JPH09500646A - Treatment of HIV with azaspiran - Google Patents

Abstract

  (57) [Summary] The present invention relates to a method of inhibiting cell entry of HIV in a human immunodeficiency virus (HIV) seropositive person, which method comprises administering to such a person an effective amount of a substituted azaspiran.

Description

Detailed Description of the Invention                     Treatment of HIV with azaspiran   The present invention relates to HIV in humans in the human immunodeficiency virus (HIV) seropositive phase. A method of inhibiting cell invasion, wherein an effective amount of a substituted azaspirane is administered to such a human Regarding the method consisting of things.                                Background of the Invention   Numerous agents that inhibit human immunodeficiency virus replication in T cells and monocytes Is currently available (Yarchoan et al., Lancet ( Lancet (1986); 1: 575-580 and Broder et al., Ran. Set (1985); 3: 627-630). These compounds have significant toxicity and And viral resistance associated with long-term use limits its usefulness (Volver Volberding et al., New England Journal of Medici N. Engl J. Med. 1990; 322: 941-949). In addition, some Proven that selected immunosuppressive / immunomodulatory agents have the ability to suppress viral replication I have. Specifically, immunomodulation of CD8 lymphocytes is associated with HI in peripheral blood mononuclear cells. It has been shown to suppress V replication (Walker et al., Saie. (Science, 234: 1563-6 (1986)), activated CD8 + T cells HI in cultures of CD4 + cells whose cells are from asymptomatic HIV seropositive individuals It has been shown to inhibit V replication (Brinchmann et al., CD8 + T Cell, Journal of Immunology (J.Immunol.) 144, 2961-2 966 (1990)). Furthermore, the immunosuppressive compound cyclosporin A ( CsA) showed a protective effect in animal models of several viral infections. Especially , Long-term treatment with CsA before and after infection with LP-BM5 murine leukemia virus Therapies have been shown to be effective against the development of immunodeficiency diseases (Selney A. (Cerny, A.) et al., European Journal of Immunology (Eur.J. Immunol.), 21: 1747-50 (1991)). AIDS using CsA And treatment of non-AIDS patients in the HIV-seropositive stage expands T4 cells, lymph nodes Evidence of inhibiting disability has also been reported (Andrieu et al. , Clinical Immunology and Immunopathology (Clin.Immunol.and I mmunopathol.) 46: 181-198 (1988)). However, the documents mentioned above In both cases, common immunosuppressive / immunomodulatory agents are used in humans in the HIV seropositive stage. It does not suggest to block HIV cell entry. Furthermore, any of the above documents Again, certain immunosuppressive / immunomodulatory agents have been shown to affect HIV in humans in the HIV seropositive phase. It does not teach or suggest a predictive means of inhibiting cell entry.   Badger et al., U.S. Pat. No. 4,963,557 (Badger I) ,formula: [In the formula, n is 3-7; m is 1 or 2; R¹And R²Are the same or different, Hydrogen or linear or branched alkyl (provided that R¹And R²Carbon contained in The total number of atoms is 5-10 in total); or R¹And R² Together form a cyclic alkyl group having 3 to 7 carbon atoms; R^ThreeAnd R^FourAre the same Or, differently, selected from hydrogen or straight-chain alkyl of 1 to 3 carbon atoms, or Or R^ThreeAnd R^FourForms a heterocyclic group having 5-8 atoms with the nitrogen atom ] Or a pharmaceutically acceptable salt or hydrate or solvate thereof Is disclosed.   Badger I is characterized by a compound of Formula I by stimulating suppressor cell activity. It is disclosed to be a series of novel compounds that induce toxic immunomodulatory action.   Badger I may be a compound of Formula I or HIV in a HIV seropositive person. It does not disclose that it is a drug that inhibits cell entry.                                Summary of the Invention   The present invention relates to a method of inhibiting HIV cell entry in humans in the HIV seropositive stage. , Such an effective amount formula for humans: [Where,   n is 3-7;   m is 1 or 2;   R¹And R²Are the same or different and are hydrogen or a straight or branched chain alkyl. Le (however, R¹And R²The total number of carbon atoms contained in is 5-10) Selected from; or R¹And R²Together form a cyclic alkane with 3 to 7 carbon atoms Forms a kill group;   R^ThreeAnd R^FourAre the same or different and are hydrogen or a linear alkyl group having 1 to 3 carbon atoms. Selected from R or R^ThreeAnd R^FourIs 5 together with the nitrogen atom 8 heterocyclic groups are formed] Or a pharmaceutically acceptable salt or hydrate or solvate thereof And administering to the subject.                             Detailed description of the invention   All compounds of formula (I) and their pharmaceutically acceptable salts, hydrates and solvents Preparation of Japanese products and their formulations are disclosed in US Pat. No. 4,963,557. , The entire contents of which are incorporated herein by reference.   Preferred compounds used in the novel method are compounds of formula (I) (R¹And R² Is propyl and R^ThreeAnd R^FourIs methyl, m is 1 and n is 3) Dihydrochloride, i.e. N, N-dimethyl-8,8-dipropyl-2-azaspiro [4.5] Decane-2-propanamine dihydrochloride.   Particularly preferred compounds for use in the novel process are compounds of formula (I) (R¹And And R²Is propyl and R^ThreeAnd R^FourIs ethyl, m is 1 and n is 3 Dihydrochloride, i.e., N, N-diethyl-8,8-dipropyl-2-azas Pyro [4.5] decane-2-propanamine dihydrochloride.   Particularly preferred compounds for use in the novel process are compounds of formula (I) (R¹And And R²Is propyl and R^ThreeAnd R^FourTogether with the nitrogen form a piperidine ring And m is 1 and n is 3), i.e., 8,8-dipropyl- 2-azaspiro [4.5] decane-2-piperidinopropyl dihydrochloride.   INDUSTRIAL APPLICABILITY The present invention is useful for inhibiting HIV cell entry in humans in the HIV seropositive stage. Compounds of formula (I) and their pharmaceutically acceptable salts or hydrates or solvents for use Disclose Japanese products.   A compound of formula I was prepared by the method of Sperber et al., AIDS Research and Institute. Human. Retroviruses (AIDS Research and Human Retroviruses), 9 No. 1, 91-98 for the ability of HIV to inhibit cell entry. To test.   The present invention provides a method for inhibiting HIV cell entry, which is useful for humans in the HIV seropositive stage. An effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or hydrate or solution thereof. Relates to a method consisting of administering a medium. Compounds of formula (I) or medicaments thereof The above acceptable salts or hydrates or solvates are compounds of formula (I) or Pharmaceutically acceptable salts or hydrates or solvates can be prepared by known techniques, for example by Jer (I), US Pat. Usual administration prepared by combining with a pharmaceutically acceptable carrier or diluent The form can be administered to such a human.   The morphology and properties of the pharmaceutically acceptable carrier or diluent combine it Those skilled in the art will appreciate that the active ingredient loading, route of administration and other well known variables will determine. You can understand. A compound of formula (I) or a pharmaceutically acceptable salt thereof Or a hydrate or solvate in an amount sufficient to inhibit HIV cell entry. To humans in the HIV seropositive stage.   The route of administration of the compound of formula (I) (“active ingredient”) is not critical, but usually It is oral or parenteral, preferably oral.   The term parenteral as used herein is intravenous, intramuscular, subcutaneous, intranasal, rectal. It includes internal, transdermal, vaginal or intraperitoneal administration. Subcutaneous and intramuscular morphology Oral administration is generally preferred. The daily parenteral dose is preferably 1 kg of the total body weight. Or about 0.01 mg to about 10 mg, most preferably about 0.1 mg / kg to It is about 1 mg / kg. Preferably, the parenteral dosage unit is about 0.1 mg each. To contain about 100 mg of the active ingredient.   Compounds of formula (I) that are active when given orally are liquids such as syrups, Formulating as suspensions or emulsions, tablets, capsules and lozenges Can be.   Liquid formulations generally include a suspending agent, a preservative of the compound or a pharmaceutically acceptable salt. A suitable liquid carrier, such as ethanol, containing a preservative, a flavor or a coloring agent, Glycerin, non-aqueous solvents (eg polyethylene glycol), oils or solutions in water Or suspension.   The composition in tablet form may be any suitable pharmaceutical carrier conventionally used to prepare solid formulations. It can be prepared using the body. Examples of such carriers are magnesium stearate, starch Includes flour, lactose, sucrose and cellulose.   Capsule-shaped compositions can be prepared using conventional encapsulation procedures. For example, active ingredient-containing pellets can be prepared using standard carriers, Fill hard gelatin capsules with; Alternatively, either dispersion or suspension With a suitable pharmaceutical carrier such as an aqueous gum, cellulose, silicates or oils. Can be prepared and then filled with the dispersion or suspension into soft gelatin capsules I do.   The daily oral dose is preferably about 0.01 mg / kg of total body weight or more. It is about 10 mg. Preferably, each oral dosage unit contains about 0.1 mg of active ingredient. To 100 mg.   While it is possible for the active ingredient to be administered alone, it should be administered as a pharmaceutical formulation. Is preferred.   A compound of formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof The optimal amount and interval between individual doses of the product will depend on the nature and extent of the condition being treated, the dose Morphology, route and site, and the individual patient being treated, One skilled in the art will understand that such optimal conditions can be determined by conventional techniques. U. Furthermore, the optimal course of treatment, ie the formula (I) administration per day Frequency of administration of the compound or its pharmaceutically acceptable salt or hydrate or solvate And treatment duration can be ascertained by one skilled in the art using routine treatment course determination tests. U.   The method of the present invention for inhibiting HIV cell entry in humans in the HIV seropositive phase is , An effective amount of HIV cell invasion inhibition of a subject of the invention in a subject in need of such inhibition. It consists of administering a pharmaceutically active compound.   The present invention also inhibits HIV cell entry in humans in the HIV seropositive phase. To provide the use of a compound of formula (I) in the manufacture of a medicament for use in is there.   The present invention also inhibits HIV cell entry in humans in the HIV seropositive phase. A pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier for use in I will provide a.   The present invention also includes a pharmaceutically acceptable carrier or diluent and a compound of formula I A process for the preparation of a pharmaceutical composition comprising a compound of formula I Providing a method consisting of combining with a body.   No unacceptable toxicological effects when compounds of the invention are administered in accordance with the invention. Unthinkable.   In addition, the compounds of the present invention may be further active ingredients such as retrovir. ) (Formerly called azidothymidine (AZT) Prevent the onset of AIDS in humans in the HIV seropositive stage, such as Can be administered with compounds known to delay.   A person skilled in the art can carry out the present invention according to the above-mentioned operation without further improvement. Is considered to be available to its full extent. Therefore, the following example It should be understood that this is merely an example and does not limit the scope of the present invention. You.                         Example 1-Capsule composition   Oral dosage forms for administering the compounds of formula (I) may be prepared in the proportions shown in Table I below. Produced by filling the ingredients into standard 2-piece hard gelatin capsules.                    Example 2-Injectable parenteral composition   An injectable form for administration of a compound of formula (I) is provided with 1.5% by weight of N, N-di Ethyl-8,8-dipropyl-2-azaspiro [4,5] decane-2-propane By stirring the amine dihydrochloride in 10% by volume propylene glycol in water. Manufacturing.                           Example 3-Tablet composition   Sucrose, calcium sulphate dihydrate and of formula (I) shown in Table II below The compounds are mixed and granulated with 10% gelatin solution in the proportions shown below. Screen wet granules, dry and mix with starch, talc and stearic acid Then, attach to the screen and tablet.   The above description and examples fully describe the invention and its preferred embodiments. However, the present invention is not limited to the individual embodiments disclosed within the scope of the claims below. Absent.

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, M C, NL, PT, SE), OA (BF, BJ, CF, CG , CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AU, BB, BG, BR, BY, CA, CN, CZ, FI, HU, JP, KP, KR, KZ, L K, MG, MN, MW, NO, NZ, PL, RO, RU , SD, SL, SK, UA, US, VN

Claims (1)

[Claims] 1. In the manufacture of a medicament for inhibiting the production of infectious HIV in a human immunodeficiency virus (HIV) seropositive person, the formula: [Wherein n is 3-7; m is 1 or 2; R ¹ and R ² are the same or different and each is hydrogen or a straight chain or branched chain alkyl (provided that the carbon atom contained in R ¹ and R ² is Is 5-10) in total; or R ¹ and R ² together form a cyclic alkyl group having 3 to 7 carbon atoms; R ³ and R ⁴ are the same or Differently, selected from hydrogen or straight-chain alkyl having 1 to 3 carbon atoms, or R ³ and R ⁴ together with the nitrogen atom form a heterocyclic group having 5 to 8 atoms]. Use of a compound or a pharmaceutically acceptable salt or hydrate or solvate thereof. 2. The compound is N, N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine; or a pharmaceutically acceptable salt, hydrate or solvate thereof. Use as stated. 3. Use according to claim 1, wherein the compound is administered orally. 4. The use according to claim 3, wherein about 0.01 mg / kg to about 10 mg / kg of the compound is administered daily. 5. Use according to claim 1, wherein the compound is administered parenterally. 6. The use according to claim 5, wherein about 0.01 mg / kg to about 10 mg / kg of the compound is administered per day.