KR20060121894A - 1-(quinoline amino) and 1-(isoquinoline amino)-substituted pentan-2-ols, method for their production and their use as anti-inflammatories - Google Patents

Abstract

The invention relates to substituted pentanols, to a method for their production and to their use as anti-inflammatories.

Description

1- (Quinoline amino) and 1- (isoquinoline amino) -substituted pentan-2-ols, methods for their preparation, and their use as anti-inflammatory agents {1- (QUINOLINE AMINO) AND 1- (ISOQUINOLINE AMINO) -SUBSTITUTED PENTAN -2-OLS, METHOD FOR THEIR PRODUCTION AND THEIR USE AS ANTI-INFLAMMATORIES}

The present invention relates to quinoline and isoquinoline derivatives, methods for their preparation, and their use as anti-inflammatory agents.

From the prior art DE 100 38 639 and WO 02/10143,

(식 중, Ar기로는 프탈리드, 티오프탈리드, 벤족사지논 또는 프탈라지논이 포함됨)의 소염제가 알려져 있다. 실험에서는, 상기 화합물이 바람직하지 않은 대사 작용이 배제된 소염 작용을 하는 것으로 나타나며, 기존의 비스테로이드성 글루코코르티코이드보다 탁월하거나, 적어도 그것만큼 우수하게 작용하는 것으로 나타난다.Chemical formula

In the formula, an anti-inflammatory agent of phthalide, thiophthalide, benzoxazinone or phthalazinone is known. In experiments, the compounds appear to have an anti-inflammatory action that excludes undesirable metabolic action, and is superior to, or at least as good as, existing nonsteroidal glucocorticoids.

However, the selectivity of prior art compounds over other steroid receptors still needs to be improved.

Accordingly, it is an object of the present invention to obtain compounds with improved selectivity for other steroid receptors.

This object is achieved by a compound according to the claims.

Accordingly, the present invention relates to compounds of formula (I), racemates thereof or stereoisomers present individually, or physiologically compatible salts thereof.

In the formula,

A is C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkoxy, C ₁ -C ₅ -alkylthio, C ₁ -C ₅ -perfluoroalkyl, halogen, hydroxy, cyano, nitro, -O -(CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -O-CH = CH-,-(CH ₂ ) _{n + 2-} (where n is 1 or 2) , The terminal oxygen atom and / or carbon atom are connected to the immediately adjacent ring-carbon atom, or NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are independently of each other hydrogen, C ₁ -C ₅ -alkyl or (CO Aryl group, benzyl group or phenethyl group, which may be optionally substituted with one or more groups from the group of (C-C ₁ -C ₅ -alkyl),

R ¹ and R ² independently of one another represent a hydrogen atom, a methyl group or an ethyl group, or together with a carbon atom represent a chain of a C ₃ -C ₆ -cycloalkyl ring,

R ³ is C ₄ -C ₈ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₇ -heterocyclyl, aryl, Optionally substituted group selected from heteroaryl, (C ₁ -C ₈ -alkyl) C ₃ -C ₈ -cycloalkyl, (C ₁ -C ₈ -alkyl) aryl or (C ₁ -C ₈ -alkyl) heteroaryl Indicate,

B represents a methylene group or a carbonyl group optionally substituted with a methyl group or an ethyl group,

Q is C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkoxy, C ₁ -C ₅ -alkylthio, C ₁ -C ₅ -perfluoroalkyl, halogen, hydroxy, cyano, nitro or NR ⁴ R ⁵ optionally substituted with at least one of from the group of (wherein, R ⁴ and R ⁵ are independently hydrogen, C ₁ -C ₅ with each other - which can be alkyl-alkyl or (CO) -C ₁ -C ₅₎ And a quinolinyl group or isoquinolinyl group connected through any position.

Aryl groups include phenyl and naphthyl. Phenyl is preferred.

Substituted aryl, benzyl or phenethyl groups have from 1 to 3, preferably 2 substituents on the ring.

Substitution patterns in the following ring A are features of the invention: 2,5-disubstituted phenyl derivatives and 2,4-disubstituted phenyl derivatives.

The C ₁ -C ₅ -alkyl group of A, R ⁴ and R ⁵ may be linear or branched, and may be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert- A butyl group or n-pentyl group, 2, 2- dimethylpropyl group, 2-methylbutyl group, or 3-methylbutyl group can be shown. Methyl or ethyl groups are preferred.

The C ₄ -C ₈ -alkyl group of R ³ may be straight or branched, and may represent, for example, butyl, isobutyl, tert-butyl, pentyl or isopentyl.

C ₂ -C ₆ -alkenyl groups are linear or branched, for example vinyl, propenyl, isopropenyl, butenyl or isobutenyl.

C ₂ -C ₆ -alkynyl groups are linear or branched, for example ethynyl, propynyl or butynyl is suitable.

As cycloalkyl groups, for example, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl are contemplated.

Heterocyclyl groups are not aromatic and may be, for example, pyrrolidine, imidazolidine, pyrazolidine or piperidine.

The C ₁ -C ₈ -alkyl (C ₃ -C ₈ ) cycloalkyl group can be, for example, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl. The linkage with the chain is carried out via an alkyl group.

Phenyl and naphthyl are considered as aryl groups, and benzyl and homobenzyl are considered as (C ₁ -C ₈ ) alkylaryl.

Heteroaryls include furanyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl and pyrimidyl,

(C ₁ -C ₈ -alkyl) heteroaryl includes all combinations of alkyl and monocyclic aromatic heterocyclic compounds as defined above. The linkage with the chain is carried out via an alkyl group, which is also linked to any possible chemical position of the heterocyclic compound.

Substituents for groups of R ³ are C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkoxy, halogen, hydroxy and NR ⁴ R ⁵ Can be.

Alkyl groups R ¹ and R ² together with the carbon atoms of the chain may form a 3 to 6 membered ring.

The C ₁ -C ₅ -alkoxy groups of A and Q may be straight or branched, and are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert- Butoxy group or n-pentoxy group, 2,2-dimethylpropoxy group, 2-methylbutoxy group or 3-methylbutoxy group. A methoxy group or an ethoxy group is preferable.

The C ₁ -C ₅ -alkylthio group of A and Q may be linear or branched, and may be methylthio group, ethylthio group, n-propylthio group, iso-propylthio group, n-butylthio group, iso-butyl Thio group, tert- butylthio group, or n-pentylthio group, 2, 2- dimethyl propyl thio group, 2-methylbutyl thio group, or 3-methylbutyl thio group can be shown. Methylthio group or ethylthio group is preferable.

The term halogen atom or halogen denotes a fluorine, chlorine, bromine or iodine atom. Preference is given to fluorine, chlorine or bromine atoms.

NR ⁴ R ⁵ groups are, for example, NH ₂ , N (H) CH ₃ , N (CH ₃ ) ₂ , N (H) (CO) CH ₃ , N (CH ₃ ) (CO) CH ₃ , N [( CO) CH ₃ ] ₂ , N (H) CO ₂ CH ₃ , N (CH ₃ ) CO ₂ CH ₃ or N (CO ₂ CH ₃ ) ₂ .

As the alkyl groups R ⁴ and R ^5, C ₁ -C ₃ -alkyl is preferable.

As the acyl groups R ⁴ and R ^5, (CO) -C ₁ -C ₃ -alkyl is preferable.

As the B group, an unsubstituted methylene group and a carbonyl group are preferable.

The Q group may be linked to the (NH) -group of the chain via any ring-carbon atom. The 4-, 5- and 8-positions are preferred for the quinoline rings, and the 1-position is preferred for the isoquinoline rings.

The compounds of formula (I) according to the invention may exist in various stereoisomers because of the presence of asymmetric centers. Both racemates and individually present stereoisomers are some of the features of the present invention.

One feature of the invention is the stereoisomers present separately, ie (+)-enantiomers and (-)-enantiomers.

Another feature of the invention is that A is C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkoxy, C ₁ -C ₅ -alkylthio, C ₁ -C ₅ -perfluoroalkyl, halogen, hydroxy, Cyano, nitro or NR ⁴ R ^{5 in which} R ⁴ and R ⁵ may independently be hydrogen, C ₁ -C ₅ -alkyl or (CO) -C ₁ -C ₅ -alkyl And to aryl, benzyl or phenethyl groups which may be optionally substituted with one or more groups from.

Another feature of the invention is that A is -O- (CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -O-CH = CH- or-(CH ₂ ) _{n + 2} -Wherein n is 1 or 2, the terminal oxygen atom and / or the carbon atom is connected to the immediately adjacent ring-carbon atom.

R ³ is C ₄ -C ₈ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₇ -heterocyclyl, aryl, heteroaryl, (C ₁ -C ₈ -alkyl) C ₃ -C _8- The compound according to claim 1, which represents an optionally substituted group selected from cycloalkyl, (C ₁ -C ₈ -alkyl) aryl or (C ₁ -C ₈ -alkyl) heteroaryl, is another feature of the invention.

R ³ is C ₃ -C ₆ -cycloalkyl, C ₃ -C ₇ -heterocyclyl, phenyl, heteroaryl, (C ₁ -C ₃ -alkyl) C ₃ -C ₆ -cycloalkyl, (C ₁ -C _The compound according to claim 1, which represents an optionally substituted group selected from ₃ -alkyl) phenyl or (C ₁ -C ₃ -alkyl) heteroaryl, is another feature of the invention.

A represents an unsubstituted phenyl group, R ¹ and R ² represent a methyl group, R ³ represents a cyclopentyl group, a methylcyclohexyl group or a phenyl group, B represents a methylene group, and Q represents a quinoline group or an isoquinoline group Compounds of formula I are another feature of the invention.

A compound of formula (I) in which A represents an unsubstituted phenyl group, R ¹ and R ² represent a methyl group, R ³ represents a cyclopentyl group, a methylcyclohexyl group or a phenyl group, B represents a methylene group and Q represents a quinoline group Is another feature of the invention.

Further features of the present invention are the use of the compound according to claim 1 for the manufacture of a medicament, the use of the compound according to claim 1 for the preparation of a medicament for the treatment of an inflammatory disease, and at least one compound according to claim 1 or a mixture thereof and Pharmaceutical formulations containing a pharmaceutically compatible vehicle.

Compounds of formula I in which R ³ represents C ₃ -C ₈ -cycloalkyl, (C ₁ -C ₈ -alkyl) C ₃ -C ₈ -cycloalkyl, benzyl or phenyl are preferred features of the invention.

Compounds of formula (I) in which R ³ represents C ₃ -C ₈ -cycloalkyl, (C ₁ -C ₈ -alkyl) C ₃ -C ₈ -cycloalkyl or phenyl are particularly preferred features of the invention, Very particular preference is given to compounds of the formula (I) in which R ³ represents cyclopentyl, methylcyclohexyl or phenyl as described.

Processes for the preparation of the compounds of WO 98/54159 (51488), WO 00/32584 (51642) and WO 02/10143 (51877) can also be used for the preparation of the compounds according to the invention. The following process steps can be carried out for the connection of quinoline or isoquinoline groups which are characteristic of the compounds according to the invention.

A1)

When B = CO

Α-keto acids of formula (II), wherein A, R ¹ and R ² have the meanings described for formula (I), may be used in the manner known to those skilled in the art, such as aminoquinoline, aminoisoquinoline or (partially) hydrogenated quinoline or isoquinoline derivatives ( Q-NH ₂ ) is converted to α-ketoamide (Formula III), wherein A, R ¹ and R ² have the meanings described above. For example, by using a dehydration coupling reagent known in the art of peptide chemistry, for example dicyclohexylcarbodiimide, or for example using thionyl chloride or POCl ₃ , the acid is converted upstream to acid chloride and subsequently Α-ketoamide (Formula III) is obtained by reacting with Q-NH ₂ .

The compound of formula III is reacted with an alkyl metal compound, eg Grignard reagent, or lithium alkyl, or in the presence of a catalyst such as a fluoride salt or a base such as an alkali carbonate In response to [J. Am. Chem. Soc. 1989, 111, 393 to form the title compound (Formula I).

In the formula, R ³ has the meaning described above, and R ⁶ represents a C ₁ -C ₅ -alkyl group.

A2)

When B = CO

Alternatively, α-keto acid (Formula II) is also a commonly used method, for example esters with compounds of formula (V) by thionyl chloride, or methyl iodide and alkali carbonate in methanol or ethanol, for example It can be converted to a compound of formula VI, similar to the reaction sequence of A1) (from compound of formula III to compound of formula I).

Wherein A, R ¹ and R ² are defined as described above and R ⁷ is C ₁ -C ₄ -alkyl.

The ester is saponified with acid (Compound VI; R ⁷ = H) under standard conditions, for example an aqueous alkali hydroxide solution. The acid is optionally coupled with an aminoquinoline or aminoisoquinoline or (partially) hydrogenated quinoline or isoquinoline derivative (Q-NH ₂ ) by conventional activation reagents, for example thionyl chloride, in the presence of a catalyst such as dimethyl aminopyridine. Ring reaction forms the title compound (Formula I).

B)

The title compound (Formula I) can also be synthesized by reductive amination of the compound of formula (XII) with Q-NH ₂ (sodium cyanoborohydride or sodium triacetoxy borohydride are considered as reducing agents).

R ⁸ represents methyl or ethyl depending on the substituents defined for the methylene group in B.

When a compound of formula (I) is present as a salt, it is for example of hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate It may be in the form.

If the compounds according to the invention are present in racemic mixtures, they can be separated in pure optically active form according to racemic separation methods well known to those skilled in the art. For example, the racemic mixture can be separated into pure isomers by chromatography on a homogeneous optically active carrier material (CHIRALPAK AD®). It is also possible to esterify the free hydroxy groups present in the racemic compound of formula (I) with optically active acids, to separate the diastereomeric esters obtained by fractional crystallization or chromatography, and in each case to saponify the separated esters with pure optical isomers. Do. As the optically active acid, for example, mandelic acid, camphorsulfonic acid or tartaric acid can be used.

In addition, the process for the preparation of the compounds according to the invention, used in the experimental section below, is also part of the disclosure for the preparation of the claimed compounds.

The binding of the substances with the glucocorticoid receptor (GR) and other steroid hormone receptors (mineral corticoid receptor (MR), progesterone receptor (PR) and androgen receptor (AR)) is investigated using receptors made by recombinant techniques. Binding studies use cytoplasmic specimens of Sf9 cells infected with recombinant baculovirus encoding GR. The materials show a high or very high affinity for GR compared to the reference material [ ³ H] -dexamethasone.

In addition, the quinolines and isoquinolines of formula I described herein exhibit high selectivity for glucocorticoid receptors.

GR-mediated inhibition of the transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory factors is believed to be an essential molecular mechanism for the anti-inflammatory action of glucocorticoids. This inhibition is caused by the interaction of GR with other transcription factors, such as AP-1 and NF-kappa-B (for review see Cato, ACB and Wade, E., BioEssays 18, 371-378, 1996 ] Reference).

The compounds of formula (I) according to the invention inhibit cytokine IL-8 secretion into the human monocyte cell line THP-1, caused by lipopolysaccharide (LPS). The concentration of cytokines was measured with a commercial ELISA kit in the supernatant.

The anti-inflammatory action of compounds of formula (I) was tested in animal experiments by testing in croton oil-induced inflammation in rats and mice [J. Exp. Med. (1995), 182, 99-108. To this end, croton oil in ethanol solution was applied topically to the animal's ears. Test substances were also applied topically or systemically at the same time as croton oil or 2 hours prior to administration of croton oil. After 16 to 24 hours, ear weight was measured as a measure for inflammatory edema, peroxidase activity as a measure for infiltration of granulocytes, and elastase activity as a measure for infiltration of neutrophil granulocytes. In this test, the compounds of formula (I) inhibited the three inflammatory parameters mentioned above, both after topical and systemic application.

One of the most frequent undesirable actions in glucocorticoid therapy is the so-called "steroid diabetes" (Hatz, HJ, Glucocorticoide: Immunologische Grundlagen, Pharmakologie und Therapierichtlinien (Glucocorticoids: Immunological Bases, Pharmacology and Therapy Guidelines), Wissens Verlagsgesellschaft mbH, Stuttgart, 1998]. The cause of steroid diabetes is the stimulation of hepatic glucose synthesis by the induction of the enzymes responsible for it and by the free amino acids produced by proteolysis (catabolic catabolism of glucocorticoids). The key enzyme for hepatic catabolism is tyrosineamino transferase (TAT). The activity of this enzyme can be determined from liver homogenates by photometry and corresponds to an excellent measure of the metabolic action of undesirable glucocorticoids. To determine TAT induction, animals are sacrificed 8 hours after administration of the test substance, livers are removed, and TAT activity is measured in homogenates. In this test, the compounds of formula (I) induce little or no tyrosineamino transferase at doses that act as anti-inflammatory.

The compounds of the formula (I) according to the invention can be used as medicaments for the treatment or prophylaxis of the following pathologies in mammals and humans, due to their anti-inflammatory, and further anti-allergic, immunosuppressive and anti-proliferative effects. In this case, the term "disease" indicates the following symptoms.

(i) Lung diseases involving inflammation, allergies and / or proliferation processes:

-Chronic obstructive pulmonary disease of any origin, mainly bronchial asthma

-Bronchitis of various origins

-All types of restrictive lung disease, mainly allergic alveolitis

-All types of pulmonary edema, mainly addictive pulmonary edema

Sarcoidosis and granulomatosis, especially Boeck's disease

(ii) rheumatoid disease / autoimmune disease / joint disease involving inflammation, allergy and / or proliferation process:

-All types of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, rheumatic polymyalgia

-Reactive arthritis

-Inflammatory soft tissue diseases of different origin

-Arthritis symptoms in degenerative joint disease (arthrosis)

-Traumatic arthritis

Glioma of any origin, for example systemic lupus erythematosus, scleroderma, polymyositis, dermatitis, Sjoegren's syndrome, Still's syndrome, Felty's syndrome

(iii) allergies involving inflammatory and / or proliferative processes:

-All types of allergic reactions, for example Quincke's edema, high fever, insect bites, drugs, blood derivatives, allergic reactions to contrast agents, anaphylactic shock, urticaria, contact dermatitis

(iv) vascular inflammation (vasculitis):

Nodular penetritis, temporal arteritis, nodular erythema

(v) skin diseases involving inflammation, allergy and / or proliferation processes:

Atopic dermatitis (mostly pediatric atopic dermatitis)

-Psoriasis

-Pore red nasal cavity

-Erythematous disease caused by various poisonings, eg radiation, chemicals, burns, etc.

-Bullous skin disease

-Thyroid disease

-Pruritus (for example, pruritus of allergic origin)

Seborrheic Eczema

-Rosacea

Imagery Sky Window

-Polymorphic erythema

-Gallitis

-Vulvitis

Hair loss, such as alopecia areata

Cutaneous T-cell lymphoma

(vi) kidney disease involving inflammation, allergy and / or proliferation processes:

Kidney Syndrome

-All nephritis

(vii) liver disease involving an inflammation, allergy and / or proliferation process:

Acute liver cell breakdown

Acute hepatitis of multiple origins (eg viruses, toxic substances, drug-induced)

Chronic aggressive hepatitis and / or chronic intermittent hepatitis

(viii) gastrointestinal diseases involving inflammation, allergies and / or proliferative processes:

-Topical enteritis (Crohn's disease)

-Ulcerative colitis

- gastritis

Reflux esophagitis

-Ulcerative colitis of different origins, for example congenital sprue

(ix) rectal diseases involving inflammation, allergy and / or proliferation processes:

-Anal eczema

-Window

Hemorrhoids

Idiopathic proctitis

(x) eye diseases that involve inflammation, allergy and / or proliferation processes:

-Allergic keratitis, uveitis, rash

-Conjunctivitis

Blepharitis

Optic neuritis

Choroiditis

-Sympathetic ophthalmitis

(xi) Otolaryngological site disease involving inflammation, allergies and / or proliferation processes:

-Allergic rhinitis, fever

-Otitis externa caused by contact dermatitis, infection, etc.

Otitis media

(xii) nervous system diseases involving inflammation, allergy and / or proliferation processes:

Brain edema, mainly tumor-induced brain edema

Multiple sclerosis

Acute encephalomyelitis

-Meningitis

-Various spasms, eg infantile spasms

(xiii) blood diseases involving inflammation, allergy and / or proliferation processes:

Acquired hemolytic anemia

Idiopathic hypoplatelets

(xiv) tumor diseases involving inflammation, allergies and / or proliferation processes:

Acute lymphocytic leukemia

Malignant lymphoma

Lymphoblastoma

Lympharcoma

-Widespread metastasis mainly in breast cancer, bronchial cancer and prostate cancer

(xv) endocrine diseases involving inflammation, allergies and / or proliferative processes:

Endocrine eye disease

-Thyroid Poisoning

De Quervain's thyroiditis

Hashimoto's thyroiditis

Base's disease

(xvi) organ and tissue transplantation, graft-versus-host disease

(xvii) severe shock conditions, such as anaphylactic shock, systemic inflammatory response syndrome (SIRS)

(xviii) Alternative Therapy in

Congenital primary adrenal insufficiency, eg congenital adrenal syndrome

Acquired primary adrenal insufficiency, for example Addison's disease, autoimmune adrenalitis, post-infectious tumor, metastasis, etc.

Congenital secondary adrenal insufficiency, such as congenital pituitary hypoplasia

Acquired secondary adrenal insufficiency, for example post-infectious tumors, etc.

(xix) vomiting involving inflammation, allergies and / or proliferation processes:

Vomiting caused by, for example, cytostatic agents when combined with 5-HT3 antagonists

(xx) Pain in inflammatory origin, eg low back pain.

In addition, the compounds of formula (I) according to the invention can be used for the treatment and prophylaxis of additional pathologies not mentioned above (synthetic glucocorticoids are currently used for the treatment and prophylaxis thereof). Hatz, HJ, Glucocorticoide: Immunologische Grundlagen, Pharmakologie und Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998).

The aforementioned symptoms (i) to (xx) are described in more detail in Hatz, H. J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie und Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998.

Suitable dosages for the therapeutic action in the above mentioned pathological conditions depend, for example, on the active concentration of the compound of formula (I), the host, the type of administration, the type and severity of the condition to be treated and the use as a prophylactic or therapeutic agent.

In addition, the present invention

(i) use of one or a mixture of compounds of formula (I) according to the invention for the manufacture of a medicament for the treatment of a disease;

(ii) a method of treating a disease comprising administering a compound according to the invention to a patient in need thereof in an amount that inhibits the disease; And

(iii) a pharmaceutical composition for the treatment of a disease comprising one or a mixture of compounds according to the invention and at least one pharmaceutical adjuvant and / or vehicle

To provide.

In general, satisfactory results can be expected in animals when the daily dosage comprises the compound according to the invention in the range of 1 to 100,000 μg per kg body weight. For larger mammals, such as humans, the recommended daily dosage ranges from 1 to 100,000 μg of the compound according to the invention per kg of body weight. A dose of 10 to 30,000 μg per kg of body weight is preferred, and a dose of 10 to 10,000 μg per kg of body weight is more preferred. For example, the dosage is suitably administered several times a day. For the treatment of acute shock (eg, anaphylactic shock), individual doses can be administered which significantly exceed those mentioned above.

Formulations of pharmaceutical formulations based on these novel compounds, in a manner known in the art, include the active ingredients commonly used in herbal medicines for vehicles, fillers, degradation inducing substances, binders, humectants, lubricants, absorbents, diluents, complexes By conversion to a desired dosage form by treatment with a flavoring agent, colorant or the like. In this case, see Remington's Pharmaceutical Science, 15th Edition, Mack Publishing Company, East Pennsylvania (1980).

Tablets, coated tablets, capsules, pills, powders, granules, papers, suspensions, emulsions or solutions are particularly suitable for oral administration.

Parenteral administration includes injections and infusions.

Correspondingly prepared crystal suspending agents can be used for intra-articular injection.

Intramuscular injections may be used with aqueous and oily injections or suspensions and the corresponding depot preparations.

Rectal administration can use the novel compounds in the form of suppositories, capsules, solutions (eg, in the form of enema), and ointments for both systemic and topical treatment.

Intrapulmonary administration may use novel compounds in the form of aerosols and inhalants.

For topical administration to the eye, ear canal, middle ear, nasal and sinus, novel compounds can be used in the corresponding pharmaceutical formulations as eye drops, ointments and tinctures.

Topical administration is possible in the form of gels, ointments, fatty ointments, creams, pastes, powders, emulsions and tinctures. To achieve sufficient pharmacological action, the dosage of the compound of formula I should be 0.01 to 20% of these formulations.

The present invention furthermore comprises the compounds of formula (I) according to the invention as therapeutically active ingredients. The compounds of formula (I) according to the invention also form part of the invention together with pharmaceutically compatible and acceptable auxiliaries and vehicles as therapeutically active ingredients.

The present invention also encompasses pharmaceutical compositions containing one or a mixture of pharmaceutically active compounds according to the invention, or pharmaceutically compatible salts thereof, and pharmaceutically compatible adjuvants and vehicles.

The following examples are intended to illustrate the invention in more detail, but are not intended to limit the invention thereto. The synthesis of important precursors not disclosed within the scope of the experiment already exists as prior art and can be derived, for example, from WO 98/54159 and WO 02/10143.

Experiment

Example 1

1- (quinolin-5-ylamino) -2-cyclopentyl-4-methyl-4-phenylpentan-2-ol

4-Methyl-4-phenyl-2-oxopentano-ethyl ester

10.0 g of 2-phenyl-2-propanol and 2- (trimethylsilyloxy) acrylic acid-ethyl ester [Bull. Chem. Soc. Jpn. 1992, 65, 3209] 30.4 g were introduced into 386 ml of CH ₂ Cl ₂ and treated with 11.5 ml of tin tetrachloride at -70 ° C. After 15 minutes at −70 ° C., the batch was introduced into a semiconcentrated potassium carbonate solution, extracted with CH ₂ Cl ₂ , dried (Na ₂ SO ₄ ) and concentrated by evaporation in vacuo. Column chromatography on silica gel with ethyl acetate-cyclohexane gave 4.64 g of the product as a colorless oil.

2-Cyclopentyl-2-hydroxy-4-methyl-4-phenylpentanoic acid-ethyl ester

2.13 ml of 2 M etheric cyclopentyl magnesium chloride solution was added dropwise to a solution of 1.0 g of 4-methyl-4-phenyl-2-oxopentano-ethyl ester in 20 ml of THF at −70 ° C. After 3 h at −70 ° C., the batch was poured into cold NH ₄ Cl saturated solution and extracted with ethyl acetate. The extract was dried (Na ₂ SO ₄ ) and concentrated by evaporation. Column chromatography on silica gel with ethyl acetate-cyclohexane gave 320 mg of product.

2-cyclopentyl-4-methyl-4-phenyl-1,2-pentanediol

320 mg of 2-cyclopentyl-2-hydroxy-4-methyl-4-phenylpentanoic acid-ethyl ester were converted to 185 mg of product by 92 mg of lithium aluminum hydride.

2-cyclopentyl-2-hydroxy-4-methyl-4-phenylpentanal

185 mg of 2-cyclopentyl-4-methyl-4-phenyl-1,2-pentanediol were converted to 160 mg of aldehyde by 438 mg of pyridine-sulfur trioxide complex, 2.5 ml of DMSO and 0.5 ml of triethylamine.

1- (quinolin-5-ylamino) -2-cyclopentyl-4-methyl-4-phenylpentan-2-ol

160 mg 2-cyclopentyl-2-hydroxy-4-methyl-4-phenylpentanal, 106 mg 5-aminoquinoline and 405 mg sodium triacetoxy borohydride in 6.3 ml of acetic acid were converted to imine.

70 mg of imine obtained by column chromatography with ethyl acetate-cyclohexane on silica gel was reduced by 21 mg sodium borohydride in THF (2 ml) and methanol (0.5 ml). Column chromatography gave 30 mg of the product.

Example 2

1- (quinolin-5-ylamino) -2-cyclohexylmethyl-4-methyl-4-phenylpentan-2-ol

2-Cyclohexylmethyl-2-hydroxy-4-methyl-4-phenylpentanoic acid-ethyl ester

Similar to Example 1, 1.0 g of 4-methyl-4-phenyl-2-oxopentano-ethyl ester was converted to 290 mg of product by Grignard reagent prepared from 1 ml of cyclohexylmethyl bromide and 174 mg of magnesium I was.

2-cyclohexylmethyl-4-methyl-4-phenyl-1,2-pentanediol

Similar to Example 1, 290 mg of 2-cyclohexylmethyl-2-hydroxy-4-methyl-4-phenylpentanoic acid-ethyl ester were converted to 160 mg of product by 76 mg of lithium aluminum hydride.

1- (quinolin-5-ylamino) -2-cyclohexylmethyl-4-methyl-4-phenylpentan-2-ol

Similar to Example 1, 160 mg of 2-cyclohexylmethyl-4-methyl-4-phenyl-1,2-pentanediol was reacted with 342 mg of pyridine-sulfur trioxide complex, 1.95 ml of DMSO and 0.39 ml of triethylamine to give 2 -Cyclohexylmethyl-2-hydroxy-4-methyl-4-phenylpentanal ('H-NMR (CDCl ₃ ); δ = 0.90-1.60 (m, 10H), 1.30 (s, 3H), 1.41 (s , 3H), 1.76 (m, 2H), 1.95 (m, 1H), 2.20 (d, 1H), 2.35 (d, 1H), 2.97 (s, 1H), 7.20 (m, 1H), 7.30 (m, 4H), 8.76 (s, 1H)). The crude product was reacted with 137 mg of 5-aminoquinoline and 524 mg of sodium triacetoxy borohydride to imine (180 mg; 'H-NMR (CDCl ₃ ); δ = 0.90-1.90 (m, 18H), 2.25 (m , 1H), 2.80 (d, 1H), 3.00 (d, 1H), 3.76 (t, 1H), 5.06 (d, 1H), 6.25 (d, 1H), 7.10-7.55 (m, 8H), 8.25 ( d, 1H), 8.87 (dd, 1H); MS (ESI), 415). Reductive amination with 49 mg sodium borohydride and column chromatography gave 130 mg of the final product.

Example 3

1- (quinolin-5-ylamino) -2,4-diphenyl-4-methylpentan-2-ol

2,4-diphenyl-2-hydroxy-4-methylpentanoic acid-ethyl ester

Similar to Example 1, 1.0 g of 4-methyl-4-phenyl-2-oxopentano-ethyl ester was converted to 980 mg of product by 2.14 ml of a 2 M phenylmagnesium chloride-THF solution.

2,4-diphenyl-4-methyl-1,2-pentanediol

Similar to Example 1, 980 mg of diphenyl-2-hydroxy-4-methylpentanoic acid-ethyl ester was converted to 450 mg of product by 289 mg of lithium aluminum hydride.

2,4-diphenyl-2-hydroxy-4-methylpentanal

Similar to Example 1, 445 mg of 2,4-diphenyl-4-methyl-1,2-pentanediol was added to 1.02 g of pyridine-sulfur trioxide complex, 5.85 ml of DMSO, and 1.16 ml of triethylamine to 390 mg Switched to

1- (quinolin-5-ylamino) -2,4-diphenyl-4-methylpentan-2-ol

Similar to Example 1, imine ('H-NMR (CDCl ₃ ); δ = 1.37 (d) from 190 mg of 2,4-diphenyl-2-hydroxy-4-methylpentanal and 122 mg of 5-aminoquinoline; , 3H), 1.42 (s, 3H), 2.70 (d, 1H), 2.94 (d, 1H), 4.67 (s, 1H), 6.14 (d, 1H), 6.22 (br., 1H), 7.12-7.40 (m, 13H), 8.34 (d, 1H), 8.85 (dd, 1H)) gave 40 mg of product.

Claims (8)

A compound of formula (I), a racemate thereof or a stereoisomer present individually, or a physiologically compatible salt thereof. <Formula I>

In the formula, A is C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkoxy, C ₁ -C ₅ -alkylthio, C ₁ -C ₅ -perfluoroalkyl, halogen, hydroxy, cyano, nitro, -O -(CH ₂ ) _n -O-, -O- (CH ₂ ) _n -CH _2- , -O-CH = CH-,-(CH ₂ ) _{n + 2-} (where n is 1 or 2) , The terminal oxygen atom and / or carbon atom are connected to the immediately adjacent ring-carbon atom, or NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are independently of each other hydrogen, C ₁ -C ₅ -alkyl or (CO Aryl group, benzyl group or phenethyl group, which may be optionally substituted with one or more groups from the group of (C-C ₁ -C ₅ -alkyl), R ¹ and R ² independently of one another represent a hydrogen atom, a methyl group or an ethyl group, or together with a carbon atom represent a chain of a C ₃ -C ₆ -cycloalkyl ring, R ³ is C ₄ -C ₈ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₇ -heterocyclyl, aryl, Optionally substituted group selected from heteroaryl, (C ₁ -C ₈ -alkyl) C ₃ -C ₈ -cycloalkyl, (C ₁ -C ₈ -alkyl) aryl or (C ₁ -C ₈ -alkyl) heteroaryl Indicate, B represents a methylene group or a carbonyl group optionally substituted with a methyl group or an ethyl group, Q is C ₁ -C ₅ -alkyl, C ₁ -C ₅ -alkoxy, C ₁ -C ₅ -alkylthio, C ₁ -C ₅ -perfluoroalkyl, halogen, hydroxy, cyano, nitro or NR ⁴ It may be optionally substituted with one or more groups from the group of R ⁵ and represents a quinolinyl group or isoquinolinyl group connected through any position. The compound of claim 1, wherein A represents an aryl group. 3. The compound of claim 1, wherein A is —O— (CH ₂ ) _n —O—, —O— (CH ₂ ) _n —CH ₂ —, —O—CH═CH— or — (CH ₂ ) _{n + 2} -wherein n is 1 or 2 and the terminal oxygen atom and / or carbon atom is connected to the immediately adjacent ring-carbon atom. ^3. The compound of claim 1, wherein R ³ is C ₄ -C ₈ -alkyl, C ₃ -C ₈ -cycloalkyl, C ₃ -C ₇ -heterocyclyl, aryl, heteroaryl, (C ₁ -C ₈ -alkyl) C ₃ -C ₈ -cycloalkyl, (C ₁ -C ₈ -alkyl) aryl or (C ₁ -C ₈ -alkyl) heteroaryl. The compound of claim 1 or 2, wherein R ³ is C ₃ -C ₆ -cycloalkyl, C ₃ -C ₇ -heterocyclyl, phenyl, heteroaryl, (C ₁ -C ₃ -alkyl) C ₃ -C _To an optionally substituted group selected from ₆ -cycloalkyl, (C ₁ -C ₃ -alkyl) phenyl or (C ₁ -C ₃ -alkyl) heteroaryl. Use of a compound according to claim 1 for the manufacture of a medicament. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of an inflammatory disease. A pharmaceutical formulation containing at least one compound according to claim 1, or a mixture thereof, and a pharmaceutically compatible vehicle.