6H),1.41(s,6H), 2, 6-difluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-trifluoromethylchroman-6' -yl) carbamoyl group]Benzoic acid (Compound 16)¹H NMR (acetone-d)₆) δ 8.30(d, J =2.3Hz,1H),8.06(d, J =2.2Hz,1H),7.59(d, J =10.32Hz,2H),1.954(s,2H),1.44(s,6H),1.41(s,6H), 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-iodochroman-6' -yl) carbamoyl]Benzoic acid (Compound 18)¹H NMR delta (acetone-d)₆)10.0(b,1H),8.24(s,1H),8.07(s,1H),7.94(m,2H),7.57(d, J =8.67Hz,1H),1.95(s,2H),1.41(s,12H), 2-fluoro-4- [ (2 ', 2', 4', 4', 8 '-pentamethylbenzodihydropyran-6' -yl) carbamoyl]Benzoic acid (Compound 20)¹H NMR delta (acetone-d)₆)9.77(b,1H),7.90(m,3H),7.65(d, J =2.0Hz,1H),7.56(dd, J =8.61,2.0Hz,1H),2.19(s,3H),1.90(s,2H),1.38(s,6H),1.37(s,6H), 4- [ (5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) thiocarbamoyl]Benzoic acid (Compound 22)¹H NMR δ 9.08(b,1H),8.17(d, J =8.61,2H),7.95(b,2H),7.77(b,1H),7.57(dd, J =8.1,2.1Hz,1H),7.37(d, J =8.2Hz,1H),1.72(s,4H),1.32(s,6H),1.31(s,6H), 2-fluoro-4- [ (5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) thiocarbamoyl]Benzoic acid (Compound 24)¹H NMR delta (acetone-d)₆)11.1(b,1H),8.27(b,J=13.2Hz,1H),8.02(t,J=8.3Hz,1H),7.89(s,1H)7.86(d, J =10.0Hz,1H),7.62(d, J =8.3Hz,1H),7.41(d, J =8.37Hz,1H),1.72(s,4H),1.30(s,12H), 2-fluoro-4- [ (3 ' -hydroxy-4 ' -bromo-5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) carbamoyl]Benzoic acid (Compound 30)

1ml of an aqueous NaOH solution (1M) was added to 2-fluoro-4- [ (3 ' -methoxymethyloxy-4 ' -bromo-5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) carbamoyl]Benzoic acid ethyl ester (Compound S)₁45mg,0.084mmol) in 1ml EtOH. The reaction mixture was stirred overnight at room temperature and acidified with 10% HCl to pH =1. The EtOH was removed and ethyl acetate and more water were added to the solution. The organic layer was separated and combined with NaHCO₃Washed with brine and over MgSO₄And (5) drying. After filtration and concentration, the reaction yielded 2-fluoro-4- [ (3 ' -methoxymethyloxy-4 ' -bromo-5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) carbamoyl group as a white solid]Benzoic acid. The methoxymethyl group can be removed by dissolving the white solid in 2ml MeOH and 3 drops of HCl (con.). After stirring overnight, the reaction mixture was concentrated to dryness. The residue was partitioned between ethyl acetate and water. Separating the organic layer with NaHCO₃Washed with brine and over MgSO₄And (5) drying. After filtration and concentration, the residual solid was eluted through a mini (pipet) column with ethyl acetate/hexane (1/1) and purified to give the title compound as a white solid (5.0 mg).¹H NMR d (acetone-d)⁶)10.19(b,1H),8.01(s,1H),7.96(t, J =8.6HZ,1H),7.76(dd, J = 11.2; 2.0Hz,1H),7.54(dd, J = 8.8; 2.0Hz,1H),1.75(m,2H),1.65(m,2H),1.61(s,6H),1.32(s,6H), 2, 6-difluoro-4- [ (3 ' -hydroxy-4 ' -bromo-5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) carbamoyl]Benzoic acid (Compound 32)

Synthesis of 2-fluoro-4- [ (3 ' -hydroxy-4 ' -bromo-5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) carbamoyl]In the same manner as in the case of benzoic acid (compound 30), the objective compound was obtained as a white solid.¹H NMR d (acetone-d)⁶)10.23(b,1H),8.01(s,1H),7.52(d,J=10.2Hz,2H),4.8(b,1H),1.75(m,2H),1.65(m,2H),1.60(s,6H),1.31(s,6H), 2, 6-difluoro-4- [ (5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) carbamoyl]Benzoic acid (Compound 34)

1ml of thionyl chloride was added to 5,5,8, 8-tetramethyl-5, 6,7, 8-tetrahydro-2-naphthoic acid (43mg,0.19 mmol). The mixture was refluxed for 2 hours. Excess thionyl chloride was removed under reduced pressure and the residue dissolved in 2ml CH₂Cl₂In (1). 4-amino-2, 6-difluorobenzoic acid methyl ester (compound H)₁7mg,0.2mmol) was added to the solution, and 0.5ml of pyridine was added. The reaction mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. Purification of the residue by column chromatography (ethyl acetate/hexane 1/5) gave the desired product as a methyl ester as a colorless oil.¹H NMR d 8.11(d,J=1.9Hz,1H),8.05(b,1H),7.86(dd,J=6.2,2.2Hz,1H),7.41(m,3H),3.93(s,3H),1.69(s,4H),1.29(s,6H),1.28(s,6H).

Using NaOH/H according to the general method₂Hydrolysis of the colorless oil with O/EtOH gave the desired product.¹H NMR d (acetone-d)⁶)9.74(b,1H),7.95(s,1H),7.70(d, J =6.8Hz,1H),7.43(d, J =8.4Hz,3H),1.71(s,4H),1.29(s,6H),1.28(s,6H), 2-nitro-4- (4 '-bromo-5', 6 ', 7', 8 '-tetrahydro-5', 5 ', 8', 8 '-tetramethylnaphthalen-2' -yl) carbamoyl]Benzoic acid (Compound 26)¹H NMR delta (acetone-d)⁶) 10.16(b,1H),8.42(d, J =2.0Hz,1H),8.09(dd, J = 8.6; 2.1Hz,1H),8.06(d, J =2.2Hz,1H),8.04(d, J =2.2Hz,1H),7.93(d, J =8.6Hz,1H),1.75(m,2H),1.65(m,2H),1.57(s,3H),1.34(s,3H), 2-fluoro-4- [ (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl]Benzoic acid (Compound 42)

¹H NMRδ(CD₃OD)7.92(t, J =8.36Hz,1H),7.82(dd, J =12.82,2.0Hz,1H),7.63(s,2H),7.55(dd, J =8.7,2.1Hz,1H),1.39(s,18H), 4- [ (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl]Benzoic acid (Compound 44)

¹H NMRδ(CD₃OD)8.02(d, J =8.85Hz,2H),7.85(d, J =8.85Hz,2H),7.63(s,2H),1.40(s,18H), 2-fluoro-4- [ (3 ', 5' -di-tert-butyl) phenylaminoRadical formyl radical]Benzoic acid (Compound 46)

¹H NMRδ(CD₃OD)7.92(t, J =8.3Hz,1H),7.80(dd, J =12.8,2.0Hz,1H),7.79(d, J =1.8Hz,2H),7.69(t, J =1.7Hz,1H),7.57(dd, J =8.7,2.1Hz,1H),1.37(s,18H), 2-fluoro-4- [ (2 ' -hydroxy-3 ', 5 ' -di-tert-butyl) phenylcarbamoyl]Benzoic acid (Compound 48)

¹H NMR delta (acetone-d)₆)12.3(b,1H),10.07(b,1H),7.98(t,J=8.48Hz,1H),7.80(m,2H),7.58(d,J=2.3Hz,1H),7.56(dd,J=8.8,2.0Hz,1H),1.44(s,9H),1.31(s,9H).

Claims (22)

1. For the treatment or prevention of RAR_αMethods of administering a retinoid compound to a mammal for a therapeutically effective disease or condition with a specific or selective retinoid agonist, wherein the compound is preferential to RAR_βAnd RAR_γRetinoid receptors. Specifically or selectively react with RAR_αRetinoid receptor binding.

2. The method according to claim 1, wherein the RAR is_αSpecificity or selectivityRetinoids and RAR_αBinding ratio of retinoid receptor to RAR_βAnd RAR_γThe retinoid receptors bind approximately 500-fold more strongly.

3. The method according to claim 1, wherein the RAR_αAdministering to a mammal a specific or selective retinoid for treating or preventing a disease or condition selected from the group consisting of: acute monocytic leukemia, cervical cancer, myeloma, ovarian cancer, head and neck cancer, Proliferative Vitreoretinopathy (PVR), and age-related macular degeneration (AMD).

4. The method according to claim 3, wherein the RAR is_αThe specific or selective retinoid is administered in a dosage of about 0.5 to 5mg per kg body weight per day.

5. The method according to claim 1, wherein the RAR_αAdministering to a mammal a specific or selective retinoid for treating or preventing a disease or condition selected from the group consisting of: actinic keratosis, arsenical keratosis, inflammatory and noninflammatory acne, psoriasis, ichthyosis, eczema, atopic dermatitis, Darriers 'disease, lichen planus, glucocorticoid damage, topical microbial infections, skin pigmentation, damage to the skin due to age and light, pre-malignant and malignant hyperproliferative diseases, kaposi's sarcoma, ocular diseases, Proliferative Vitreoretinopathy (PVR), retinal detachment, xerophthalmia and other keratopathies, cardiovascular diseases, dyslipidemias, prevention of restenosis after angioplasty, various diseases associated with Human Papilloma Virus (HPV), various inflammatory diseases, neurodegenerative diseases, pituitary dysfunction, hair growth deficiency, diseases associated with the immune system and wound healing.

6. The method according to claim 1, wherein the RAR is_αSpecific or selective retinoids have the formula(ii) a structure of formula (i) or (ii)

Wherein X₁Is O or X₁Is [ C (R) ]₁)₂]_nWherein n is an integer between 0 and 2;

R₁independently H or alkyl of 1 to 6 carbon atoms;

R₂independently hydrogen, or lower alkyl of 1 to 6 carbon atoms;

R₃is hydrogen, lower alkyl of 1 to 6 carbon atoms or F;

m is an integer of 0 to 5;

o is an integer of 0 to 4;

p is an integer of 0 to 2;

r is an integer of 0 to 2;

X₂is N or CH;

y is a phenyl or naphthyl group, or a heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl (pyrrazolyl), said phenyl, naphthyl and heteroaryl groups optionally substituted with one or 2R₂Substituted by groups;

W₁is independently selected from C substituted by F, Br, Cl, I, fluorine_1-6Alkyl radical, NO₂And OH, provided that:

when the compound corresponds to formula (i) and Z is O, then the sum of p and r is at least 1 and W₁Cannot be a fluoro group at the 3-position of the tetralin ring;

(ii) when the compound corresponds to formula (i), r is 0, p is 1 and W₁When OH, then the OH group is alpha to the L group;

W₂is independently selected from C substituted by F, Br, Cl, I, fluorine_1-6Alkyl radical, NO₂And OH;

W₃is independently selected from the group consisting of F, Br, Cl, I, C_1-6Alkyl, fluoro substituted C_1-6Alkyl radical, NO₂And OH, provided that: when the compound is in accordance with formula 2, X₂Is CH, and r is 0, then p cannot be 0 and at least one W₃The group is not alkyl;

l is- (C = Z) -NH-or-NH- (C = Z) -;

z is O or S, and

b is COOH or a pharmaceutically acceptable salt thereof, COOR₈、CONR₉R₁₀、-CH₂OH、CH₂OR₁₁、CH₂OCOR₁₁、CHO、CH(OR₁₂)₂、CHOR₁₃O、-COR₇、CR₇(OR₁₂)₂、CR₇OR₁₃O, wherein R₇Is alkyl, cycloalkyl or alkenyl having 1 to 5 carbon atoms, R₈Is an alkyl group having 1 to 10 carbon atoms or a trimethylsilylalkyl group having 1 to 10 carbon atoms in the alkyl group, or is a cycloalkyl group having 5 to 10 carbon atoms, or R₈Is phenyl or lower alkylphenyl, R₉And R₁₀Independently of one another hydrogen, an alkyl radical having 1 to 10 carbon atoms, or a cycloalkyl radical having 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R₁₁Is lower alkyl, phenyl or lower alkylphenyl, R₁₂Is lower alkyl, and R₁₃Is a divalent alkyl group containing 2 to 5 carbon atoms.

7. The method according to claim 6, wherein the RAR is_αSpecific or selective retinoids are in accordance with formula (i).

8. The method according to claim 7, wherein the RAR_αSpecific or selective retinoids of formula X₁Is [ C (R) ]₁)₂]_nAnd n is 1.

9. The method according to claim 8, wherein the RAR is_αSpecific or selective retinoids have the formula wherein Y is phenyl.

10. According to claim6, wherein the RAR_αSpecific or selective retinoids are in accordance with formula (ii).

11. The method according to claim 10, wherein the RAR is_αA specific or selective retinoid-derived compound wherein Y is phenyl.

12. For the treatment or prevention of RAR_αMethods of administering a retinoid compound to a mammal in preference to RAR for a disease or condition for which a specific or selective retinoid agonist is therapeutically effective_βAnd RAR_γRetinoid receptors, specifically or selectively react with RAR_αRetinoid receptor engagement when said retinoid compounds are combined with RAR in a binding assay_αRatio of kd value for receptor binding to RAR_βAnd RAR_γRetinoid receptor binding with kd values about 500-fold less then RAR_αRetinoid receptors are specific or selective over RAR_βAnd RAR_γRetinoid receptors.

13. The method according to claim 12, wherein the RAR is_αAdministering to a mammal a specific or selective retinoid for treating or preventing a disease or condition selected from the group consisting of: actinic keratosis, arsenical keratosis, inflammatory and noninflammatory acne, psoriasis, ichthyosis, eczema, atopic dermatitis, Darriers 'disease, lichen planus, glucocorticoid damage, topical microbial infection, skin pigmentation, damage to the skin due to age and light, hyperproliferative diseases pre-malignant and malignant, Kaposi's sarcoma, ocular diseases, Proliferative Vitreoretinopathy (PVR), retinal detachment, xerophthalmia and other keratopathy, cardiovascular diseases, dyslipidaemia, prevention of restenosis after angioplasty, various diseases associated with Human Papilloma Virus (HPV), various inflammatory diseases, neuropathy, pituitary dysfunction, hair growth deficiency, diseases associated with HPVImmune system related diseases and wound healing.

14. The method according to claim 13, wherein the RAR is_αAdministering to a mammal a specific or selective retinoid compound for treating or preventing a disease or condition selected from the group consisting of: acute monocytic leukemia, cervical cancer, myeloma, ovarian cancer, head and neck cancer, Proliferative Vitreoretinopathy (PVR), and age-related macular degeneration (AMD).

15. The method according to claim 13, wherein the RAR is_αThe specific or selective retinoid compound has the structure of formula (i) or formula (ii)

Wherein X₁Is O or X₁Is [ C (R) ]₁)₂]_nWherein n is an integer between 0 and 2;

R₁independently H or alkyl of 1 to 6 carbon atoms;

R₂independently hydrogen, or lower alkyl of 1 to 6 carbon atoms;

R₃is hydrogen, lower alkyl of 1 to 6 carbon atoms or F;

m is an integer of 0 to 5;

o is an integer of 0 to 4;

p is an integer of 0 to 2;

r is an integer of 0 to 2;

X₂is N or CH;

y is a phenyl or naphthyl group or a heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl (Pyrrazolyl), said phenyl, naphthyl and heteroaryl groups optionally being substituted by one or 2R₂Substituted by groups;

W₁is independently selected from C substituted by F, Br, Cl, I, fluorine_1-6Alkyl radical, NO₂And OH, provided that:

when the compound corresponds to formula (i) and Z is O, then the sum of p and r is at least 1 and W₁Cannot be a fluoro group at the 3-position of the tetralin ring;

(ii) when the compound corresponds to formula (i), r is 0, p is 1 and W₁When OH, then the OH group is alpha to the L group;

W₂is independently selected from C substituted by F, Br, Cl, I, fluorine_1-6Alkyl radical, NO₂And OH;

W₃is independently selected from the group consisting of F, Br, Cl, I, C_1-6Alkyl, fluoro substituted C_1-6Alkyl radical, NO₂And OH, provided that: when the compound is in accordance with formula 2, X₂Is CH, and r is 0, then p cannot be 0 and at least one W₃The group cannot be alkyl;

l is- (C = Z) -NH-or-NH- (C = Z) -

Z is O or S, and

b is COOH or a pharmaceutically acceptable salt thereof, COOR₈、CONR₉R₁₀、-CH₂OH、CH₂OR₁₁、CH₂OCOR₁₁、CHO、CH(OR₁₂)₂、CHOR₁₃O、-COR₇、CR₇(OR₁₂)₂、CR₇OR₁₃O, wherein R₇Is alkyl, cycloalkyl or alkenyl having 1 to 5 carbon atoms, R₈Is an alkyl group having 1 to 10 carbon atoms or a trimethylsilylalkyl group having 1 to 10 carbon atoms in the alkyl group, or is a cycloalkyl group having 5 to 10 carbon atoms, or R₈Is phenyl or lower alkylphenyl, R₉And R₁₀Independently of one another hydrogen, an alkyl radical having 1 to 10 carbon atoms, or a cycloalkyl radical having 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R₁₁Is lower alkyl, phenyl or lower alkylphenyl, R₁₂Is lower alkyl, and R₁₃Is a divalent alkyl group containing 2 to 5 carbon atoms.

16. The method of claim 15, wherein saidRAR_αSpecific or selective retinoids are in accordance with formula (i).

17. The method according to claim 15, wherein the RAR is_αSpecific or selective retinoids are in accordance with formula (ii).

18. Administration to mammals in preference to RAR_βAnd RAR_γRetinoid receptors, specifically or selectively react with RAR_αA method of treating or preventing a disease or condition selected from the group consisting of: acute monocytic leukemia, cervical cancer, myeloma, ovarian cancer, head and neck cancer, Proliferative Vitreoretinopathy (PVR) and age-related macular degeneration (AMD) when retinoids are combined with RAR in a binding assay_αRatio of kd value for receptor binding to RAR_βAnd RAR_γWhen the kd value for retinoid receptor binding is less than about 500 times, the compound is useful for RAR_αRetinoid receptors are specific or selective over RAR_βAnd RAR_γA retinoid receptor, the retinoid having a structure of formula (i) or formula (ii).

Wherein X₁Is O or X₁Is [ C (R) ]₁)₂]_nWherein n is an integer between 0 and 2;

R₁independently H or alkyl of 1 to 6 carbon atoms;

R₂independently hydrogen, or lower alkyl of 1 to 6 carbon atoms;

R₃is hydrogen, lower alkyl of 1 to 6 carbon atoms or F;

m is an integer of 0 to 5;

o is an integer of 0 to 4;

p is an integer of 0 to 2;

r is an integer of 0 to 2;

X₂is N or CH;

y is a phenyl group orA naphthyl group, or a heteroaryl group selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrazolyl (pyrrazolyl), said phenyl, naphthyl and heteroaryl groups optionally being substituted with one or 2R₂Substituted by groups;

W₁is independently selected from C substituted by F, Br, Cl, I, fluorine_1-6Alkyl radical, NO₂And OH, provided that:

when the compound corresponds to formula (i) and Z is O, then the sum of p and r is at least 1 and W₁Cannot be a fluoro group at the 3-position of the tetralin ring;

(ii) when the compound corresponds to formula (ii), r is 0, p is 1 and W₁When OH, then the OH group is alpha to the L group;

W₂is independently selected from C substituted by F, Br, Cl, I, fluorine_1-6Alkyl radical, NO₂And OH;

W₃is independently selected from the group consisting of F, Br, Cl, I, C_1-6Alkyl, fluoro substituted C_1-6Alkyl radical, NO₂And OH, provided that: when the compound is in accordance with formula 2, X₂Is CH, and r is 0, then p cannot be 0 and at least one W₃The group cannot be alkyl;

l is- (C = Z) -NH-or-NH- (C = Z) -;

z is O or S, and

b is COOH or a pharmaceutically acceptable salt thereof, COOR₈、CONR₉R₁₀、-CH₂OH、CH₂OR₁₁、CH₂OCOR₁₁、CHO、CH(OR₁₂)₂、CHOR₁₃O、-COR₇、CR₇(OR₁₂)₂、CR₇OR₁₃O, wherein R₇Is alkyl, cycloalkyl or alkenyl having 1 to 5 carbon atoms, R₈Is an alkyl group having 1 to 10 carbon atoms or a trimethylsilylalkyl group having 1 to 10 carbon atoms in the alkyl group, or is a cycloalkyl group having 5 to 10 carbon atoms, or R₈Is phenyl or lowerAlkyl phenyl, R₉And R₁₀Independently of one another hydrogen, an alkyl radical having 1 to 10 carbon atoms, or a cycloalkyl radical having 5 to 10 carbon atoms, or phenyl or lower alkylphenyl, R₁₁Is lower alkyl, phenyl or lower alkylphenyl, R₁₂Is lower alkyl, and R₁₃Is a divalent alkyl group containing 2 to 5 carbon atoms.

19. The method according to claim 18, wherein the RAR is_αThe specific or selective retinoid is according to formula (i) and Y is phenyl.

20. The method according to claim 19, wherein the RAR is_αThe specific or selective retinoid is selected from the group consisting of:

ethyl 2-fluoro-4- [ (5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) carbamoyl ] benzoate;

2-fluoro-4-1 (5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) carbamoyl ] benzoic acid;

ethyl 2-fluoro-4- [ (5 ', 6', 7 ', 8' -tetrahydro-4 '-bromo-5', 5 ', 8', 8 '-tetramethylnaphthalen-2' -yl) carbamoyl ] benzoate;

2-fluoro-4- [ (4 '-bromo-5', 6 ', 7', 8 '-tetrahydro-5', 5 ', 8', 8 '-tetramethylnaphthalen-2' -yl) carbamoyl ] benzoic acid;

ethyl 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-bromochroman-6' -yl) carbamoyl ] benzoate;

2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-bromochroman-6' -yl) carbamoyl ] benzoic acid;

ethyl 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-trifluoromethylchroman-6' -yl) carbamoyl ] benzoate;

2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-trifluoromethylchroman-6' -yl) carbamoyl ] benzoic acid;

ethyl 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-azidochroman-6' -yl) azido) carbamoyl ] benzoate;

2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-azidochroman-6' -yl) azido) carbamoyl ] benzoic acid;

ethyl 2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-iodochroman-6' -yl) carbamoyl ] benzoate;

2-fluoro-4- [ (2 ', 2', 4', 4' -tetramethyl-8 '-iodochroman-6' -yl) carbamoyl ] benzoic acid;

ethyl 4- [ (5 ', 6', 7 ', 8' -tetrahydro-5 ', 5', 8', 8' -tetramethyl-2-naphthalenyl) thiocarbamoyl ] benzoate, and

4- [ (5 ', 6 ', 7 ', 8' -tetrahydro-5 ', 5 ', 8', 8' -tetramethylnaphthalen-2 ' -yl) thiocarbamoyl ] benzoic acid.

21. The method according to claim 18, wherein the RAR is_αThe specific or selective retinoid is according to formula (ii) and Y is phenyl.

22. The method according to claim 19, wherein the RAR is_αSpecific or selective retinoids are:

ethyl 2-fluoro-4- [ (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl ] benzoate, or

2-fluoro-4- [ (2 ', 6 ' -di-tert-butylpyridin-4 ' -yl) carbamoyl ] benzoic acid.